cord-000137-idffrnac	2009	The study further found that the induction of the negative regulators of TLR signaling IL-1R-associated kinase-M, Toll-interacting protein and A20 by intratracheal LPS in vivo and in macrophages in vitro was significantly reduced in CD44 -/mice. Thus, the study demonstrates a novel mechanism underlying HS-augmented lung inflammation, namely that induction of increased TLR2 surface expression in lung endothelial cells, which is induced by HS/R and mediated by HMGB1 activation of TLR4 signaling, is an important mechanism responsible for EC-mediated inflammation and organ injury following HS (122) . These results provide evidence for direct activation of the NLRP3 inflammasome by biglycan and suggest a fundamental paradigm of how tissue stress and injury are monitored by innate immune receptors detecting the release of the extracellular matrix components and turning such a signal into a robust inflammatory response (147) .
cord-000492-ec5qzurk	2011	Plasmid transfer (closed Easily produced at low cost No specifi c cell targeting Electroporation-mediated gene transfer of the dsDNA circles) Very ineffi cient Na + ,K + -ATPase rescues endotoxin-induced lung injury [60] Nonviral DNA complexes Complexes protect DNA Less effi cient than viral vectors Cationic lipid-mediated transfer of the Na + ,K + -(lipoplexes or polyplexes) Modifying transgene DNA to eliminate bacterial motifs [75, 76] Development of high-effi ciency tissue-specifi c promoters [77] [78] [79] [80] Development of promoters that regulate gene expression [83] Enhanced therapeutic targeting Nebulization technologies [9] Strategies to target the pulmonary endothelium [10] Improved cellular uptake of vector Surface active agents to enhance vector spread [84] Reduce ubiquitination of viral capsid proteins [85] Better therapeutic targets Enhancement or restoration of lung epithelial and/or endothelial cell function [86] Strengthening lung defense mechanisms against injury [87] Speeding clearance of infl ammation and infection Enhancement of the repair process following ALI/ARDS [88] .
cord-000812-mu5u5bvj	2012	Based on clinical bedside observations and published reports [4, 5, 8] , we hypothesize that ALI/ARDS secondary to pandemic influenza is associated with similar ICU outcomes but increased resource utilization and higher hospital charges due to the frequent need for rescue interventions and prolonged ventilatory assistance. A Research Electronic Data Capture (REDCap) database was constructed with a complete listing of the patient''s demographic and clinical information, including age, gender, height, weight, body mass index (BMI), presenting symptoms, past medical history, primary reason for admission to the ICU, vital signs, presence of vasopressors, laboratory values, ventilator settings and respiratory parameters, Acute Physiology and Chronic Health Evaluation (APACHE) III and Sequential Organ Failure Assessment (SOFA) scores on admission to the MICU, number of intubated days, duration of ICU and hospital stay, mortality, and rescue therapies (namely inhaled nitric oxide, proning, high-frequency oscillatory ventilation, and extracorporeal membrane oxygenation [ECMO]) [22] .
cord-001020-2iwsx727	2013	Herein, we discuss the advantages and potential limitations of using adipose-derived stem cells as therapeutics for human acute lung injury. A strength of the paper is its novel focus on ASCs as a therapy for ALI, and its approach to test ASCs therapeutically (rather than prophylactically) in an ALI model Abstract Acute lung injury is characterized by intense neutrophilic lung infl ammation and increased alveolar-capillary barrier permeability leading to severe hypoxemia, and is associated with high mortality despite improvements in supportive care. Zhang and colleagues tested the effi cacy of adipose-derived stem cells in acute lung injury in mice. While the LPS model studied by Zhang and coworkers induces robust neutrophilic lung infl ammation, it causes only modest alveolar-capillary barrier injury, which is a hallmark of ALI/ARDS. Comparison of the therapeutic eff ects of human and mouse adipose-derived stem cells in a murine model of lipopolysaccharide-induced acute lung injury
cord-001473-aki28lhp	2014	The knockdown of airway epithelial cell-derived hepcidin aggravated the polymicrobial sepsis-induced lung injury and pulmonary bacterial infection and increased mortality (53.33% in Ad-shHepc1-treated mice versus 12.5% in Ad-shNeg-treated mice, P <0.05). The severe lung injury in the airway epithelial cell-derived hepcidin knockdown mice is at least partially related to the altered intracellular iron level and function of alveolar macrophages. These results demonstrated that in the current study the intratracheal administration of Ad-shHepc1 only silenced the hepcidin gene transcription in AECs, which was in accordance with previous studies that adenovirus-mediated intratracheal gene delivery specifically inhibited targeted gene expression in lung epithelial cells but not in alveolar macrophages and other organs [29, 30] . The current study explored the role of AEC-derived hepcidin in polymicrobial sepsis-induced ALI, which is at least partially related to the altered intracellular iron level and function of alveolar macrophages.
