key: cord-0945696-wds4jw1a
authors: He, Yu-Qiong; Zhou, Can-Can; Yu, Lu-Yao; Wang, Liang; Deng, Jiu-ling; Tao, Yu-Long; Zhang, Feng; Chen, Wan-Sheng
title: Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms
date: 2020-09-29
journal: Pharmacol Res
DOI: 10.1016/j.phrs.2020.105224
sha: 289f4bcdb2ae3c6ff54ea372774987c3c961320d
doc_id: 945696
cord_uid: wds4jw1a

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) as common life-threatening lung diseases with high mortality rates are mostly associated with acute and severe inflammation in lungs. With increasing in-depth studies of ALI/ARDS, significant breakthroughs have been made, however, there are still no effective pharmacological therapies for treatment of ALI/ARDS. Especially, the novel coronavirus pneumonia (COVID-19) is ravaging the globe, and causes severe respiratory distress syndrome. Therefore, developing new drugs for therapy of ALI/ARDS is in great demand, which might also be helpful for treatment of COVID-19. Natural compounds have always inspired drug development, and numerous natural products have shown potential therapeutic effects on ALI/ARDS. Therefore, this review focuses on the potential therapeutic effects of natural compounds on ALI and the underlying mechanisms. Overall, the review discusses 159 compounds and summarizes more than 400 references to present the protective effects of natural compounds against ALI and the underlying mechanism.

Acute lung injury (ALI) and its more serious form, acute respiratory distress syndrome (ARDS), as respiratory diseases with high mortality rates, are manifested by acute hypoxemic respiratory failure, increased alveolar permeability and severe alveolar edema with normal cardiac filling pressures [1] . Despite advances in treatment methods, the morbidity and mortality of ALI and ARDS remains high. In the United States, for ALI and ARDS, the incidence for patients >15 years is 78.9 and 58.7 cases per 100,000 individuals per year and J o u r n a l P r e -p r o o f overall mortality rate is still a significant 38.5% and 41.1%, respectively [2] . A study in intensive care units (ICUs) in Shanghai reported that the incidence of ARDS for patients >15 years is 2%, with a mortality rate of 70% [3] . A retrospective cohort study performed by researchers at the University of Washington reported that morbidity and mortality among 146 ,058 patients <18 years in ICUs during 2007-2016 were 1.8% and 20%, respectively [4] . A study in Thailand found that mortality and morbidity of the 1,738 patients <15 years in pediatric ICUs (PICUs) for 2013-2016 were as high as 7.4% and 51.2%, respectively [5] . Additionally, an international observational study performed in total 145 PICUs from 27 countries for 2016-activated to produce pro-inflammatory factors such as TNF-α, IL-1, IL-9 and IL-8, inflammatory mediators such as elastin, cathepsins, collagenases and gelatinases, cytokines, chemokines and other inflammatory transmitters, which conversely cause damage to the cells above and to alveolar epithelial cells. Then, the alveolar endothelial cells are damaged, resulting in the increased permeability of microvascular barriers, which is associated with the extravascular accumulation of protein-rich edema fluid as well as the transfer of leukocytes, erythrocytes and inflammasome-regulated cytokines into the alveolar space [22] [23] [24] . During the inflammatory process of ALI/ARDS, several signal transduction pathways such as nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK), nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3), toll like receptors (TLRs), adrenergic receptors and JAK/STAT signaling pathways are involved [25] [26] [27] . Inhibition of NF-κB expression can inhibit the expression of inflammatory cytokines in the lungs, significantly reduce the inflammatory response in the lungs and improve the survival rate of lipopolysaccharide (LPS)-induced ALI mice [28] . In addition, the ablation of proteins such as NAMPT, Rip2 and Pfkfb3, which could activate the NF-κB signaling pathway, were found to prevent lung injury and inflammatory response in ischemia-reperfusion (I/R), LPS or cigarette smoke-induced ALI mice [29] [30] [31] [32] . The MAPK (JNK, ERK and p38) is an important signaling pathway regulating inflammatory responses. The activation of MAPK can promote In LPS-challenged alveolar epithelial cells, autophagy activation or AMPK stimulation remarkably ameliorate LPS-induced airway inflammation [46] . In addition, inhibition of autophagy by chloroquine treatment significantly improves the permeability of human pulmonary microvascular endothelial cells (HPMECs) stimulated by LPS as well as attenuating LPS-lung injury in mice [47] . Therefore, the effects of autophagy in ALI/ARDS depends on cell type. Similarly, the effects of apoptosis in ALI/ARDS also depend on condition. In ALI/ARDS patients, the apoptosis and autophagy of PMNs are decreased, which can be confirmed by fewer apoptotic PMNs in bronchoalveolar lavage fluid (BALF). This phenomenon is partly induced by anti-apoptotic factors, like granulocyte-macrophage colonystimulating factor, which can promote PMN survival through decreasing apoptosis of PMN, resulting in accumulation at the inflammation site [48, 49] . However, in ALI/ARDS patients, the apoptosis of alveolar epithelial cells, alveolar macrophages and VEC is enhanced, leading to disturbed microvascular integrity, increased microvascular permeability and release of proinflammatory cytokines [50] . Therefore, apoptosis and autophagy also play important roles in ALI/ARDS development.

Hypoxemia and pulmonary bilateral infiltrate are the clinical characteristic of ALI/ARDS, therefore, it is important to effectively clear the edema fluid in the alveoli to guarantee effective gas exchange for patients with ALI/ARDS to survive. Therefore, alveolar fluid clearance (AFC)

is an important factor for the treatment of ALI/ARDS, and those patients with maximal AFC have lower mortality [51] . During the AFC process, the alveolar epithelium plays a primary role with epithelial sodium channels (ENaCs), Na + /K + -ATPase, aquaporin (AQP), cystic fibrosis transmembrane regulator (CFTR), K + channels and other channels also actively J o u r n a l P r e -p r o o f embolism, paraquat, cigarette smoke or pancreatitis [77] [78] [79] [80] [81] [82] [83] [84] [85] . Baicalin could alleviate pulmonary inflammation through down-regulating expression of pro-inflammatory cytokines TNF-a, IL-1β, IL-6, IL-8, IL-18, IL-23 and MMP9 [77] . Additionally, baicalin suppressed lung oxidative injury through decreasing MDA as well as retaining SOD and CAT [81] . In terms of mechanism, the NLRP3 inflammasome and TLRs/NF-κB signaling pathways were down-regulated by baicalin but the Nrf2-HO-1 signaling pathway was up-regulated [77, 81] . Interestingly, baicalin was proven to be a promising anti-mycobacterial and anti-inflammatory agent through inhibiting the PI3K/Akt/NF-κB signal pathway and NLRP3 inflammasome, as well as upregulating LC3II expression in RAW264.7 cells stimulated by Mycobacterium tuberculosis [86] . Studies showed that baicalin was more effective than DEX. Baicalin at 50 mg/kg significantly improved pulmonary function, inflammatory cell infiltration and cytokine expression (TNF-a, IL-6 and MMP9), whereas 1 mg/kg DEX failed to significantly improve any of these [85, 87] .

Tanshinone IIA 4 is the major active compound isolated from Salvia miltiorrhizae Bunge.

Tanshinone IIA has various activities including cardioprotective, anti-atherosclerotic, anticancer, anti-bacterial and anti-viral activities. Moreover, tanshinone IIA increased the survival rate as well as attenuated lung histopathologic changes and lung edema in animals with ALI induced by LPS, paraquat, seawater, bleomycin, pancreatitis or aspiration [88] [89] [90] [91] [92] . Interestingly, tanshinone IIA exerted inhibitory effects on lung inflammatory condition via inhibition of expression of pro-inflammatory cytokines TNF-a, IL-1β and IL-6. In addition, oxidative stress was attenuated by tanshinone IIA via its suppression of ROS, MDA5 and IRE-a. In regard to mechanism, tanshinone IIA prevented ALI through suppressing TRPM7 expression [93] , ACE2 J o u r n a l P r e -p r o o f and Ang-(1-7) expression [92] , PLA2 activity [90] , the HIF-1α pathway [94] and the Sirt1/NF-κB signaling pathway [95] . Additionally, tanshinone IIA could prevent oxidative stress through up-regulating the Nrf2 signaling pathway [88] . Apoptosis, an important role in ALI, was also suppressed by tanshinone IIA through up-regulating Bcl-2 and down-regulating Bax and Caspase-3, which were partly mediated by the inhibition of the PI3K/Akt/FoxO1 signaling pathway [91] . At the same time, tanshinone IIA also inhibited lung edema and lung damage via inhibition of AQP1 and AQP5 over-expression [96] .

Salvia miltiorrhizae Bunge, has anti-tumor, anti-inflammatory, cardioprotective, visceral protective and other properties [97] . At the same time, the increased MPO activity, pulmonary fibrosis, lung edema and lung histopathologic changes in animals with ALI induced by LPS, radiation or I/R were prominently suppressed by cryptotanshinone, which demonstrated the protective role of cryptotanshinone in ALI model [98] [99] [100] . In addition, cryptotanshinone exerted anti-inflammatory activity via down-regulating the expression of proinflammatory cytokines (TNF-α, IL-1β, IL-6 and COX-2), which might be due to its ability to inhibit the TLR4-mediated NF-κB signaling pathway [98] . Interestingly, expressions of the pro-fibrotic signals TGF-1 and NOX-4 were down-regulated but the anti-fibrotic enzyme MMP-1 was promoted by cryptotanshinone, indicating that cryptotanshinone could prevent pulmonary fibrosis [99] . Tang also found that 40 mg/kg cryptotanshinone had protective effects on LPSinduced lung inflammation and lung histopathological changes, comparable to the effects of 1 mg/kg DEX (1 mg/kg) [98] .

Tanshinone IIA sulfonate sodium 6, a water-soluble derivative of tanshinone IIA, was J o u r n a l P r e -p r o o f found to inhibit seawater aspiration-induced ALI through up-regulating Na + /K + -ATPase activity in mice and alveolar type II cells, which was partly mediated by the ERK1/2 signaling pathway [101] . Additionally, tanshinone IIA sulfonate sodium exerted protective effects against LPS or cigarette smoke-induced lung injury evidenced by attenuated lung edema, reduced inflammatory cell infiltration, improved lung function and ameliorated expression of proinflammatory cytokines IL-6 and IL-8. These effects of tanshinone IIA sulfonate sodium were mediated by suppressing ERK1/2 and NF-κB activation [102, 103] . Moreover, these protective effects of 10 mg/kg tanshinone IIA sulfonate sodium were comparable to those of 1 mg/kg DEX [102] .

Hyperoside 7 is a natural flavonoid found in Leonurus artemisia (Lour.) S. Y. Hu. The flavonoids of Polygonum hydropiper L. mainly contain rutin, quercetin, hyperoside and quercitrin, which have been found to inhibit LPS-induced ALI through suppressing MAPK signaling pathway [104] . Flavonoids from Houttuynia cordata containing 8.8% rutin, 26 .7% hyperoside and 31.7% quercitrin have been found to alleviate H1N1-induced ALI in mice, which was related to anti-viral and anti-inflammatory effects through suppressing influenzal NA activity and TLR signaling [105] . Of note, hyperoside improved animal survival as well as reduced histological changes and lung edema in ALI murine model induced by LPS or hypoxia.

What's more, inflammatory cell infiltration, MPO activity and expression of inflammatory cytokines TNF-α, IL-1β and IL-6 were inhibited by hyperoside, and these effects were mediated by blocking the NF-κB signaling pathway [106] . Interestingly, hyperoside also inhibited hypoxia-induced survival and proliferation of A549 cells, which were induced by regulation of the AMPK/HO-1 axis [107] .

J o u r n a l P r e -p r o o f showed inhibitory effects on inflammatory responses and oxidative stress. At 100 mg/kg, kaempferol exhibited inhibitory effects on lung pathological changes and lung edema in mice with LPS-induced ALI, which was likely induced by regulating the polyubiquitination of TRAF6 as well as inhibiting the MAPK and NF-κB signaling pathways [123, 124] . Another study found that kaempferol also inhibited H9N2 virus-induced ALI through inhibiting TLR4/MyD88-mediated NF-κB and MAPKs pathways [125] . What's more, in an ALI murine model induced by CLP, kaempferol exhibited inhibitory effects via suppression of ICAM-1 pathways [126] .

Astragalin 11, a flavonoid widely found in many traditional herbs and medicinal plants,

can prevent LPS-induced ALI in mice via its anti-inflammatory and anti-oxidant activities.

Astragalin significantly improved lung pathological changes, lung edema and animal survival.

During the process, astragalin significantly reduced the production of inflammatory cytokines TNF-α, IL-1β, IL-6 and MMP9. Astragalin obviously down-regulated the NF-κB signaling pathway [127] and activated the Nrf2/HO-1 signaling pathway [128] .

Isorhamnetin 12 is an abundant flavonol aglycone extracted from Hippophae rhamnoides L. This compound has shown anti-oxidant and anti-inflammatory effects in previous studies.