cord-001945-ueccexxc	2016	All these findings indicate Fig. 1 Schematic illustration of the exogenous and endogenous stem/progenitor cells as well as the regular delivery routes in the repair and regeneration in acute lung injury that the bone marrow-derived stem/progenitor cells exhibit the mobilizing courses, and play a substantial role in the regression of excessive inflammatory responses and repair in injured lungs. Concerning the protective roles of bone marrow-and peripheral blood-derived EPCs in ALI, recent studies showed that their peripheral infusion could lead to homing in injured lung tissues [24] , relieving the inflammatory injury [25, 26] and promote the endothelial repair and recovery of immune function dissonance [26, 27] , which may be enhanced by the treatment of simvastatin [28] .
cord-002329-7s0ytfed	2016	CONCLUSIONS: AEC2s are damage resistant during acute lung injury and the HGF/c-Met signaling pathway is of vital importance in the proliferation of AEC2s after ALI. Using a microfluidic magnetic activated cell sorting system, our previous study has isolated mouse lung multipotent stem cells (MLSCs) which play an important role in bronchiolar and alveolar epithelial cells injury repair [8] . The rat whole lung cell suspensions were incubated with FITC conjugated to anti-proSPC antibody, the percentage of AEC2s was analyzed by flow cytometry analysis (Fig. 1e) , in sham-operated mice, there were no differences in numbers of AEC2s at various time points. It can significantly accelerate AEC2 cell cycle in vitro, indicating that the proliferation of AEC2 after acute lung injury may be induced by the elevated HGF. HGF/c-Met signaling is likely a major factor responsible for the pulmonary epithelial cell proliferation after acute lung injury.
cord-005812-hx6lkuj0	2007	To complement that report this review focuses on how intact organ and animal models and clinical studies have facilitated our understanding of alveolar edema fluid clearance in acute lung injury and acute respiratory distress syndrome. Given the established importance of the type II cell in AFC [6] and the emerging importance of the type I cell in AFC with the recent discovery that type I cells also contain functional sodium and chloride channels [12] , this epithelial damage Fig. 1 Factors that cause impaired alveolar fluid clearance in ALI/ARDS that have been investigated in animal and organ models and in clinical studies. This idea was further supported by the observations that adenovirus-mediated transfer of β-adrenergic receptor genes to live rats improved AFC due to increased sensitivity to endogenous catecholamines and consequent upregulation of Na,K-ATPase activity and ENaC protein expression the lung [73] .
cord-005832-p1joajvn	2013	The purpose of this study was to evaluate the effect of gossypol on acute lung injury (ALI) induced by lipopolysaccharide (LPS) in mice. Additionally, gossypol reduced the inflammatory cells in BALF, decreased the wet/dry ratio of lungs and inhibited the phosphorylation of IκB-α, p65 NF-κB, p46–p54 JNK, p42–p44 ERK, and p38 caused by LPS. CONCLUSION: The data suggest that anti-inflammatory effects of gossypol against the LPS-induced ALI may be due to its ability of inhibition of the NF-κB and MAPKs signaling pathways. The results showed that pretreatment with gossypol attenuated lung damage induced by LPS and decreased the W/D ratio, proinflammatory cytokine production, inflammatory cell migration into the lung, protein leakage, the activation of NF-jB and MAPK. In conclusion, the present study demonstrated that gossypol has a protective effect against LPS-induced ALI, which may be related to its suppression of NF-jB and MAPKs activation, and subsequently leads to the reduction the inflammatory cell infiltration and proinflammatory cytokine expression in lung tissues.
cord-005980-e2s0racp	2019	Twenty-four hours later, lung bronchoalveolar lavage fluid (BALF) was acquired to analyse cells and protein, arterial blood was collected for arterial blood gas analysis and the determination of pro-inflammatory factor levels, and lung issues were collected for histologic examination, transmission electron microscopy (TEM), TUNEL staining, wet/dry (W/D) weight ratio analysis, myeloperoxidase (MPO) activity analysis and blot analysis of protein expression. RESULTS: We found that TIPE2 overexpression markedly mitigated LPS-induced lung injury, which was evaluated by the deterioration of histopathology, histologic scores, the W/D weight ratio, and total protein expression in the BALF. CONCLUSIONS: Our study shows that the increased expression of AAV-mediated TIPE2 in the lungs of mice inhibits acute inflammation and apoptosis and suppresses the activation of NF-κB and JNK in a murine model of ALI. Compared with those in the control group, the PMN/total cell ratio in the BALF (Fig. 4c) and lung MPO activity (Fig. 4d) in LPS-challenged mice were dramatically increased, and these levels were inhibited by AAV-TIPE2 treatment.
cord-006507-amo8e81h	2013	This study investigated whether HMGB1 was involved as a stimulating factor, and whether its downstream Toll-like receptor 4 (TLR4), p38 mitogen-activated protein kinase (p38MAPK), and activator protein-1 (AP-1) signaling pathways act as mediators in the development of liver I/R injury-induced ALI. To study the role of TLR4 and its downstream p38MAPK and AP-1 signaling pathways in the pathogenesis of liver I/R injury-induced ALI, TLR4-small hairpin RNA (shRNA) lentivirus were used to inhibit TLR4 expression in rat lung tissue. As is shown in Figure 3b , relative levels of HMGB1 mRNA in the lung tissue from I/R, shNT þ I/R, and shTLR4 þ I/R groups increased significantly at 18 h after liver I/R injury when compared to the control group, respectively. TLR4-mediated ALI after liver I/R injury Z Yang et al Figure 3 Expression of high-mobility group box protein 1 (HMGB1) in serum and lung tissue from rats at 18 h after liver ischemia/reperfusion (I/R) injury or sham operation.
cord-006573-mwtqxwbw	2018	title: SOCS-1 Suppresses Inflammation Through Inhibition of NALP3 Inflammasome Formation in Smoke Inhalation-Induced Acute Lung Injury Similar to oxidized ATP, high protein level of SOCS-1 dampened the formation of NALP3 inflammasome and the activation of caspase-1 and IL-1β induced by smoke exposure in mouse alveolar macrophages. In conclusion, SOCS-1 relieves smoke inhalation-induced pulmonary inflammation and injury by inhibiting NALP3 inflammasome formation. To test whether SOCS-1 exerts anti-inflammatory effect through inhibition of NALP3 inflammasome formation and consequent activation of caspase-1 and IL-1β, Ad-GFP, or Ad-SOCS-1-adminstered mice were exposed to smoke for 15 min and euthanized 1 day later to collect alveolar macrophages. Alveolar macrophages were isolated from C57BL/6 mice, treated with or without oxATP, exposed to smoke for 30 min, and then analyzed for a ATP release, b extracellular, and c intracellular K + levels, d expression of inflammasome components NALP3, ASC, and caspase-1, and e the complex formed by NALP3 and ASC.
cord-006605-tsk3pakb	2006	The hypothesis that the expression of protease-activated receptors (PARs) protein is regulated at the level of transcription and that PAR isoforms, PAR-1, PAR-2, PAR-3, and PAR-4, in lung tissue show different patterns of expression in lipopolysaccharide (LPS)-induced acute lung injury (ALI) was tested. LPS administration induced significant increases in the expression of PAR isoforms (protein) at the level of transcription in ALI. We conclude that LPS induces increase in protein expression of PAR isoforms at the level of transcription in rats with ALI. Here, we also found that LPS induces increases in the protein expression of PARs isoforms 1 to 4 in the lung of rats. While our previous study demonstrated the immunolocalization of PAR-1 in these cells and tissues in LPS-treated rabbits, the present study showed strong immunoreactivities for all isoforms of PARs in the endothelium, alveolar epithelium, and lung macrophages using a rat model of ALI [10] .