Due to these activities, isorhamnetin significantly attenuated lung pathological damage, lung edema and MPO activity in mice. Additionally, isorhamnetin obviously inhibited inflammatory cytokine release (TNF-α, IL-1β, IL-6, iNOS and COX-2) and MDA level as well as increased SOD level in vivo and in vitro. In terms of underlying mechanism, isorhamnetin significantly blocked the MAPK and NF-κB signaling pathways [129] [130] [131] . The lung protective effects of 60 mg/kg isorhamnetin on lung injury and inflammatory cytokine release (TNF-α, IL-1β and J o u r n a l P r e -p r o o f inhibited inflammatory cytokines TNF-α, IL-6, iNOS and COX-2 and MDA and ROS levels, as well as up-regulated SOD and GSH activities. Moreover, isovitexin suppressed ICAM-1 and VCAM-1 expression. Regarding mechanism, these protective effects of isovitexin were associated with inhibition of the MAPK and NF-κB pathways and activation of the HO-1/Nrf2 pathway [137] .

Wogonin 15, a natural flavonoid extracted from Scutellaria baicalensis Georgi, prevented lung injury in ALI murine model by suppressing production of inflammatory cytokines TNF-α, IL1-β, IL-6, iNOS, COX-2 and MIP-2. In terms of mechanism, wogonin blocked Akt and RhoA activation, reduced p38 MAPK and JNK phosphorylation, as well as suppressed the peroxisome proliferator-activated receptor gamma (PPARγ)-involved NF-κB signaling pathway [138] [139] [140] .

Of note, 10 mg/kg wogonin exhibited inhibitory effects on lung edema as well as expression of iNOS and COX-2 comparable to that of 1 mg/kg DEX in an LPS-induced ALI murine model [139] .

Georgi. This compound at 20 mg/kg significantly prevented LPS-or I/R-induced lung injury.

The inhibitory effects were induced by its suppression of MPO, MDA, TNF-α, iNOS and COX-2 as well as up-regulation of GSH and SOD. Scutellarin exerted these protective effects by blocking the NF-κB [141] and Bax/Bcl-2 signaling pathways [142] .

Tectorigenin 17 is a natural isofavone isolated from Belamcanda chinensis (L.) Redouté (Iridaceae). At 10 mg/kg, this compound significantly attenuated lung edema, improved lung pathological inflammation and prevented release of inflammatory cytokines TNF-α, IL-1β and IL-6, which might be associated with NF-κB p65 activity. However, compared with 2 mg/kg J o u r n a l P r e -p r o o f DEX, tectorigenin had a slightly weaker effect on ameliorating inflammatory responses [143] .

Glycitin 18 is an active constituent extracted from Glycyrrhiza uralensis Fisch., which is a traditional medicine for moistening lungs and suppressing coughs. It is reported that glycitin significantly alleviated histopathological changes, MPO activity and expression of proinflammatory cytokines IL-1β, IL-6 and TNF-α in mice with LPS-induced ALI. Additionally, glycitin inhibited inflammatory cytokine expression in RAW264.7 cells stimulated by LPS.

Moreover, the lung protective and anti-inflammatory effects of 20 mg/kg glycitin were slightly weaker than of 5 mg/kg DEX. The inhibition by glycitin and DEX might be associated with suppressing the TLR4-mediated NF-κB and MAPKs signaling pathways [144] .

Rhamnazin 19 as a natural flavonoid known for the ability of antioxidant and antiinflammatory activities was reported to inhibit lung histopathology change, MPO activity, lung edema and LDH activity in LPS-induced ALI rats. In addition, rhamnazin also lowers inflammatory cytokine production (TNF-α, IL-1β and IL-6) and MDA and H2O2 levels.

Rhamnazin exerted these protective effects through activating the Nrf2 signaling pathway [145] .

Isoliquiritigenin 20 alleviated LPS-induced ALI in mice via its inhibition of oxidative damage and inflammatory injury. During the process, isoliquiritigenin suppressed MDA levels and production of inflammatory cytokines TNF-α, IL-1β, IL-6, COX-2 and iNOS.

Isoliquiritigenin also up-regulated SOD and GSH activities. The underlying mechanism might involve the activation of AMPK/Nrf2/ARE and PPARγ signaling as well as inhibition of the NF-κB pathway and NLRP3 inflammasome [146, 147] . activity and the expression of the cytokines TNF-α, IL-6, IL-1β and IL-18 as well as improved SOD activity in LPS-induced ALI mice, which were due to the blunting of the lung NLRP3 inflammasome. However, protective effects of 40 mg/kg morin were weaker than of 2 mg/kg DEX [148] .

Formononetin 22 is a major constituent of Astragalus mongholicus Bunge. This compound at 20 mg/kg significantly exerted protective effects against ALI by markedly attenuating lung histopathologic changes, lung edema, MPO activity and inflammatory cytokine production (TNF-α and IL-6) as well as increasing SOD activity. This may be associated with up-regulating PPAR-γ gene expression but further studies are needed to confirm this hypothesis. Compared with 2 mg/kg DEX, 20 mg/kg formononetin had weaker lung protective effects [149] .

Naringenin 23 is a naturally occurring plant bioflavonoid mainly found in the fruits of citrus paradise, oranges and other citrus species. Naringenin significantly increased the survival rate, alleviated lung injury, suppressed inflammatory mediator expression (TNF-α, IL-1β, IL-6 and MIP-2) and down-regulated ROS and MDA levels in ALI mice induced by LPS through blocking the PI3K/Akt signaling pathway [150, 151] .

Naringin 24, a well-known flavanone glycoside found in grapefruit and other citrus fruits, is an effective anti-inflammatory compound. Naringin exerted protective effects in ALI models induced by LPS or paraquat and improved survival rates and reduced lung injury and lung fibrosis [152, 153] . Naringin at 100 μM obviously prevented production of inflammatory cytokines IL-8, MCP-1 and MIP-1α [154] . The effects of naringin on ALI were due to its inhibition of inflammatory responses via suppressing inflammatory cytokine expression (TNF-J o u r n a l P r e -p r o o f α, TGF-β1, MMP-9 and TIMP-1) and oxidative stress via promoting SOD, GSH-Px and HO-1 expression, which was induced by blocking the NF-κB pathway [152] . Also, naringin exhibited mucoactive effects with reduction of goblet cell hyperplasia, inhibition of mucus hypersecretion and promotion of sputum excretion [155] . Moreover, 36.8 mg/kg naringin had stronger effects than 2.4 mg/kg prednisone in inhibiting lung inflammatory condition in cigarette smokeinduced ALI mice [156] . The protective effects of 60 mg/kg naringin and 5 mg/kg DEX were comparable [152] .

Hesperidin 25, a flavanone glycoside found in sweet oranges and lemons, has antiinflammatory properties. This compound could prevent lung injury and lung inflammatory condition induced by LPS, H1N1, CLP or I/R [157] [158] [159] [160] . Hesperidin obviously inhibited the pro-inflammatory cytokines and chemokines expression (IL-1β, IL-6, TNF-α, Inos, HMGB1, IL-12 and MCP-1) in ALI mice, A549 cells and THP-1 cells stimulated by LPS through downregulating the NF-κB and MAPKs signaling pathways [158, 161] . What's more, hesperidin suppressed the Hsp70/TLR4/MyD88 signaling pathway in CLP-induced lung injury mice [157] .

Hesperitin 26, a major bioflavonoid occurring in sweet oranges and lemons, has been reported to have anti-fibrotic and anti-inflammatory activities. Hesperitin could attenuate lung edema and lung inflammatory condition in ventilator, acrolein or LPS-induced ALI murine model. During the process, hesperitin obviously suppressed chemokines expression (IL-1β, IL-6, TNF-α, iNOS and MIP-2) and MDA activity, on the other hand, but also up-regulated SOD and GSH activities [162, 163] . In terms of the underlying mechanism, hesperitin markedly activated PPAR-γ, blocking MD2/TLR4 complex formation and suppressed the NF-κB and J o u r n a l P r e -p r o o f vegetables. Troxerutin (150 mg/kg) effectively improved alveolar wall thickening, lung edema, inflammatory cell infiltration and inflammatory cytokine expression (TNF-α, IL-6 and IL-1β) in a mouse model with LPS-induced ALI. Troxerutin also increased the expression of IL-10.

These effects of troxerutin were comparable with those of 5 mg/kg DEX. Network pharmacology analysis and in vivo experiments showed that troxerutin markedly prevented the MAPK and NF-κB signaling pathway [174] .

Engeletin 34 is a flavanonol glycoside isolated from the radix of Smilax china L. Engeletin effectively attenuated lung histopathological changes, lung edema and inflammatory cell infiltration. In addition, engeletin suppressed inflammatory cytokine expression (TNF-α, IL-6 and IL-1β) via inhibition of the NF-κB signaling pathway, possibly due to its ability to activate PPAR-γ. Moreover, the protective effects of 100 mg/kg engeletin treatment 1 h before LPS were better than when applied 1 h after LPS [175] . anti-inflammatory mechanism of silibinin was associated with its inhibition of NF-κB and NLRP3 inflammasome [176, 177] . 

Alkaloids are an important class of alkaline nitrogenous organic compounds, and have been reported to have anti-tumor, anti-inflammatory, anti-oxidant and anti-bacterial activities [185] [186] [187] . Most alkaloids are water-insoluble or hardly water-soluble. However, some alkaloids have toxic effects on heart, liver, spleen and other organs [188] [189] [190] . Therefore, we should also pay attention not only to the protective effects but also the toxicity of alkaloids. The alkaloids reported to have anti-lung injury activity are summarized below.

Berberine 40 is a natural alkaloid isolated from Corydalis yanhusuo W. T. Wang plants, which have various activities including analgesic, anti-inflammatory, anti-tumor, anti-bacterial effects. Berberine is a well-known anti-bacterial agent; however, it also effectively alleviated lung injury by reducing lung edema, lung inflammatory condition and neutrophil infiltration in mice with ALI stimulated by LPS or cigarette smoke. During the process, expression of proinflammatory cytokines or mediators (TNF-α, IL-6, IL8, KC, MIP-2, cPLA-2 and MCP-1) was down-regulated. Of note, the PERK-mediated Nrf2/HO-1 signaling axis was up-regulated [191, 192] and the NF-κB signaling pathway was down-regulated [193] . However, compared with effects of 5 mg/kg DEX, the protective effects of berberine against lung injury, lung edema, MPO activity, inflammatory cell infiltration and pro-inflammatory mediator expression (IL-6 and KC) were significantly weaker, possibly induced by the stronger activation of DEX on the Nrf2/HO-1 signaling pathway [192] . Also, 30 mg/kg cavidine and 5 mg/kg DEX had comparable protective effects [195] .

Corynoline 43, an isoquinoline alkaloid isolated from Corydalis bungeana Turcz, markedly improved histopathological changes, lung edema, MPO activity and expression of pro-inflammatory cytokines TNF-α, IL-1β and IL-6. Protective effects of 60 mg/kg corynoline were comparable with 5 mg/kg DEX. The mechanism of the effects of corynoline was related to up-regulation of the Nrf2 signaling pathway, which subsequently inhibited NF-κB activation [196] .

Ukrain 44 is an active alkaloid extracted from Chelidonium majus L. This compound was reported to markedly inhibit lung damage and histopathological changes in mice with ALI induced by I/R, which were associated with increasing total anti-oxidant status, as well as decreasing total oxidant status and oxidative stress index levels [197] .

L. At 20 mg/kg, tetrahydhydrocoptisine dramatically ameliorated lung pathological changes, J o u r n a l P r e -p r o o f decreased the mortality rate and lung edema, inhibited inflammatory cell infiltration and MPO activity, as well as reduced TNF-α and IL-6 production in mouse ALI model induced by LPS.

However, these protective effects of 20 mg/kg tetrahydhydrocoptisine were slightly weaker than of 5 mg/kg DEX. Additionally, the effects of tetrahydhydrocoptisine were due to its inhibition of the NF-κB signaling pathway [198] . Of note, the protective effects of protostemonine were related to inactivation of the MAPK and Akt signaling pathways [199, 200] . in vitro showed that bergenin could significantly ameliorate histological changes and pulmonary edema as well as reduce MPO activity, inflammatory cell infiltration and expression of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) in mice with LPS-induced ALI. These protective effects of bergenin were comparable to those of 5 mg/kg DEX. Bergenin exerted these protective effects both in vitro and in vivo through suppressing the NF-κB signaling pathway [201] .

Betanin 48, a natural compound isolated from Portulaca oleracea L. dose-dependently J o u r n a l P r e -p r o o f attenuated lung injury via its inhibitory effects on pro-inflammatory cytokine expression (TNFα and IL-1β) and NF-κB activity in ALI rats induced by paraquat. In addition, betanin also protected the barrier function of the alveolar epithelium, demonstrated by increased expression of ZO-1 and claudin-4 [202] .

Cordycepin 49, a natural compound derived from Cordyceps militaris (L.ex Fr.) Link., was found to decrease the lung edema, MPO activity, MDA content, and inflammatory cytokines production (TNF-α, IL-1β, IL-6, iNOS and NO) in ALI mice induced by LPS. In terms of the underlying mechanism, cordycepin dramatically up-regulated the Nrf2 signaling pathway and down-regulated the NF-κB signaling pathways [203, 204] . 

Terpenoids, a class of compounds commonly found in plants, possess various activities.

Most terpenoids can prevent inflammation, and the process involves the NF-κB and MAPK J o u r n a l P r e -p r o o f signaling pathways [207] [208] [209] . In addition to anti-inflammatory and antioxidant effects, terpenoids also possess anti-tumor activity through promoting apoptosis via regulating the NF-κB, Akt, Bax/bcl-2 and P53 signaling pathways. What's more, terpenoids also have antidiabetic, liver protective, neuroprotective and anti-lung injury activities [210, 211] .

Pogostone 52 is a natural sesquiterpene isolated from Pogostemon cablin (Blanco) Benth.

It remarkably improved survival rate, attenuated lung histological alterations, decreased lung edema, reduced MPO and MDA levels as well as down-regulated the levels of proinflammatory mediators (TNF-a, IL-1β and IL-6) in mice with ALI induced by LPS via the regulation of KEAP1-Nrf2/NF-κB signaling pathways [212] . Furthermore, pogostone can also attenuate cell injury in A549 cells induced by TNF-a through regulating the balance between the Nrf2 and NF-κB p65 signaling pathways. In addition, the protective effects of 20 mg/kg pogostone were comparable with those of 5 mg/kg DEX [213] Patchouli alcohol 53, also a natural sesquiterpene isolated from Pogostemon cablin (Blanco) Benth., inhibited ALI induced by LPS in mice via its inhibitory effects on inflammatory responses and oxidative stress. Patchouli alcohol significantly inhibited proinflammatory mediators (TNF-a, IL-1β and IL-6), suppressed MDA activity as well as increased activities of anti-oxidant enzymes SOD and GSH-Px. These protective effects of 40 mg/kg patchouli alcohol were comparable to those of 5 mg/kg DEX. In terms of the mechanism, the NF-κB signaling pathway was involved [214, 215] .

Eucalyptol 54 is a natural compound isolated from Zingiber officinale Rosc., which can be used as medicine and food. Previous studies demonstrated that 30 mg/kg eucalyptol significantly prevented lung histological and pulmonary inflammation induced by LPS in the J o u r n a l P r e -p r o o f ALI murine model, associated with inhibition of the NF-κB pathway [216, 217] . Additionally, eucalyptol obviously mitigated lung damage caused by cigarette smoke through inhibiting ICAM-1 expression [218] . In addition, the anti-inflammatory effects of 100 mg/kg eucalyptol and 0.5 mg/kg prednisone were comparable [216] . Moreover, the inhibitory effects of eucalyptol on TLR4 expression were significantly stronger than those of prednisone. Also, 400 mg/kg eucalyptol had a stronger inhibitory effect on inflammatory cell infiltration than 1 mg/kg DEX [217] .

Zerumbone 55, a sesquiterpene found in Zingiber zerumbet Smith, has various activities.

Due to inhibitory effects on inflammation and oxidative stress, zerumbone significantly inhibited lung edema, MPO activity and pro-inflammatory cytokines production (TNFα, IL-6, IL-1β, MIP-2, iNOS and COX-2) as well as reversed the anti-oxidative enzymes activities (SOD, CAT and GSH) in LPS-induced ALI murine model. The protective effects of zerumbone were associated with down-regulating the MAPK [219] and Akt-NF-κB pathways [220] as well as up-regulating the Nrf2/HO-1 signaling pathway [221] .

Limonene 56 is a natural monoterpene derivative widely found in fruits, such as lemon, orange and grape. This compound significantly inhibited lung edema, MPO activity and proinflammatory cytokine production (TNFα, IL-6 and IL-1β) in mice with LPS-induced ALI. In regard to the underlying mechanism, these effects of limonene were associated with suppressing the NF-κB and MAPK signaling pathways. During the process, 75 mg/kg limonene had a stronger inhibitory effect on activation of the NF-κB signaling pathway than 0.5 mg/kg DEX [222] .

Thymol 57, a natural monoterpene from Thymus vulgaris L., inhibited lung J o u r n a l P r e -p r o o f histopathologic lung alteration, lung edema and MPO activity in LPS-induced ALI murine model. These protective effects were associated with suppressing inflammatory responses via ameliorating pro-inflammatory cytokine production (TNFα, IL-6 and IL-1β) as well as attenuating oxidative stress via increasing SOD activity and inhibiting MDA levels. These effects of thymol were associated with its inhibition of the NF-κB signaling pathway and activation of the Nrf2 signaling pathway [223, 224] . P-Cymene 58 is a biological constituent of Chenopodium ambrosioides L. This compound significantly prevented lung pathological changes, lung edema, inflammatory cell infiltration, MPO activity and pro-inflammatory cytokine production (TNFα, IL-6 and IL-1β) in mice with LPS-induced ALI. However, the protective effects of 10 mg/kg p-cymene were weaker than of 5 mg/kg DEX, possibly due to the stronger inhibitory effects of DEX on the NF-κB and MAPK signaling pathways [225, 226] Linalool 59, a natural component of essential oils in aromatic plants, is widely used to make shampoos, detergents and soaps. Linalool effectively prevented lung pathological changes and inflammatory cell infiltration in LPS-induced ALI mice. Additionally, this compound also dramatically suppressed inflammatory cytokine production (TNFα and IL-6) in LPS-stimulated mice and RAW264.7 cells. However, these effects of 25 mg/kg linalool were much weaker than those of 5 mg/kg DEX. In addition, during the process, linalool dramatically blocked the NF-κB and MAPK signaling pathways [227] . 3-Dehydroandrographolide 61, a natural andrographolide product, was demonstrated to decrease LPS-induced ALI in mice, associated with inactivation of the NF-κB/Akt signaling pathway. However, these protective effects were attenuated by α7nAchR siRNA or methyllycaconitine, demonstrating that 3-dehydroandrographolide protected against ALI through the cholinergic anti-inflammatory pathway [230] .

Decne. Costunolide significantly suppressed lung edema, MPO activity and inflammatory cytokine production (TNF-α, IL-6, iNOS and KC) in mice induced by lipoteichoic acid or heatkilled Staphylococcus aureus (HKSA) [231] . Additionally, costunolide dose-dependently reduced inflammatory cytokine expression in murine bone marrow-derived macrophages and alveolar macrophages stimulated by lipoteichoic acid or HKSA. These effects of costunolide were related to inhibition of the MAPK signaling pathway [232] .

Dehydrocostus lactone 63, also a sesquiterpene extracted from the radix of Aucklandia lappa Decne., exerted protective effects against ALI via anti-inflammatory effects. In vitro and in vivo experiments revealed that dehydrocostus lactone effectively attenuated LPS-induced pathological injury and reduced pro-inflammatory mediator expression (TNF-α, IL-6, IL-1β, iNOS, NO and IL-12) in lung and macrophages through suppressing the p38 MAPK/MK2 and Akt-mediated NF-κB signaling pathways [233] . Ginsenoside Rg3 could attenuate histopathological alterations, lung edema and inflammatory cytokines expression (TNF-α, IL-1β and IL-6) as well as promote the polarization of M2 macrophages in mice with LPS-induced ALI, which were associated with activating the MerTK-dependent PI3K/Akt/mTOR signaling pathway [234] . Ginsenoside Rg3 was also found to inhibit LPS-induced ALI in mice through down-regulating the NF-κB signaling pathway [235] . However, anti-lung injury and anti-inflammatory effects of ginsenoside Rg3 were significantly weaker than of DEX, possibly because of the stronger effects of DEX on activation of the PI3K/Akt/mTOR signaling pathway [234] .

Ginsenoside Rg5 65, also a natural compound isolated from Panax ginseng C. A. Meyer, could prevent ALI in vivo and in vitro via its anti-inflammatory activity. Ginsenoside Rg5 significantly attenuated lung injury and lung inflammatory condition in LPS-induced ALI mice.

Additionally, this compound dramatically suppressed pro-inflammatory cytokine expression (TNF-α, IL-1β, iNOS and COX-2) in mice and alveolar macrophages, which were associated with preventing the binding of LPS to TLR4 and subsequently down-regulating the NF-κB signaling pathway. These protective effects of 10 mg/kg ginsenoside Rg5 were comparable to those of 5 mg/kg DEX [236] .

Pseudoginsenoside-F11 (PF11) 66, another natural compound isolated from Panax ginseng C. A. Meyer, can protect against ALI via its anti-inflammatory effects. PF11 significantly prevented lung injury, lung edema and inflammatory cytokines production (TNFα, IL-1β and IL-6). Additionally, PF11 inhibited neutrophil infiltration by reducing MIP-2 and ICAM-1 expression as well as promoted neutrophil clearance through enhancing neutrophil J o u r n a l P r e -p r o o f apoptosis and phagocytosis. Both 30 mg/kg PF11 and 1 mg/kg DEX could prevent lung inflammation and neutrophil phagocytosis by macrophages; however, only PF11 inhibited neutrophil apoptosis, and 1 mg/kg DEX had no such effect [237] .

Betulin 67 is a naturally occurring triterpene extracted from Eucommia ulmoides Oliv.

Betulin at 8 mg/kg could remarkably alleviate lung injury in mice induced by LPS, Escherichia coli or CLP. In addition, betulin dramatically suppressed inflammatory cytokine release (TNF-α, IL-1β and IL-6) and promoted IL-10 expression in RAW264.7 cells and ALI mice stimulated by LPS or E. coli. Betulin was also able to enhance the clearance of E. coli. All the protective effects of betulin may be associated with suppressing the NF-κB signaling pathway [238, 239] .

Betulinic acid 68, also a triterpene isolated from Eucommia ulmoides Oliv., could inhibit ALI induced by LPS or CLP. The effects of betulinic acid were induced by suppressing proinflammatory cytokine production (TNF-α, IL-1β, iNOS, MCP-1 and MMP9) and promoting activities of anti-oxidant enzymes SOD and GSH. In terms of the underlying mechanism, NF-κB activity was involved [240, 241] .

Bigelovii A 69 is a nor-oleanane type triterpene saponin extracted from Salicornia bigelovii Torr. Bigelovii A obviously inhibited lung edema, neutrophil infiltration and lung permeability in LPS-induced ALI murine model. Additionally, this compound significantly down-regulated inflammatory mediator expressions (IL-6, MCP-1, MIP-1α and MIP-2) in mice and MH-S cells.

These effects of bigelovii A were associated with down-regulating the NF-κB and p38 MAPK/ERK1/2-C/EBPδ signaling pathways [242] . Senegenin might exert these effects through suppressing the NF-κB and MAPK signaling pathways. These protective effects of 8 mg/kg senegenin were comparable to those of 5 mg/kg DEX [243, 244] .

Echinocystic acid 71 is an important constituent of Albizia julibrissin Durazz. This compound could prevent lung injury and lung inflammation in LPS-induced ALI mice, and the protective effects of 5 mg/kg echinocystic acid and 5 mg/kg DEX were comparable. In addition, 5 μM echinocystic acid markedly prevented pro-inflammatory cytokine and mediator expression (TNF-α, IL-1β, iNOS, COX2, NO and PGE2) in alveolar macrophages stimulated by LPS. All the effects of this compound were related to its inhibition of the binding of LPS to TLR4 and the subsequent NF-κB and MAPK activation [245] .

Esculentoside A 72 is a natural compound in Phytolacca acinosa Roxb. This compound could prevent lung injury, lung edema, inflammatory cell infiltration and MPO activity in LPSinduced ALI mice, and its protective effects were related to inhibition of the NF-kB and MAPKs signaling pathways [246] . Additionally, esculentoside A was able to attenuate airway inflammation induced by ovalbumin , which was related to its up-regulation of the Nrf2 signaling pathway [247] .

Taraxasterol 73 is a pentacyclic-triterpene isolated from Taraxacum officinale F. H. Wigg.

The treatment of taraxasterol 1 h before LPS administration or 7 h after LPS administration could attenuate lung edema, MPO activity, inflammatory cell infiltration and pro-inflammatory J o u r n a l P r e -p r o o f cytokine expression (TNF-α, IL-1β, IL-6, PGE-2 and COX-2) in ALI mice. These protective effects of 10 mg/kg taraxasterol were comparable with 0.5 mg/kg DEX. The effects of taraxasterol might be related to its inhibition of the NF-κB and MAPK signaling pathways [248] .

Sclareol 74 as a natural labdane-type diterpene found in Salvia Sclare L. can ameliorate lung histological alterations, lung edema, MPO activity, inflammatory cell infiltration and proinflammatory cytokine expression (TNF-α, IL-1β, IL-6, iNOS and COX-2) in ALI mice.

Additionally, sclareol inhibited oxidative stress through increasing SOD and GSH-Px levels.

These effects of sclareol might be related to its inhibition of NF-κB and MAPK activation and up-regulation of HO-1. Of note, the anti-lung injury and anti-inflammatory effects of 10 mg/kg sclareol were comparable to those of 10 mg/kg DEX but scareol had a weaker anti-oxidant effect than DEX [249] . Interestingly, sclareol could also protect Staphylococcus aureus USA300-stimulated A549 cells through suppressing alpha-hemolysin production [250] .

Triptolide 75 is a natural diterpenoid compound isolated from Tripterygium wilfordii Hook. f. and can prevent lung injury, lung edema and inflammatory cell infiltration in ALI murine model induced by LPS, chlorine or radiation. Triptolide also down-regulated expression of inflammatory cytokines or chemokines TNF-α, IL-1β, IL-6, IL-8, MIP-1, MCP-1, IP-10, MIP-2 and VCAM-1. However, the anti-lung injury and anti-inflammatory effects of 15 μg/kg triptolide were slightly weaker than of 5 mg/kg DEX. These effects might be associated with activating PPAR-γ and thereby attenuating NF-κB and MAPK activation [251] [252] [253] [254] . In addition, the effects of triptolide on ALI were associated with regulation of ATP-binding cassette transporter A1 (ABCA1) expression [255] .