cord-006778-qnxyhmw5	2017	Results showed that downregulation of PALM3 improved the survival rate, attenuated lung pathological changes, alleviated pulmonary edema, lung vascular leakage and neutrophil infiltration, inhibited the production of proinflammatory cytokines and activation of nuclear factor κB and interferon β regulatory factor 3, and promoted the secretion of anti-inflammatory cytokine interleukin-10 and expression of suppressor of cytokine signaling-3 in the ALI rat model. Adult Wistar rats (n = 6 per group) were treated as described in the BMaterials and Methods^section BEstablishment of ALI Rat Model and Experimental Design.^At 24 h after LPS challenge, the right lungs were harvested and stored in liquid nitrogen for the analysis of NF-κB phospho-p65, phospho-IRF3, TLR4, MyD88, TRIF, suppressor of cytokine signaling 3 (SOCS3) protein levels and coimmunoprecipitation assay, and the left lungs were harvested for the analysis of lung wet/dry weight ratio.
cord-007858-1ijxilpb	2005	Furthermore, pretreatment with oxymatrine significantly alleviated oleic acid-induced lung injury accompanied by reduction of lung index and wet-to-dry weight ratio, decreases in serum TNF-α level and inhibition of phosphorylated p38 MAPK. These findings suggest that oxymatrine has a beneficial effect on acute lung injury induced by oleic acid in mice and may inhibit the production of proinflammatory cytokine, TNF-α, by means of the inhibition of p38 MAPK. Light microscopic findings in the lung at 6 h after oleic acid injection demonstrated a marked lung injury resembling those seen in lung of patients with ALI/ARDS, represented by prominent atelectasis, intraalveolar and interstitial patchy hemorrhage, edema, thickened alveolar septum, formation of hyaline membranes and the existence of inflammatory cells in alveolar spaces (Fig. 1A) , which were not observed in the control group (Fig. 1B) . Effect of oxymatrine on serum TNF-␣ level in mice with lung injury induced by oleic acid.
cord-010983-2bzllo0n	2020	MRP8 CRE Arntl fl/fl mice, which have a neutrophil-specific deletion of Arntl (which encodes Bmal1, referred hereafter as Bmal1 ΔN ) showed no circadian differences in MPO + granule content between ZT5 and ZT13 (Extended Data Fig. 4a ) and NET formation (Extended Data Fig. 4b ) in blood Ly6G + neutrophils compared to neutrophils from wild-type controls, suggesting that Bmal1 controlled the changes in the neutrophil proteome. Proteome analysis in Ly6G + neutrophils purified at ZT5 (day) or ZT13 (night) from the blood of Bmal1 ΔN mice (Extended Data Fig. 4c and Supplementary Table 5) indicated that Bmal1 ΔN neutrophils did not show circadian changes in granule proteins or in NET-associated proteins (Extended Data Fig. 4d,e) . We measured neutrophil counts in blood and performed proteomic analysis, granule content and NET-formation assays in neutrophils isolated at 8:00, 14:00 and 17:00 (Extended Data Fig. 9a ), when diurnal patterns in neutrophil number and phenotype are prominent in humans 12 , from ten healthy volunteers.
cord-012045-1cqqj84n	2020	IL-1R8/Sigirr [40] Suppresses lung inflammation [40] PTEN [41] Regulates cell apoptosis [41] MCL1 [42] Regulates transformation of fibroblasts [42] STAT1 [55] Regulates IFN Signaling [55] STING [56] Negatively regulates antiviral responses [56] USP-14 I-kB [31] Increases cytokine release [31] CBP [32] Lung inflammation [32] USP-15 IκBα [57] NF-κB activation [57] USP-17 HDAC2 [58] Reverses glucocorticoid resistance [58] TRAF2/TRAF3 [59] Lung inflammation [59] [92] Inhibits type I IFN signaling and antiviral response [92] POH1 pro-IL-1β [93] Negatively regulates the immune response [93] BRCC3 NLRP3 [94] Promotes the inflammasome activation [94] STAMBP NALP7 [95] Reduces pro-inflammatory stress [95] Alveolar residential macrophages are central to the development of the inflammatory response by recruiting neutrophils and circulating macrophages to the site of injury, their functions are modulated by deubiquitinating enzymes [96, 97] .
cord-014996-p6q0f37c	2009	Data recorded on admission were the patient demographics with, acute physiology and chronic health evaluation II score (APACHE II), and type of admission; during intensive care stay, sepsis-related organ failure assessment score (SOFA) and clinical concomitant factors and conditions. For each severe septic patient the following data was registered: time delay, APACHE II and SOFA scores at ICU admission, diagnosis, the rate of compliance with the resucitation and management bundles, microbiological data, evolution of levels of serum lactate, empiric antibiotic therapy, length of stay and mortality in ICU. Sepsis and septic shock remain the most important causes of acute kidney injury (AKI) in critically ill patients and account for more than 50% of cases of acute renal failure (ARF) in intensive care units (ICU). There were no significant differences between the demographic data (sex, age) or the data on admission to intensive care (APACHE II score, ratio of medical to surgical patients) and duration of mechanical ventilation between the two groups.