Acanthoic acid 76, a pimaradiene diterpene isolated from Acanthopanax senticosus (Rupr.

J o u r n a l P r e -p r o o f et Maxim.) Harms, was demonstrated to prevent LPS-induced ALI via its inhibitory effects on inflammatory response. During the process, acanthoic acid inhibited inflammatory cytokines expression (TNF-α, IL-1β and IL-6) through activating LXRα and suppressing the NF-κB signaling pathway [256] .

Asiaticoside 77, a triterpene glycoside isolated from Centella asiatica (Linn.) Urban, was reported to dose-dependently inhibit inflammatory cells infiltration, histopathological changes, pulmonary edema and pro-inflammatory cytokines production (TNF-α and IL-6), which were associated with down-regulating the NF-κB signaling pathway [257] .

Platycodin D 78, the major triterpene saponin isolated from root of Platycodon grandiflorus (Jacq.) A. DC., significantly decreased lung histopathologic changes, lung edema, MPO activity, MDA activity and pro-inflammatory cytokines levels (TNF-α, IL-1β and IL-6) in ALI murine model and A549 cells stimulated by LPS. In addition to the NF-κB signaling pathway, the LXRα-ABCA1 pathway and Bax/Bcl-2 were also involved in the effects of platycodin D on ALI [258, 259] .

Mogroside V 79 is a natural constituent of Siraitia grosvenorii (Swingle) C. Jeffrey ex Lu et Z. Y. Zhang. Previous study found that at 10 mg/kg mogroside V protected against lung injury, MPO activity, pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, iNOS and COX-2) in an ALI model induced by LPS. However, these protective effects of mogroside V were slightly weaker than those of 2 mg/kg DEX. The mechanism might involve suppressing the NF-κB signaling pathway [260] .

Stevioside 80 is a major constituent in leaves of Stevia rebaudiana Bertoni. This compound at 50 mg/kg dramatically inhibited lung injury, lung edema, MPO activity, J o u r n a l P r e -p r o o f inflammation cell infiltration and release of inflammatory cytokines TNF-α, IL-1ß, IL-6, iNOS and COX-2. Also, the protective effects of stevioside were comparable to those of 5 mg/kg DEX. Of note, the mechanism involved blocking of the NF-κB signaling pathway [261] .

Saikosaponin A 81, a triterpene saponin isolated from Bupleurum chinense DC., has antiinflammatory and anti-oxidant activities. Saikosaponin A dose-dependently inhibited lung histopathological changes, lung edema, MPO activity and inflammatory cytokine production (TNF-α and IL-1β), which were associated with blocking the activation of NF-κB and NLRP3

inflammasome [262] .

Carnosic acid 82 is a phenolic diterpene compound isolated from Rosmarinus officinalis L. and markedly inhibited lung injury, lung edema, MPO activity and production of inflammatory cytokines TNF-α, IL-1β and IL-6. In addition, 40 mg/kg carnosic acid promoted neutrophil apoptosis. The effects of this compound might be associated with suppressing the TLR4/ NF-κB signaling pathway [263] .

L. Previous study demonstrated that OA could effectively alleviate lung injury and play a protective role in N-methyl-D-aspartate (NMDA)-induced ALI murine model and NMDAstimulated MLE-12 cells, which were associated with its anti-inflammatory, anti-oxidant and anti-apoptosis effects. Both SIRT1 and NF-κB were involved in the process [264] . Moreover, another study demonstrated that OA could also alleviate lung injury induced by paraquat via its anti-inflammatory and anti-oxidant activities [265] .

Bardoxolone 84, a synthetic triterpenoid based on OA, was also demonstrated to exert protective effects on ALI induced by LPS. Bardoxolone dose-dependently suppressed lung J o u r n a l P r e -p r o o f injury, lung edema and production of inflammatory cytokines TNF-α, IL-1β, IL-6, iNOS, COX-2 and HMGB1. Additionally, bardoxolone down-regulated MDA expression and promoted GSH and SOD levels. During the process, bardoxolone down-regulated the NF-κB and MAPK signaling pathways. Interestingly, all these effects were Nrf2-dependent [266] .

2α-Hydroxyl-3β-angeloylcinnamolide 85 is a drimane-type sesquiterpenoid isolated from Polygonum jucundum Lindex. (Polygonaceae), which is a traditional Chinese medicine.

Results in mice and RAW 264.7 induced by LPS demonstrated that 2α-hydroxyl-3βangeloylcinnamolide could inhibit ALI via its anti-inflammatory effects through suppressing the TLR4-mediated MAPK pathway in activated macrophages [267] .

Isoforskolin 86, a natural constituent in Coleus forskolin Briq., at 5 mg/kg effectively increased animal survival as well as attenuated lung edema, MPO activity and proinflammatory cytokine production in rat with ALI induced by LPS. In human mononuclear leukocyte, isoforskolin also lowered LPS-induced inflammatory cytokine production (TNF-α, IL-1β, IL-6 and IL-8) as well as promoted PGE1,6-keto-PGF1α and cAMP levels. During the process, 5 mg/kg DEX showed more potential anti-inflammatory effect than 5 mg/kg isoforskolin, but less effect on cAMP and 6-keto-PGF1α levels. Also, 5 mg/kg isoforskolin and 5 mg/kg DEX resulted in 100% and 80% survival of animals challenged by LPS, respectively [268] . cells. Moreover, the protective effects of bixin were Nrf2 dependent [274] [275] [276] .

Polyphenols, secondary metabolites of plants, are widely existed in many plants, such as cocoa, tea, coffee, cereals and vegetables. Numerous studies have demonstrated that polyphenols could be potential treatment of cancer [277] , diabetes [278] , obesity [279] , hypertension [280] , Parkinson's disease [281] and osteoporosis [282] , which may be due to their modulation of autophagy, apoptosis, inflammation and oxidative stress. The anti-lung [292, 293] . It also attenuated LPS-induced ALI via inhibition of inflammation through regulating PPARγ/HO-1-mediated HMGB1/RAGE and AMPK signaling pathways [294, 295] and inhibited CLP-induced ALI through down-regulating the TGF-β1/SMAD3 pathway [296] .

Additionally, curcumin could suppress CLP-induced lung injury and inflammation, which may be associated with the differentiation of CD4+T cells and IL-10 immune modulation [297] .

Another study found that solubilized curcumin significantly attenuated lung injury, inflammation and survival in a pneumonia murine model induced by lethal Gram-negative bacteria through promoting polarization of M2s as well as regulating HIF and NF-kB proinflammatory pathways [298] . Terpinen-4-ol 97 is a natural polyphenol in tea tree oil. It inhibited lung histopathological changes, MPO activity and lung edema in a murine model of LPS-induced ALI. During the process, terpinen-4-ol also down-regulated TNF-α and IL-1β production. These protective effects of terpinen-4-ol were mediated by activation of PPAR-γ and subsequent inactivation of the NF-κB signaling pathway [301] .

Resveratrol 98 is a type of polyphenol widely found in many plants and has multiple activities. Previous studies have found that resveratrol has inhibitory effects on lung injury in various animal models of ALI. Resveratrol significantly inhibited CLP-induced ALI via inhibition of inflammation, oxidative stress and cell apoptosis through suppressing the PI3K/Nrf2/HO-1 signaling pathway [302] , inhibited SEB-induced ALI by regulating miR-193a which targets TGF-β signaling pathway [303] as well as protected against LPS-induced ALI via inhibition of NLRP3 inflammasome [304] and activation of Sirt1 [305] . During the process, this compound markedly inhibited inflammatory cytokine expression (TNF-α, IL-1β and iNOS) and MDA activity as well as up-regulated SOD and IL-10 levels.

The protective effects might be induced by inhibiting HIF-1α and NF-κB activity [307, 308] , activating the Trx-1 pathway [309] and up-regulating connexin 43 [310] .

Procyanidin B2 101 is a dietary phytochemical compound in leaves of Eriobotrya japonica (Thunb.) Lindl. Procyanidin B2 could inhibit acute lung injury in rat model of ALI induced by paraquat via the inhibition of MDA activity and expression of inflammatory mediators TNF-a, IL-1β and IL-18 [311] . Further study found that procyanidin B2 significantly increased cell viability in LPS-treated human alveolar epithelial cells and lung fibroblasts, and suppressed LPS-induced cell apoptosis, which were associated with reduced Bax expression and promoted Bcl-2 expression. In terms of mechanism, the NF-κB signaling pathway and NLRP3 inflammasome were involved in the inhibition of procyanidin B2 on ALI [312] .

Epigallocatechin-3-gallate 102, a major active polyphenol in green tea, has been demonstrated to inhibit lung injury in different ALI animal models. Several studies revealed that this compound significantly inhibited ALI induced by LPS or paraquat in mice via its antiinflammatory effect through suppressing TLR4-dependent NF-κB signaling pathways [313, 314] , inhibited ALI induced by H9N2 swine influenza virus through the TLR4/NF-κB/Tollinteracting protein (Tollip) pathway [315] , suppressed ALI induced by thermal injury or hip fracture through limiting mtDNA release [316, 317] as well as reduced seawater aspiration-J o u r n a l P r e -p r o o f induced ALI via inhibiting the JNK and STAT1-caspase-3/p21 pathway [318, 319] .

Chlorogenic acid 103, one of the most abundant polyphenol compounds in the human diet, markedly inhibited lung edema and pulmonary MPO activity in mice with LPS-induced ALI. Additionally, chlorogenic acid prevented inflammatory mediator expression (iNOS and NO) in mice stimulated by LPS, and these effects of 50 mg/kg chlorogenic acid were comparable with those of 2 mg/kg DEX [320] . Furthermore, chlorogenic acid also suppressed pancreatitis-associated lung injury via its anti-inflammatory activity [321] .

honeybee propolis. At 50 mol/kg, CAPE significantly prevented oleic acid-induced ALI in vivo via inhibition of oxidative damage through decreasing MDA levels and up-regulating enzymatic activity of Na + /K + -ATPase [322] . Further, CAPE protected against phosgeneinduced ALI through inhibiting oxidative stress and inflammationthese effects were related to blocking the NF-κB signaling pathway but not the p38 MAPK signaling pathway [323] .

Similarly, this compound also inhibited LPS-induced ALI in vivo and in vitro via its antiinflammatory activities, and the effects were induced by its high affinity with MD2 and the suppressed formation of the LPS/MD2/TLR4 complex [324] . Geraniin 108 is a natural phenolic compound isolated from Phyllanthus urinaria Linn.

Geraniin markedly attenuated LPS-induced lung pathological changes, inflammatory cell infiltration, MPO activity and inflammatory cytokines production (TNF-α, IL-6 and IL-1β) in LPS-induced ALI mice. In addition, geraniin exerted these effects by inhibiting NF-κB and activating Nrf2 signaling pathways [327] .

This compound at 20 mg/kg obviously improved pulmonary function, inhibited inflammatory cytokines expression (TNF-α, COX-2, IL-6 and IL-1β) and suppressed lung cell apoptosis in I/R-induced ALI through blocking the JNK/MAPK pathway [328] . Additionally, corilagin attenuated bleomycin-induced lung injury and lung fibrosis through down-regulating the NF-κ B and TGF-β1 signaling pathways [329] .

Rosmarinic acid 110 is a natural polyphenolic compound isolated from Sarcandra glabra (Thunb.) Nakai. Studies showed that rosmarinic acid could dose-dependently inhibit lung injury, lung edema, inflammatory cell infiltration and inflammatory cytokine production (TNF-α, IL-J o u r n a l P r e -p r o o f 6 and IL-1β) for in vivo models of ALI induced by LPS. These effects of rosmarinic acid were related to inhibition of the ERK/MAPK signaling pathway [330] . 

ribavirin had no such effect [331] .

This compound at 10 mg/kg significantly inhibited hydrochloric acid or CCl4-initiated ALI in mice. During the process, ellagic acid dramatically inhibited production of inflammatory cytokines IL-1β, IL-6 and COX-2, as well as increased CAT, GSH and IL-10 expression. These effects were associated with its activation of caspase-3 as well as down-regulation of the Bcl-2/Bax and NF-κB signaling pathways [332, 333] .

Protocatechuic acid 113, a natural compound isolated from Melissa officinalis L., at 10 mg/kg significantly decreased the lung histopathological changes, lung edema and inflammatory cytokines production (TNF-α, IL-1β and IL-6) in mice with LPS-induced ALI.

These protective effects of 30 mg/kg protocatechuic acid were comparable with those of 1 mg/kg DEX. These effects might be associated with blocking the p38 MAPK and NF-κB signal J o u r n a l P r e -p r o o f pathways [334, 335] . Additionally, protocatechuic acid also prevents intestinal I/R-induced ALI, which is related to regulation of p66shc-mediated anti-oxidative/anti-apoptotic factors [336] .

Hu, can attenuate lung injury, lung edema, neutrophil infiltration and MPO activity. In addition, this compound down-regulated TNF-α and IL-6 levels in LPS-induced ALI mice. These protective effects of 50 mg/kg 3,5-dicaffeoylquinic acid were comparable to those of 10 mg/kg DEX. In terms of mechanism, this compound exerted these effects through suppressing the SRKs/Vav signaling pathway [337] .

challenged ALI mice, 20 mg/kg chicoric acid obviously attenuated histological changes, lung edema, inflammatory cell infiltration, MPO activity and generation of pro-inflammatory cytokines TNF-α, IL-1β and IL-6. Additionally, this compound suppressed oxidative stress through decreasing ROS and MDA activities as well as increasing SOD and GSH expression.

These effects of 40 mg/kg chicoric acid were comparable with those of 5 mg/kg DEX. The responsible mechanism may be through chicoric acid regulating the MAPK and Nrf2 signaling pathways and NLRP3 inflammasome [338] .

Veratric acid 116 is a hydrophobic phenolic compound widely occurring in many fruits, vegetables and medicinal plants. This compound dose-dependently attenuated lung histopathologic changes, lung edema, inflammatory cell infiltration and pro-inflammatory cytokines expression (TNF-α, IL-6 and IL-1β) in mice with LPS-induced ALI through downregulating the NF-κB signaling pathway. However, these protective effects of 50 mg/kg veratric acid were slightly weaker compared to 5 mg/kg DEX [339] . The effects of punicalagin were induced by its inhibitory effects on the TLR4/NF-κB signaling pathway. These protective effects of 50 mg/kg punicalagin and 5 mg/kg DEX were comparable [341] .

Linn., effectively inhibited lung injury, lung edema, inflammatory cell infiltration and TNF-α expression in LPS-induced ALI rats, which were induced by its inhibitory effects on the NAMPT/NAD-mediated TLR4/NF-κB signaling pathway [342, 343] .

Linn., significantly improved pulmonary histopathologic changes and reduced production of pro-inflammatory cytokines and chemokines TNF, IL-6, MCP-1 and MIP-2. All the protective effects could be abolished by ZM241385 (an antagonist of adenosine A(2A) receptor) [344, 345] . Additionally, as a PPARγ agonist, cannabidiol possesses anti-viral activity and anti-J o u r n a l P r e -p r o o f fibrotic activity. These activities indicate that cannabidiol may be an potential agent against the COVID-19 pandemic [346] .

Apocynin 121, a natural polyphenolic constituent extracted from Nerium indicum Mill., is a NOX inhibitor. This compound remarkably attenuated ALI induced by LPS or acute pancreatitis via its anti-inflammatory properties. During the process, apocynin significantly inhibited production of inflammatory cytokines TNF-α, IL-1β and IL-6. All the effects of apocynin were associated with suppressing NLRP3 inflammasome activation and the TLR4mediated NF-κB signaling pathway [347] .

Linn. This compound dramatically suppressed lung histopathologic changes, lung injury, inflammatory cell infiltration and pro-inflammatory cytokines expression (TNF-α, IL-6 and IL-1β) in mice with LPS-induced ALI. These protective effects of 40 mg/kg gossypol were comparable to those of 0.5 mg/kg DEX. In terms of the underlying mechanism, gossypol markedly inhibited the NF-κB and MAPK signaling pathways [348] .

could prevent lung edema and the inflammatory cytokines production (TNF-α, IL-1β, COX-2, iNOS and NO) in mice stimulated with LPS through inhibiting the TLR4/PI3K/Akt-mediated MAPK and NF-κB signaling pathways. However, protective effects of 5 mg/kg 3,4dihydroxybenzalacetone were slightly weaker than those of 10 mg/kg DEX [349] . Fisch. et Mey., could prevent lung injury, lung edema, inflammatory cell infiltration, proinflammatory cytokines expression (TNF-α, IL-6 and IL-1β) and MDA activity in mice with LPS-induced ALI. In addition, acteoside increased SOD activity. Also, the anti-oxidant activities of 30 mg/kg acteoside were stronger than 2 mg/kg DEX but the anti-inflammatory effects were comparable. Regarding mechanism, acteoside significantly down-regulated the NF-κB signaling pathway [350] . Syringin 125, a major active substance from Acanthopanax senticosus (Rupr. et Maxim.)

Harms, dose-dependently inhibited histopathologic changes, lung edema, MPO activity, MDA content and inflammatory cytokines production (TNF-a, IL-1β and IL-6) by activating the Nrf2 and inhibiting the NF-κB signaling pathway [351] .

Quinonoids are a class of natural compounds with quinone structure. In previous Studies, quinonoids are found to possess strong anti-tumor, anti-cancer activities, anti-bacterial, antiinflammatory and anti-malarial activities [352, 353] . Some compounds are found to have antiinflammatory, anti-oxidant and lung protective effects.

Previous study revealed that chrysophanol significantly attenuated lung pathological changes and lung edema, decreased MPO and MDA activity, reduced pro-inflammatory cytokines production (TNF-α, IL-1β and IL-6) as well as promoted SOD activity, which were demonstrated to be associated with improving PPAR-γ expression and inhibiting the NF-κB signaling pathway in mice with paraquat-induced ALI. Moreover, 20 mg/kg chrysophanol and 2 mg/kg DEX had comparable effects [354] . suppressing the mTOR/HIF-1α/VEGF signaling pathway and inhibiting the NF-κB signaling pathway [355] [356] [357] . Additionally, emodin also protected against acute pancreatitis-induced ALI by decreasing expression of pre-B-cell colony-enhancing factor, promoting alveolar epithelial barrier function, enhancing PMN apoptosis and up-regulating expressions of AQP1 and AQP5 [358, 359] . Moreover, emodin also attenuated cigarette smoke-induced ALI in a mouse model via promoting the Nrf2/HO-1 pathway [360] . Also, proteomic analysis revealed that the protective effect of emodin against SAP-induced ALI might be associated with Lamc2, Serpina1 and Serpinb1 [361] . Previous studies have demonstrated that shikonin possesses anti-cancer, anti-osteoporosis, antiinflammatory and anti-bacterial activities [365] [366] [367] . As regards ALI, shikonin could prevent LPS-or CLP-induced ALI in mice, and effects of shikonin were due to its inhibitory effects on expression of pro-inflammatory cytokine TNF-α, IL-1β, NO, IL-6, COX-2, iNOS, NO and MCP-1. The effects of 4 mg/kg shikonin and 0.5 mg/kg DEX were comparable [368] [369] [370] . In regard to underlying mechanism, shikonin significantly inhibited MD2-TLR4 complex formation and then down-regulated the NF-κB and MAPK signaling pathways [371] .

Additionally, miRNA-140-5p was also involved in the protective effects of shikonin [368] . Juglanin 132, a natural constituent mainly extracted from Juglans mandshurica Maxim., could protect against LPS-triggered ALI in vivo and in vitro via inhibition of fibrosis markers (TGF-β1, α-SMA, collagen type III and collagen type I) and inflammatory cytokine production (TNF-α, IL-1β, IL-18, IL-6, IL-4 and IL-17) through blocking the NF-κB signaling pathway [372] . Due to its anti-inflammatory and anti-fibrosis activities, juglanin could also prevent bleomycin-induced lung injury, which is related to inhibition of the Sting signaling pathway [373] .

Aurantio-obtusin 133, an anthraquinone isolated from seeds of Cassia obtusifolia L., significantly ameliorated lung injury in a mouse model of LPS-induced ALI via the inhibition of lung inflammatory responses, which might be associated with inactivating the MAPK and NF-κB signaling pathways. During the process, 100 mg/kg aurantio-obtusin showed more potential inhibitory effects on inflammatory cell recruitment than 30 mg/kg DEX [374] .

Apart from the natural compounds mentioned above, a number of coumarins, steroidal saponins and other compounds were also found to have anti-ALI activities.

Osthole 134, is a natural coumarin isolated from Peucedanum praeruptorum Dunn, which is a traditional Chinese medicine possessing anti-pyretic and expectorant effects. Osthole could effectively inhibit ALI due its various anti-inflammatory and anti-oxidant activities. Osthole significantly improved lung pathological damage, decreased lung edema as well as reduced pro-inflammatory cytokine production (TNF-α and IL-6) and oxidative stress biomarkers (H2O2, MDA and ·OH) in LPS-, H1N1 virus-, I/R-or T/H-induced ALI models. These protective effects might be related to the inhibition of NF-κB activity [375] , up-regulation of angiotensinconverting enzyme 2 (ACE2) [376, 377] , activation of Nrf2/TRX-1 [378, 379] and inhibition of cAMP/PKA-mediated Akt and ERK activities [380] . Imperatorin 135, also an important compound of Peucedanum praeruptorum Dunn, significantly attenuated ALI induced by zymosan or LPS in mice via inhibiting histological changes, lung edema, MPO activity and production of pro-inflammatory mediators TNF-α, IL-1β, IL-6, COX-2, iNOS, NO and PGE-2. Imperatorin exerted these effects through inhibiting the JAK1/STAT3, NF-κB and MAPK signaling pathways [381, 382] .

Dunn, at 20 mg/kg remarkably attenuated lung histological changes and lung inflammation in mice with LPS-induced ALI as well as reduced inflammatory response in IL-1β-treated A549 cells and LPS-treated MH-S cells [383] .

Isofraxidin 137 is a natural coumarin compound isolated from Morinda officinalis How.

Isofraxidin significantly reduced mortality, lung edema, MPO activity, inflammatory cell infiltration and pro-inflammatory cytokines production (TNF-α, IL-6, PGE2 and COX-2) in LPS-induced ALI mice. However, these protective effects of isofraxidin (15 mg/kg) were slightly weaker than that of DEX (5 mg/kg) [384] . Moreover, isofraxidin also inhibited H1NI1induced lung injury through suppressing the Akt and MAPK signaling pathways [385] . RORγt/IL-17 signaling pathways. Esculetin (40 mg/kg) showed comparable inhibitory effects on lung inflammation to 5 mg/kg DEX but stronger inhibitory effects on RORγt expression [386, 387] Esculin 139, the glucoside of esculetin, has been demonstrated to inhibit lung histopathological changes, lung edema, MPO activity as well as pro-inflammatory cytokines production (TNF-α, IL-1β and IL-6) in mice with LPS-induced ALI, which was associated with inhibiting the TLR/NF-κB signaling pathway. The protective effects of 40 mg/kg esculin were comparable to those of 2 mg/kg DEX [388] . Additional to lungs, esculin also attenuated liver and kidney injury by LPS via inhibition of inflammation [389] .

inhibit LPS-induced ALI in a mouse model. During the process, this compound at 1.5 μg/kg significantly decreased the mortality of ALI mice from 80% to 20% as well as inhibited lung injury and inflammatory cell infiltration, which were stronger than that of 1.5 μg/kg esculin.

Additionally, 3-O-β-d-glycosyl aesculin also reduced ROS generation. All the effects of 3-Oβ-d-glycosyl aesculin were induced by its up-regulation of the Nrf2 signaling pathway [390] .

Asperuloside 141 is a natural iridoid glycoside obtained from Plantago asiatica L., which is a traditional Chinese herbal medicine. This compound at 20 mg/kg remarkably inhibited lung histological alterations, lung edema and MPO activity in a murine model of LPS-induced ALI.

In addition, asperuloside also down-regulated pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) in mice and in RAW264.7 cells stimulated by LPS through inhibiting the MAPK and NF-κB signaling pathways [391] .

in vivo experiments demonstrated that aucubin could increase animal survival rate and attenuate lung pathogenic change in LPS-induced mice. These effects of aucubin were associated with suppressing inflammatory cytokine expression (TNF-α, IL-1β, COX2 and iNOS) and MDA activity as well as increasing SOD and GSH levels. In terms of the underlying mechanism, aucubin remarkedly up-regulated the Nrf2 and down-regulated the AMPK signaling pathway [392] .

Trillin 143 is a natural saponin isolated from Dioscorea opposita Thunb., which is used as medicine and food. Trillin could ameliorate pulmonary histopathologic alteration, lung J o u r n a l P r e -p r o o f edema and MPO activity in a mouse model of LPS-induced ALI via up-regulation of antioxidant markers (SOD, CAT, GSH and GSH-Px) and suppressing production of proinflammatory cytokines TNF-α and IL-6. These protective effects of 100 mg/kg trillin were comparable to those of 2 mg/kg DEX. During the process, trillin significantly promoted the Nrf-2/HO-1 and blocked the NF-κB signaling pathway [393] . [394, 395] . Due to its anti-inflammatory and anti-oxidative activities, dioscin also prevented bleomycin-induced pulmonary damage [396] .

Dioscorea zingiberensis C. H. Wright. Diosgenin effectively inhibited lung histopathologic change, lung edema and NO expression in LPS-induced ALI mice, which were associated with its inhibitory effects on NF-κB and MAPK/p38 signaling pathways. Also, 10 mg/kg diosgenin showed much stronger inhibitory effects on NO expression and NF-κB activity than 50 mg/kg berberine which was used as the positive drug [397] .

Dihydrodiosgenin 146, a spiroacetal ring opened analogue of diosgenin, could protect against acute pancreatitis-associated lung injury. During the process, dihydrodiosgenin significantly prevented tauro-induced lung edema and lung inflammation through protecting J o u r n a l P r e -p r o o f mitochondria and suppressing the PI3Kγ/Akt signaling pathway [398] .