cord-015384-bz7ui5a0	2008	From a perspective of C/L psychiatry persisting cognitive dysfunctions, anxiety and mood disorders, posttraumatic stress disorders (PTSD) in their negative impact on healthIn the etiopathogenesis of PTSD associated with ALI/ ARDS, many influences have to be discussed, e.g., increases in CO 2 triggering panic affects, a mismatch of norepinephric overstimulation and cortisol insufficiency, negative effects of high doses of benzodiazepines resulting in oversedation, prolonged phases of weaning and more frequent states of delirium. Social support during intensive care unit stay might improve mental impairment and consequently health-related quality of life in survivors of severe acute respiratory distress syndrome Risk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: A prospective cohort study Post-traumatic stress disorder and posttraumatic stress symptoms following critical illness in medical intensive care unit patients: Assessing the magnitude of the problem Health-related quality of life and posttrauamtic stress disorder in survivors of the acute respiratory distress syndrome
cord-016142-7j5cdt1b	2010	In this chapter, we will (1) address the role of cytoskeletal rearrangement in mechanistic regulation of pulmonary vascular barrier function and permeability, (2) define current strategies designed to enhance the integrity of the lung vascular endothelium, and (3) identify vascular biomarkers and potential prognostic determinants of acute inflammation. Phosphorylation of the substrate myosin light chain (MLC) by nmMLCK is central to paracellular gap formation and increased permeability by many edemagenic agents, including thrombin [18] and vascular endothelial growth factor (VEGF) [19] , both in vitro and in preclinical models of inflammatory lung injury. Protein kinase C (PKC)-mediated pathways exert a prominent effect on barrier regulation in a time-and speciesspecific manner without significantly increasing MLC phosphorylation and without inducing formation of actin stress fibers, but with alterations in other components of the endothelial cytoskeleton [18, 83, 84] .
cord-017107-sg8n12hs	2008	A recently completed, retrospective, community cohort study in Olmsted County, Minnesota included patients treated with NIV and found an even higher incidence of ALI, 156 per 100,000 person-years (personal communication, Rodrigo Cartin -Ceba), Mortality from ALI varies greatly depending upon the age of the patient, underlying chronic illnesses, ALI risk factors, and non-pulmonary organ dysfunctions [15] . In an international cohort study [4] , acute exacerbation of COPD was a principal indication for initiating mechanical ventilation in 13 % of patients with acute respiratory failure. The majority of patients with interstitial lung disease and acute respiratory failure admitted to the ICU require invasive mechanical ventilation . In a retrospective review [39] of 75 patients with interstitial lung disease who were mechanically ventilated at Mayo Clinic from 2003 to 2005, acute respiratory failure was the most common cause of ICU admiss ion (77 %), followed by sepsis (11 %) and cardiopulmonary arrest (4 %).
cord-017217-zjab7o2o	2008	A 47-year-old patient with Crohn''s disease presents for evaluation of new onset arthritis. Although the patient has not had prior thromboses she is at high risk for developing antiphospholipid antibody syndrome in view of these blood tests. A 19-year-old previously healthy student is evaluated for new onset fever, joint pain, and rash. Her lab work reveals leukocytosis with lymphocytic predominance, normal renal function, mild transaminitis, and low serum albumin. Yousaf Ali, Self Assessment Questions in Rheumatology, DOI: 10.1007/ 978-1-59745-497-1, Humana Press, a part of Springer Science + Business Media, LLC 2009 A 55-year-old female with chronic renal failure is seen for evaluation of lower extremity edema and ankle pain. This 41-year-old patient presents with a 4-year history of recurrent sinusitis in the setting of a positive P-ANCA, destructive nasopharyngeal mass, and ophthalmoplegia.The differential diagnosis includes infection with a refractory organism, such as mucormycosis or tuberculosis, malignancy, midline granuloma, or vasculitis.