Ruscogenin 147, a natural saponin found in Ophiopogon japonicus (Linn. f.) Ker-Gawl., has been found to decrease lung injury and lung edema through decreasing pro-inflammatory cytokines expression (TNF-α, IL-6, iNOS and NO) and attenuating pulmonary endothelial apoptosis in LPS-induced ALI mice. In addition, ruscogenin also prevented apoptosis of pulmonary endothelial cells. The TLR4/MYD88/NF-κB and Bax/Bcl-2 signaling pathways were involved in the process [399, 400] .

medicine Anemarrhena asphodeloides Bunge. Timosaponin B-II inhibited lung injury, pulmonary edema and inflammatory cytokines production (TNF-a, IL-1β and IL-6), which were associated with inhibiting the TLR/NF-κB signaling pathway. Moreover, these protective effects of 40 mg/kg timosaponin B-II and 2 mg/kg DEX were comparable [401] .

Bunge, could prevent lung injury, inflammatory cell infiltration and inflammatory cytokines production (IL-1β and IL-6), which were induced by its suppression of STAT3 activation.

However, 50 mg/kg timosaponin-AIII had slightly lower inhibitory potency than 30 mg/kg DEX [402] .

Linn. Previous studies revealed that alliin markedly inhibited lung pathological injury, MPO activity, lung edema and pro-inflammatory cytokines production (TNF-α and IL-1β) in mice with LPS-induced ALI by activating PPARγ and subsequently inactivating the NF-κB signaling pathway [403] . Additionally, alliin also prevented I/R-induced pulmonary damage through J o u r n a l P r e -p r o o f promoting autophagy [404] .

S-allylmercaptocysteine 151, a remarkable aqueous soluble sulfur-containing compound found in Allium sativum Linn., also had inhibitory effects on LPS-induced lung damage via inhibition of pro-inflammatory cytokines production (TNF-α, IL-1β, IL-6, COX-2 and iNOS) and up-regulation of anti-oxidant markers (SOD and GSH), which were associated with inhibiting NF-κB activation and up-regulating the Nrf2 signaling pathway. Moreover, sallylmercaptocysteine (60 mg/kg) exerted much more potential inhibitory effects on lung injury, flammatory cells infiltration and inflammatory cytokines production (TNF-α, IL-1β, IL-6 and iNOS) than NAC (500 mg/kg), but comparable effects on SOD and GSH expression [405] .

Diallyl disulfide 152 is an organosulfur compound in Allium sativum Linn. This compound markedly attenuated lung injury and MPO activity. In addition, diallyl disulfide also suppressed ALP, H2S, CSE, PPTA, NK1R and NO levels. These effects were associated with inhibiting the CSE/H2S, SP/NK1R and NF-кB signaling pathways. Also, 200 μg/kg diallyl disulfide had stronger inhibitory effects on NF-кB activity than 40 mg/kg indomethacin [406] . Sulforaphane 153 is a natural compound in many green vegetables, possessing antiinflammatory and anti-oxidative activities. Sulforaphane significantly prevented pulmonary damage induced by LPS through activating the Nrf2-ARE signaling pathway [407] , protected against inhaled arsenic-induced ALI through activating the Nrf2-defense responses [408] , ameliorated hyperoxia-induced ALI through regulating HMGB1 activity [409] as well as prevented chromium-induced pulmonary toxicity in rats through regulating the Nrf2-mediated Akt/GSK-3β/Fyn signaling pathway [410] . Moreover, sulforaphane also inhibited lung injury induced by oleic acid in rabbits through up-regulating the Nrf2 signaling pathway [411] .

Schisantherin A 154, a natural dibenzocyclooctadiene lignan extracted from the fruit of Schisandra sphenanthera Rehd. et Wils., has been reported to reduce lung histopathologic changes, lung edema, MPO activity, inflammatory cell infiltration as well as pro-inflammatory cytokine expression (TNF-α, IL-6 and IL-1β) in mice stimulated by LPS, which were associated with blocking the NF-κB and MAPK signaling pathways. However, 40 mg/kg schisantherin A had slightly weaker anti-inflammatory effects than 5 mg/kg DEX [412] . and A549 cells with IC50 of 6.1 and 2.2 µM, respectively [416] .

Dehydromatricarin A 158, an active compound from Artemisia argyi Lévl. et Van., markedly inhibited lung injury, inflammatory cell infiltration and pro-inflammatory cytokines expression (TNF-α, IL-6 and iNOS) in LPS-induced ALI mice. These effects might be associated with suppressing NF-κB phosphorylation [400, 417] . 

Currently, there is no effective drug in modern medicine that can effectively prevent ALI.

Dexamethasone, ulinastatin, prednisone and prednisolone are used for clinical treatment of acute inflammation or allergy. Because of their favorable anti-inflammatory and immunomodulatory effects, they are commonly used for treatment of ALI. However, the use of these drugs may result in patients with more severe gastrointestinal irritation, allergic reactions and other side effects; therefore, efficacy of these drugs is still unsatisfactory [56, 419] . Many natural compounds are reported to prevent ALI in vivo and in vitro, and so might be potential drugs for ALI. Nowadays, traditional Chinese patent medicines (CPMs) that contain various natural compounds have been used to treat COVID-19 to prevent virus, inflammation and lung J o u r n a l P r e -p r o o f injury. These CPMs such as Tanreqing injection (TRQI), Lianhua Qingwen capsule (LHQWC) and Xuebijing injection (XBJI) have good therapeutic efficacy in COVID-19 treatment [420] .

Baicalin, baicalein, rutin, wogonin, quercetin, luteolin, kaempferol and chlorogenic acid are the main ingredients of TRQI, which is approved by the National Drug Regulatory Authority of China (China SFDA, number: Z20030045) [421] . In previous studies, Xi-juan Qiao et al. found that combined use of TRQI and ribavirin granules was significantly more effective than iibavirin granules alone in treatment of viral pneumonia in children. Additionally, the combination of TRQI and ribavirin granules significantly shortened body temperature recovery time and hospitalization time as well as reduced adverse reactions compared with ribavirin granules alone [422] . Pharmacological research showed that TRQI significantly prevented airway inflammation and lung injury caused by LPS through inhibiting the MAPK/NF-κB pathway [423] . Due to these effects, TRQI is recommended in therapeutic regimens of COVID-19 in China.

Rutin, quercetin, luteolin, kaempferol, chlorogenic acid, hyperoside and emodin are the main ingredients of LHQWC, which is approved by China SFDA (Number: Z20040063) [424] .

During COVID-19, LHQWC was widely and effectively used for the treatment of COVID-19, and the effect of a combination of other drugs (umifenovir, ribavirin, lopinavir/ritonavir) plus LHQWC was superior to single or dual agents [425, 426] . Chun-juan Ye found that the combination of LHQWC and other drugs like ribavirin and cefuroxime resulted in higher total efficiency than other drugs alone (90.63% and 68.75%, respectively) [427] . Pharmacological research revealed that LHQWC could prevent LPS-induced ALI through inhibiting inflammatory responses as well as attenuate PM2.5-induced lung injury through suppressing J o u r n a l P r e -p r o o f pulmonary oxidative lesions via up-regulating Nrf2 signaling pathway [428, 429] .

Hydroxysafflor yellow A, tanshinone IIA, rutin, quercetin, luteolin, kaempferol, chlorogenic acid, hyperoside and protocatechuic acid are important ingredients of XBJI [330] .

In Qin's study, the use of XBJI could improve lung injury in patients with severe or critical COVID-19 [331] . In addition, in 2019, a randomized controlled trial was performed with 710 patients to investigate the efficacy of XBJI on severe community acquired pneumonia in China.

The combination of XBJI and the routine anti-infective treatment could reduce the 28-day mortality of patients with severe pneumonia complicated with sepsis by 8.8%, shorten mechanical ventilation time by 5.5 days as well as shorten the ICU length of stay by 4 days [432] . In addition, a meta-analysis revealed that the combined treatment of XBJI and western medicine showed better efficiency than western medicine treatment alone with significantly decreasing 28-day mortality and shorting ICU stay time [433] . Pharmacological research revealed that XBJI could prevent CLP-, dichlorvos-, paraquat-or I/R-induced ALI through decreasing inflammatory responses and oxidative stress; during the process, p38 MAPK and TLR4-mediated NF-κB signaling pathways were involved [434] [435] [436] [437] .

In this review, pure compounds against ALI/ARDS from 1995-2020 were categorized by the chemical structures, and the pharmacological effects and the underlying mechanism of all the compounds were clarified. The anti-ALI effects of natural compounds were mainly attributed to their anti-inflammatory and anti-oxidant activities. Different kinds of compounds may have similar protective effects and similar targets. Interestingly, during the process, the NF-κB, MAPK and Nrf2 signaling pathways were the pathways most frequently involved. COVID-19 has resulted in demand for therapeutic agents to ameliorate and stop this epidemic. Therefore, this article may provide potential agents to treat the lung injury caused by COVID-19. With the development of science and technology, the pathological pathways of ALI/ARDS have been discovered and specific research is needed to better explain the traditional use of herbal medicines, identify active constituents and explore the underlying mechanisms. Therefore, more studies are needed to substantiate anti-ALI activities of natural compounds. These studies will significantly facilitate research to discover novel drugs from natural products to treat ALI/ARDS induced by various factors, by summarizing the pharmacological effects and presenting their underlying mechanistic functions.

The authors declare that they have no conflict of interest. The molecular mechanisms of ALI. The black arrow refers to the role of promotion, the symbol" " refers to the role of inhibition, the symbol " " refers to down-regulation, and the symbol " " refers to up-regulation. The number represents the corresponding compound. The arrow refers to the role of promotion, the symbol" " refers to the role of inhibition. J o u r n a l P r e -p r o o f 

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Patchouli alcohol protects against lipopolysaccharide-induced acute lung injury in mice

Protective effects of patchouli alcohol isolated from Pogostemon cablin on lipopolysaccharide-induced acute lung injury in mice

Tang, 1,8-cineol attenuates LPS-induced acute pulmonary inflammation in mice

Eucalyptol suppresses matrix metalloproteinase-9 an extracellular signal-regulated kinase-dependent nuclear factor-kappa B pathway to exert anti-inflammatory effects in an acute lung inflammation model

Treatment with eucalyptol mitigates cigarette smoke-induced lung injury through suppressing ICAM-1 gene expression

Zerumbone from Zingiber zerumbet Ameliorates Lipopolysaccharide-Induced ICAM-1 and Cytokines Expression via p38 MAPK/JNK-IkappaB/NF-kappaB Pathway in Mouse Model of Acute Lung Injury

Zerumbone reduced the inflammatory response of acute lung injury in endotoxin-treated mice via Akt-NFkappaB pathway

Protective effect of zerumbone reduces lipopolysaccharide-induced acute lung injury via antioxidative enzymes and Nrf2/HO-1 pathway

Suppression of MAPK and NF-kappaB pathways by limonene contributes to attenuation of lipopolysaccharide-induced inflammatory responses in acute lung injury

Protective effects of thymol on LPS-induced acute lung injury in mice

Preventive and Therapeutic Effects of Thymol in a Lipopolysaccharide-Induced Acute Lung Injury Mice Model

p-Cymene protects mice against lipopolysaccharide-induced acute lung injury by inhibiting inflammatory cell activation

Protective effect of p-cymene on lipopolysaccharideinduced acute lung injury in mice

Anti-inflammatory effects of linalool in RAW 264.7 macrophages and lipopolysaccharide-induced lung injury model

Andrographolide protects against LPS-induced acute lung injury by inactivation of NF-kappaB

Pretreatment with andrographolide pills((R)) attenuates lipopolysaccharide-induced pulmonary microcirculatory disturbance and acute lung injury in rats

3-Dehydroandrographolide protects against lipopolysaccharide-induced inflammation through the cholinergic anti-inflammatory pathway

Costunolide ameliorates lipoteichoic acid-induced acute lung injury via attenuating MAPK signaling pathway

Costunolide alleviates HKSA-induced acute lung injury via inhibition of macrophage activation

Dehydrocostus Lactone Suppresses LPS-induced Acute Lung Injury and Macrophage Activation through NF-kappaB Signaling Pathway Mediated by p38 MAPK and Akt

Ginsenoside Rg3 Attenuates Lipopolysaccharide-Induced Acute Lung Injury via MerTK-Dependent Activation of the PI3K/AKT/mTOR Pathway

Ginsenoside Rg3 ameliorates lipopolysaccharide-induced acute lung injury in mice through inactivating the nuclear factor-kappaB (NF-kappaB) signaling pathway

Ginsenoside Rg5 ameliorates lung inflammation in mice by inhibiting the binding of LPS to toll-like receptor-4 on macrophages

Pseudoginsenoside-F11 Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Suppressing Neutrophil Infiltration and Accelerating Neutrophil Clearance

Betulin protects mice from bacterial pneumonia and acute lung injury

Betulin attenuates lung and liver injuries in sepsis

Effect of betulinic acid on neutrophil recruitment and inflammatory mediator expression in lipopolysaccharide-induced lung inflammation in rats

Betulinic acid attenuates lung injury by modulation of inflammatory cytokine response in experimentally-induced polymicrobial sepsis in mice

Bigelovii A Protects against Lipopolysaccharide-Induced Acute Lung Injury by Blocking NF-kappaB and CCAAT/Enhancer-Binding Protein delta Pathways

Tenuigenin ameliorates acute lung injury by inhibiting NF-kappaB and MAPK signalling pathways

Senegenin Ameliorate Acute Lung Injury Through Reduction of Oxidative Stress and Inhibition of Inflammation in Cecal Ligation and Puncture-Induced Sepsis Rats

Echinocystic acid ameliorates lung inflammation in mice and alveolar macrophages by inhibiting the binding of LPS to TLR4 in NF-kappaB and MAPK J o u r n a l P r e -p r o o f pathways

Protective effect of esculentoside A on lipopolysaccharide-induced acute lung injury in mice

Esculentoside A Attenuates Allergic Airway Inflammation via Activation of the Nrf-2 Pathway

Protective effect of taraxasterol on acute lung injury induced by lipopolysaccharide in mice

Sclareol ameliorate lipopolysaccharide-induced acute lung injury through inhibition of MAPK and induction of HO-1 signaling

Sclareol Protects Staphylococcus aureus-Induced Lung Cell Injury via Inhibiting Alpha-Hemolysin Expression

Triptolide Mitigates Radiation-Induced Pulmonary Fibrosis

N-acetyl cysteine improves the effects of corticosteroids in a mouse model of chlorine-induced acute lung injury

Anti-inflammatory effects of triptolide in LPS-induced acute lung injury in mice

Anti-inflammatory effects of triptolide by inhibiting the NF-kappaB signalling pathway in LPS-induced acute lung injury in a murine model

Effect of triptolide on the regulation of ATPbinding cassette transporter A1 expression in lipopolysaccharideinduced acute lung injury of rats

Acanthoic acid ameliorates lipopolysaccharideinduced acute lung injury

Asiaticoside attenuates lipopolysaccharide-induced acute lung injury via down-regulation of NF-kappaB signaling pathway

Platycodin D attenuates acute lung injury by suppressing apoptosis and inflammation in vivo and in vitro

Platycodin D on Lipopolysaccharide-Induced Acute Lung Injury by Activating LXRalpha-ABCA1

Protective effects and mechanisms of mogroside V on LPS-induced acute lung injury in mice

Stevioside protects LPS-induced acute lung injury in mice

Saikosaponin a Ameliorates LPS-Induced Acute Lung Injury in Mice

Carnosic acid protects against lipopolysaccharide-induced acute lung injury in mice

The protective effect of oleanolic acid on NMDA-induced MLE-12 cells apoptosis and lung injury in mice by activating SIRT1 and reducing NF-kappaB acetylation

Effects of oleanolic acid on pulmonary morphofunctional and biochemical variables in experimental acute lung injury

Bardoxolone treatment alleviates lipopolysaccharide (LPS)-induced acute lung injury through suppressing inflammation and oxidative stress regulated by Nrf2 signaling

An Active Drimane-Type Lactone from Polygonum jucundum Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Mice Through TLR4-MAPKs Signaling Pathway

Isoforskolin pretreatment attenuates lipopolysaccharide-induced acute lung injury in animal models

Bakuchiol Protects Against Acute Lung Injury in Septic Mice

Crocin attenuates lipopolysacchride-induced acute lung injury in mice

Crocin attenuates cigarette smoke-induced lung injury and cardiac dysfunction by anti-oxidative effects: the role of Nrf2 antioxidant system in preventing oxidative stress

Oridonin protects LPS-induced acute lung injury by modulating Nrf2-mediated oxidative stress and Nrf2-independent NLRP3 and NF-kappaB pathways

Oridonin protects the lung against hyperoxia-induced injury in a mouse model

Therapeutic potential of bixin in PM2.5 particles-induced lung injury in an Nrf2-dependent manner

Bixin protects against particle-induced long-term lung injury in an NRF2-dependent manner

Bixin protects mice against ventilation-induced lung injury in an NRF2-dependent manner

Natural Polyphenols for Prevention and Treatment of Cancer

High-cocoa polyphenol-rich chocolate improves blood pressure in patients with diabetes and hypertension

The Two-Way Polyphenols-Microbiota Interactions and Their Effects on Obesity and Related Metabolic Diseases

Polyphenol protection and treatment of hypertension

The Effect of Resveratrol on Neurodegenerative Disorders: Possible Protective Actions Against Autophagy, Apoptosis, Inflammation and Oxidative Stress

Polyphenol-Rich Foods and Osteoporosis

Honokiol rescues sepsis-associated acute lung injury and lethality via the inhibition of oxidative stress and inflammation

Honokiol attenuates lipopolysaccharide-induced acute respiratory distress syndrome via activation of mitochondrion

Honokiol protects pulmonary microvascular endothelial barrier against lipopolysaccharide-induced ARDS partially via the

Sirt3/AMPK signaling axis

Paeonol ameliorates lipopolysaccharides-induced acute lung injury by regulating TLR4/MyD88/ NF-kappaB signaling pathway

Paeonol attenuates acute lung injury by inhibiting HMGB1 in lipopolysaccharide-induced shock rats

The effect of magnolol on the Toll-like receptor 4/nuclear factor kappaB signaling pathway in lipopolysaccharide-induced acute lung injury in mice

Magnolol ameliorates lipopolysaccharide-induced acute lung injury in rats through PPAR-gamma-dependent inhibition of NF-kB activation

Protective effect of magnolol-loaded polyketal microparticles on lipopolysaccharide-induced acute lung injury in rats

Protective effect of magnolol on lipopolysaccharide-induced acute lung injury in mice

Curcumin Suppresses Epithelial Growth Factor Receptor (EGFR) and Proliferative Protein (Ki 67) in Acute Lung Injury and Lung Fibrosis In J o u r n a l P r e -p r o o f vitro and In vivo

Curcumin down-regulates IL-17A mediated p53-fibrinolytic system in bleomycin induced acute lung injury in vivo

Effect of curcumin (Curcuma longa extract) on LPS-induced acute lung injury is mediated by the activation of AMPK

Curcumin Attenuates Pulmonary Inflammation in Lipopolysaccharide Induced Acute Lung Injury in Neonatal Rat Model by Activating Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) Pathway

The effect of curcumin on sepsisinduced acute lung injury in a rat model through the inhibition of the TGF-beta1/SMAD3 pathway

Curcumin regulates the differentiation of naive CD4+T cells and activates IL-10 immune modulation against acute lung injury in mice

Direct pulmonary delivery of solubilized curcumin reduces severity of lethal pneumonia

Zingerone attenuates lipopolysaccharide-induced acute lung injury in mice

Anti-inflammatory effect of octyl gallate in alveolar macrophages cells and mice with acute lung injury

The Protective Effects of Terpinen-4-ol on LPS-Induced Acute Lung Injury via Activating PPAR-gamma

Alleviation of Acute Lung Injury in Rats with Sepsis by Resveratrol via the Phosphatidylinositol 3-Kinase/Nuclear Factor-Erythroid 2 Related Factor 2/Heme Oxygenase-1 (PI3K/Nrf2/HO-1) Pathway

Resveratrol protects mice against SEB-induced acute lung injury and mortality by miR-193a modulation that targets TGF-beta signalling

Resveratrol ameliorates LPS-induced acute lung injury via NLRP3 inflammasome modulation

Resveratrol reduces acute lung injury in a LPSinduced sepsis mouse model via activation of Sirt1

Protective effects of polydatin on lipopolysaccharide-induced acute lung injury through TLR4

3,5,4'-Tri-O-acetylresveratrol attenuates seawater aspiration-induced lung injury by inhibiting activation of nuclear factor-kappa B and hypoxia-inducible factor-1alpha

Jin, 3,5,4'-Tri-O-acetylresveratrol decreases seawater inhalation-induced acute lung injury by interfering with the NF-kappaB and i-NOS pathways

3,5,4'-Tri-O-acetylresveratrol attenuates seawater inhalation-induced acute respiratory distress syndrome via thioredoxin 1 pathway

3,5,4'-tri-Oacetylresveratrol ameliorates seawater exposure-induced lung injury by upregulating connexin 43 expression in lung

Procyanidin B2 protects rats from paraquat-induced acute lung injury by inhibiting NLRP3 inflammasome activation

Procyanidin B2 Suppresses Lipopolysaccharides-Induced Inflammation and Apoptosis in Human Type II Alveolar Epithelial Cells and Lung Fibroblasts

Epigallocatechin-3-gallate ameliorates lipopolysaccharideinduced acute lung injury by suppression of TLR4/NF-kappaB signaling activation

Epigallocatechin Gallate Attenuates Hip Fracture-Induced Acute Lung Injury by Limiting Mitochondrial DNA (mtDNA) Release

Mitochondrial DNA-Induced Inflammatory Responses and Lung Injury in Thermal Injury Rat Model: Protective Effect of Epigallocatechin Gallate

Epigallocatechin-3-gallate suppresses alveolar epithelial cell apoptosis in seawater aspiration-induced acute lung injury via inhibiting STAT1-caspase-3/p21 associated pathway

Epigallocatechin-3-gallate ameliorates seawater aspiration-induced acute lung injury via regulating inflammatory cytokines and inhibiting JAK/STAT1 pathway in rats

Chlorogenic acid protects mice against lipopolysaccharide-induced acute lung injury

Protective effect of chlorogenic acid on the inflammatory damage of pancreas and lung in mice with l-arginine-induced pancreatitis

Oleic acid-induced lung injury in rats and effects of caffeic acid phenethyl ester

Mechanism of acute lung injury due to phosgene exposition and its protection by cafeic acid phenethyl ester in the rat

Discovery of caffeic acid phenethyl ester derivatives as novel myeloid differentiation protein 2 inhibitors for treatment of acute lung injury

Tannic acid protects against experimental acute lung injury through downregulation of TLR4 and MAPK

Ethyl gallate attenuates acute lung injury through Nrf2 signaling

Geraniin attenuates LPS-induced acute lung injury via inhibiting NF-kappaB and activating Nrf2 signaling pathways

Corilagin protects the acute lung injury by ameliorating the apoptosis pathway

Corilagin attenuates aerosol bleomycin-induced experimental lung injury

Effects of a natural prolyl oligopeptidase inhibitor, rosmarinic acid, on lipopolysaccharide-induced acute lung injury in mice

Anti-inflammatory effects of rosmarinic acid-4-O-beta-D-glucoside in reducing acute lung injury in mice infected with influenza virus

Anti-inflammatory effects of ellagic acid on acute lung injury induced by acid in mice

Ellagic acid ameliorates lung damage in rats via modulating antioxidant activities, inhibitory effects on inflammatory mediators and apoptosis-inducing activities

Protective effects of protocatechuic acid on acute lung injury induced by lipopolysaccharide in mice via p38MAPK and NF-kappaB signal pathways

Protocatechuic acid attenuates lipolysaccharide-induced acute lung injury

Suppression of the p66shc adapter protein by protocatechuic acid prevents the development of lung injury induced by intestinal ischemia reperfusion in mice

Ilex kaushue and Its Bioactive Component 3,5-Dicaffeoylquinic Acid Protected Mice from Lipopolysaccharide-Induced Acute Lung Injury

Chicoric acid alleviates lipopolysaccharide-induced acute lung injury in mice through anti-inflammatory and anti-oxidant activities

Protective effect of veratric acid on lipopolysaccharide-induced acute lung injury in mice

Usnic acid protects LPS-induced acute lung injury in mice through attenuating inflammatory responses and oxidative stress

Punicalagin ameliorates lipopolysaccharide-induced acute respiratory distress syndrome in mice

alpha-Mangostin Alleviated Lipopolysaccharide Induced Acute Lung Injury in Rats by Suppressing NAMPT/NAD Controlled Inflammatory Reactions

Activation of cholinergic J o u r n a l P r e -p r o o f anti-inflammatory pathway involved in therapeutic actions of alpha-mangostin on lipopolysaccharide-induced acute lung injury in rats

Cannabidiol, a non-psychotropic plant-derived cannabinoid, decreases inflammation in a murine model of acute lung injury: role for the adenosine A(2A) receptor

Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury

The potential of cannabidiol in the COVID-19 pandemic

Apocynin alleviates lung injury by suppressing NLRP3 inflammasome activation and NF-kappaB signaling in acute pancreatitis

Protective effect of gossypol on lipopolysaccharide-induced acute lung injury in mice

4-dihydroxybenzalacetone attenuates lipopolysaccharide-induced inflammation in acute lung J o u r n a l P r e -p r o o f injury via down-regulation of MMP-2 and MMP-9 activities through suppressing ROS-mediated MAPK and PI3K/AKT signaling pathways

Effects of acteoside on lipopolysaccharide-induced inflammation in acute lung injury via regulation of NF-kappaB pathway in vivo and in vitro

Protective effects of syringin against lipopolysaccharide-induced acute lung injury in mice

In Vitro Antioxidant, Antiinflammation, and Anticancer Activities and Anthraquinone Content from Rumex crispus Root Extract and Fractions

Plumbagin induces the apoptosis of human tongue carcinoma cells through the mitochondria-mediated pathway

Activating Peroxisome Proliferator-Activated Receptors (PPARs): a New Sight for Chrysophanol to Treat Paraquat-Induced Lung Injury

Emodin ameliorates LPS-induced acute lung injury, involving the inactivation of NF-kappaB in mice

Emodin alleviated pulmonary inflammation in rats with LPS-induced acute lung injury through inhibiting the mTOR/HIF-1alpha/VEGF signaling pathway

Emodin reactivated autophagy and alleviated inflammatory lung injury in mice with lethal endotoxemia

Emodin ameliorates acute lung injury induced by severe acute pancreatitis through the up-regulated expressions of AQP1 and AQP5 in lung

Emodin alleviates severe acute pancreatitis-associated acute lung injury by decreasing pre-B-cell colony-enhancing factor expression and promoting polymorphonuclear neutrophil apoptosis

Emodin Attenuates Cigarette Smoke Induced Lung Injury in a Mouse Model via Suppression of Reactive Oxygen Species Production

Proteomic analysis reveals the protective effects of emodin on severe acute pancreatitis induced lung injury by inhibiting neutrophil proteases activity

Rhein Suppresses Lung Inflammatory Injury Induced by Human Respiratory Syncytial Virus Through Inhibiting NLRP3 Inflammasome Activation via NF-kappaB Pathway in Mice

Aloe-emodin Attenuates Staphylococcus aureus Pathogenicity by Interfering With the Oligomerization of alpha-Toxin, Front Cell Infect

Aloin reduces inflammatory gene iNOS via inhibition activity and p-STAT-1 and NF-kappaB

Signaling Pathway Contributes to the Anti-Melanoma Activities of Shikonin

Shikonin ameliorates D-galactose-induced oxidative stress and cognitive impairment in mice via the MAPK and nuclear factor-kappaB signaling pathway

Shikonin Attenuates Hepatic Steatosis by Enhancing Beta Oxidation and Energy Expenditure via AMPK Activation

Shikonin improve sepsis-induced lung injury via regulation of miRNA-140-5p/TLR4-a vitro and vivo study

Shikonin exerts anti-inflammatory effects in a murine model of lipopolysaccharide-induced acute lung injury by inhibiting the nuclear factor-kappaB signaling pathway

Shikonin attenuates lipopolysaccharide-induced acute lung injury in mice

Shikonin inhibits myeloid differentiation protein 2 to prevent LPS-induced acute lung injury

Juglanin suppresses fibrosis and inflammation response caused by LPS in acute lung injury

Juglanin alleviates bleomycininduced lung injury by suppressing inflammation and fibrosis via targeting sting signaling

Aurantio-obtusin, an anthraquinone from cassiae semen, ameliorates lung inflammatory responses

Osthole Protects against Acute Lung Injury by Suppressing NF-kappaB-Dependent Inflammation

Osthole protects lipopolysaccharide-induced acute lung injury in mice by preventing down-regulation of angiotensin-converting enzyme 2

Osthole Alleviates Bleomycin-Induced Pulmonary Fibrosis via Modulating Angiotensin-Converting Enzyme 2/Angiotensin-(1-7) Axis and Decreasing Inflammation Responses in Rats

Osthole improves acute lung injury in mice by up-regulating Nrf-2/thioredoxin 1

Osthole prevents intestinal ischemia-reperfusion-induced lung injury in a rodent model

Osthol attenuates neutrophilic oxidative stress and hemorrhagic shock-induced lung injury via inhibition of phosphodiesterase 4

Preventive effect of Imperatorin on acute lung injury induced by lipopolysaccharide in mice

Anti-inflammatory Property of Imperatorin on Alveolar Macrophages and Inflammatory Lung Injury

Inhibition of airway inflammation by the roots of Angelica decursiva and its constituent, columbianadin

Protective effects of Isofraxidin against lipopolysaccharide-induced acute lung injury in mice

Isofraxidin ameliorated influenza viral inflammation in rodents via inhibiting platelet aggregation

Effects of esculetin on lipopolysaccharide (LPS)-induced acute lung injury via regulation of

CyrillicB pathways in vivo and in vitro

Esculetin Ameliorates Lipopolysaccharide-Induced Acute Lung Injury in Mice Via Modulation of the AKT/ERK/NF-kappaB and RORgammat/IL-17 Pathways

Esculin Inhibits the Inflammation of LPS-Induced Acute Lung Injury in Mice Via Regulation of TLR/NF-kappaB Pathways

Esculin attenuates endotoxin shock induced by lipopolysaccharide in mouse and NO production in vitro through inhibition of NF-kappaB activation

Glycosylation enables aesculin to activate Nrf2

Pretreatment with the compound asperuloside decreases acute lung injury via inhibiting MAPK and NF-kappaB signaling in a murine model

Aucubin protects against lipopolysaccharide-induced acute pulmonary injury through regulating Nrf2 and AMPK pathways

The protective effect of Trillin LPS-induced acute lung injury by the regulations of inflammation and oxidative state

Dioscin prevents LPSinduced acute lung injury through inhibiting the TLR4/MyD88 signaling pathway via upregulation of HSP70

Protective Effects of Dioscin against Lipopolysaccharide-Induced Acute Lung Injury through Inhibition of Oxidative Stress and Inflammation

Dioscin attenuates Bleomycin-Induced acute lung injury via inhibiting the inflammatory response in mice

Diosgenin down-regulates NF-kappaB p65/p50 and p38MAPK pathways and attenuates acute lung injury induced by lipopolysaccharide in mice

Dihydrodiosgenin protects against experimental acute pancreatitis and associated lung injury through mitochondrial protection and PI3Kgamma/Akt inhibition

Ruscogenin alleviates LPS-induced pulmonary endothelial cell apoptosis by suppressing TLR4 signaling

Ruscogenin J o u r n a l P r e -p r o o f inhibits lipopolysaccharide-induced acute lung injury in mice: involvement of tissue factor, inducible NO synthase and nuclear factor (NF)-kappaB

Timosaponin B-II inhibits lipopolysaccharide-induced acute lung toxicity via TLR/NF-kappaB pathway

Therapeutic Potential of the Rhizomes of Anemarrhena asphodeloides and Timosaponin A-III in an Animal Model of Lipopolysaccharide-Induced Lung Inflammation

Effects of alliin on LPS-induced acute lung injury by activating PPARgamma

Alliin alleviates myocardial ischemia-reperfusion injury by promoting autophagy

S-allylmercaptocysteine ameliorates lipopolysaccharide-induced acute lung injury in mice by inhibiting inflammation and oxidative stress via nuclear factor kappa B and Keap1/Nrf2 pathways

Protective effect of diallyl disulfide against ceruleininduced acute pancreatitis and associated lung injury in mice

Sulforaphane exerts anti-inflammatory effects against lipopolysaccharide-induced acute lung injury in mice through the Nrf2/ARE pathway

Sulforaphane prevents pulmonary damage in response to inhaled arsenic by activating the Nrf2-defense response

Dietary Antioxidants Significantly Attenuate Hyperoxia-Induced Acute Inflammatory Lung Injury by Enhancing Macrophage Function via Reducing the Accumulation of Airway HMGB1

Sulforaphane prevents chromium-induced lung injury in rats via activation of the Akt/GSK-3beta/Fyn pathway

Protective mechanism of sulforaphane in Nrf2 and antilung injury in ARDS rabbits

Schisantherin A protects lipopolysaccharide-induced acute respiratory distress syndrome in mice through inhibiting NF-kappaB and MAPKs signaling pathways

Phillyrin attenuates LPS-induced pulmonary inflammation via suppression of MAPK and NF-kappaB activation in acute lung injury mice

Protective effects of phillyrin against influenza A virus in vivo

Smiglaside A ameliorates LPS-induced acute lung injury by modulating macrophage polarization via AMPK-PPARgamma pathway

Protective anti-inflammatory activity of tovophyllin A against acute lung injury and its potential cytotoxicity to epithelial lung and breast carcinomas

Artemisia argyi attenuates airway inflammation in lipopolysaccharide induced acute lung injury model

Therapeutic effect of methyl salicylate 2-O-beta-d-lactoside on LPS-induced acute lung injury by inhibiting TAK1/NF-kappaB phosphorylation and NLRP3 expression

Rationale and design of a prospective, multicentre, randomised, conventional treatment-controlled, parallel-group trial to evaluate the efficacy and safety of ulinastatin in preventing acute respiratory distress syndrome in high-risk patients

Chinese Patent Medicines in the Treatment of Coronavirus Disease 2019 (COVID-19) in China

Simultaneous quantitation J o u r n a l P r e -p r o o f of 23 bioactive compounds in Tanreqing capsule by high-performance liquid chromatography electrospray ionization tandem mass spectrometry

Clinical study on Tanreqing Injection combined with ribavirin in treatment of viral pneumonia in children

Tanreqing Injection Attenuates Lipopolysaccharide-Induced Airway Inflammation through MAPK/NF-kappaB Signaling Pathways in Rats Model

A network analysis of the Chinese medicine Lianhua-Qingwen formula to identify its main effective components

Efficacy and Safety of Integrated Traditional Chinese and Western Medicine for Corona Virus Disease 2019 (COVID-19): a systematic review and meta-analysis

Effect of combination antiviral therapy on hematological profiles in 151 adults hospitalized with severe coronavirus disease

Clinical Study of Lianhua Qingwen Capsule in Treatment of Influenza Combined with Bronchial Pneumonia

Effects of Lianhua Qingwen on Pulmonary Oxidative Lesions Induced by Fine Particulates (PM2.5) in Rats

Efficacy and mechanism of Lianhua Qingwen Capsules(LHQW) on chemotaxis of macrophages in acute lung injury (ALI) animal model

The Current Evidence for the Treatment of Sepsis with Xuebijing Injection: Bioactive Constituents, Findings of Clinical Studies and Potential Mechanisms

The study on the treatment of Xuebijing injection (XBJ) in adults with severe or critical Corona Virus Disease 2019 and the inhibitory effect of XBJ against SARS-CoV-2

XueBiJing Injection Versus Placebo for Critically Ill Patients With Severe Community-Acquired Pneumonia: A Randomized Controlled Trial

Could Xuebijing Injection Reduce the Mortality of Severe Pneumonia Patients? A Systematic Review and Meta-Analysis

Xuebijing Ameliorates Sepsis-Induced Lung Injury by Downregulating HMGB1 and RAGE Expressions in Mice

Protective effect of Xuebijing injection on paraquat-induced pulmonary injury via down-regulating the expression of p38 MAPK in rats

Protective effect of Xuebijing injection against acute lung injury induced by left ventricular ischemia/reperfusion in rabbits

Xuebijing injection induces antiinflammatory-like effects and downregulates the expression of TLR4 and NF-kappaB in lung injury caused by dichlorvos poisoning

LPS (2.5 mg/kg) RAW 264.7 (1.25 μg/mL) None Suppression of TLR4-mediated MAPK and NF-κB signaling pathways

MPO↓ TNF-α↓ IL1-β↓ IL-6↓ Inhibition of NF-κB signaling pathway 201

Betanin 48

mg/kg) MPO↓ TNF-α↓ IL1-β↓ MDA↓ SOD↑ IL-10↑ Inhibition of NF-B activity 202

Cordycepin 49

LPS (30 mg/kg) MPO↓ TNF-α↓ IL1-β↓ iNOS↓ NO↓ MDA↓ LDH↓ IL-10↑ Inhibition of NF-κB activation

LPS (20 mg/kg)

TNF-α↓ IL1-β↓ IL-6↓ COX-2↓ iNOS↓ MCP-1↓ IL-13↓ CCL-5↓ Inhibition of NF-κB and MAPK signaling pathways

SEB (100 mg/kg) T cells (25 μM) None Down-regulation of miR-222 and -494 expression Up-regulation of p27kip1

LPS (25 mg/kg) MPO↓ TNF-α↓ IL-1β↓ IL-6↓

COX-2↓ iNOS↓ Inhibition of NF-κB signaling pathway 261

Saikosaponin A 81 LPS (10 mg/kg) MPO↓TNF-α↓ IL-1β↓ Inhibition of NF-κB and NLRP3

mg/kg) MPO↓ TNF-α↓ IL-1β↓ IL-6↓ Inhibition of NF-κB signaling pathway 263

Oleanolic acid 83

mg/kg)

MPO↓ TNF-α↓ IL-1β↓ IL-6↓

Up-regulation of SIRT1 Reduction of NF-κB p65 acetylation

MPO↓ TNF-α↓ IL-1β↓ IL-6↓

2↓ iNOS↓ HMGB1↓ IL-4↑ IL-10↑ Inhibition of Nrf2-dependent NF-κB and MAPKs signaling pathways

TNF-α↓ iNOS↓ NO↓ Inhibition of TLR4-MAPKs signaling

LPS (100 mg/kg) MPO↓ TNF-α↓ IL-1β↓ IL-6↓ SOD↑ cAMP↑ IL-8↓ PGE-1↑

CLP (60 mg/kg) MPO↓ TNF-α↓ IL-1β↓ IL-6↓

MDA↓ SOD↑ ICAM-1↓ HMGB1↓ Claudin-1↑ VE

MPO↓ TNF-α↓ IL-1β↓ IL-6↓

mg/kg)

MPO↓ TNF-α↓ IL-1β↓ IL-6↓

Regulation of TLR4/MyD88/NF-κB axis Activation of Akt/Nrf2 and MAPK/Nrf2

TGF-β↓ MMP9↑ ROS↓ Activation of Nrf2 signaling pathway

Syringin 125

LPS (25 mg/kg) MPO↓ TNF-α↓ IL-1β↓ IL-6↓

This work was supported by the National Natural Science Foundation of China