cord-017853-mgsuwft0	2010	In this chapter, we utilize a systems biology approach combining cellular signaling pathway analysis with population-based association studies to review established and suspected candidate genes that contribute to dysfunction of endothelial cell barrier integrity and ALI susceptibility. Genes encoding proinflammatory cytokines, growth factors and mediators, receptors for barrier-regulatory agonists, and mechanical-stress-sensitive genes expressed in endothelium which regulate inflammatory responses also serve as attractive ALI candidate genes and are representative of the diverse but fertile areas of exploration for candidate SNPs affecting ALI susceptibility and severity. Interrogating the prospective pathways involved in endothelial permeability and correlation with these differentially expressed genes in VALI models identified the most putative ALI genes such as myosin light chain kinase (MYLK), sphingosine 1-phosphate receptor 1, cMet, and vascular endothelial growth factor (VEGF) mechanical stress [37, 38] . Role of macrophage migration inhibitory factor (MIF) in human and animal models of acute lung injury (ALI) and sepsis: association of a promoter polymorphism and increased gene expression
cord-023890-z346hh2c	2015	However, at present, the issue of lipid therapy in ALI/ARDS is still controversial due, at least in part, to inconclusive or contradicting results in several recent clinical trials using n-3 PUFAs. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are inflammatory diseases whose clinical severity depends on the grade of inflammatory response. The first RCT showed the ability of an enteral formula with a high n-3/n-6 PUFA ratio (1:1) to reduce pulmonary inflammation and improve clinical outcomes, i.e., better oxygenation, shorter requirement for mechanical ventilation, shorter ICU-LOS, and less incidence of new organ failure; however, no difference in mortality was observed in ARDS patients (Gadek et al. The first RCT analyzed the effect of an enteral n-3 PUFA-enriched diet in septic patients with ALI or ARDS showing that the administration of the study formula, compared to a control formula with less lipids than in the previous three studies, was associated to a shorter ICU-LOS but not to an improvement in gas exchange or in a lower incidence of novel organ failures (Grau-Carmona et al.
cord-023928-9a1w174h	2011	authors: Thomas, Neal J.; Dahmer, Mary K.; Quasney, Michael W. Examples of the infl uence of genetic variations in proteins involved in recognition of pathogens on the severity of infections include polymorphisms in the genes coding for mannose binding Individual variability in the susceptibility to and outcome from critical care diseases has long been observed, and advances in genomic medicine now gives an opportunity to understand these differences.
cord-029488-l11ufs6k	2020	Expression levels of VEGF were significantly reduced in lung tissues from mice with both intranasal LPS administration and cecal ligation and puncture (CLP)-induced sepsis, which may stem from decreases in non-endothelial cells-dependent VEGF production in the lungs. In support of this assumption, stimulation with LPS and interferon-γ (IFN-γ) significantly increased VEGF in human pulmonary microvascular endothelial cells (HPMECs) at mRNA and protein levels. Taken together, our results indicate that VEGF can contribute to the development of non-cardiogenic lung edema in sepsis-associated ALI due to increased VEGF secretion from pulmonary vascular endothelial cells through multiple MAPK-dependent pathways. We thus examined whether expression of VEGF in human pulmonary microvascular endothelial cells is regulated by MAPKs. When HPMEC-ST1.6R cells were treated with PD98059, an inhibitor of MAPK kinase which is an ERK1/2 upstream activator, or SB203580, which is widely used as a specific inhibitor of p38 MAPK, the LPS/IFN-γinduced increase in VEGF protein levels was strongly blocked (Fig. 4b) .
cord-102958-q8jamg07	2020	We ablated cardiopulmonary spinal afferents through either epidural T1-T4 dorsal root ganglia (DRG) application or intra-stellate ganglia delivery of a selective afferent neurotoxin, resiniferatoxin (RTX) in rats 3 days post bleomycin-induced lung injury. Our data showed that both epidural and intra-stellate ganglia injection of RTX significantly reduced plasma extravasation and reduced the level of lung pro-inflammatory cytokines providing proof of principle that cardiopulmonary spinal afferents are involved in lung pathology post ALI. Therefore, in the current study we hypothesized that ablation of lung afferent innervation (thoracic spinal) by application of an ultrapotent, selective afferent neurotoxin, resiniferatoxin (RTX) will modify the course of the pathology including lung edema and local pulmonary inflammation associated with progressive ALI. 2 1 Our data suggest that pulmonary spinal afferent ablation by intra-stellate injection of RTX reduces plasma extravasation and local pulmonary inflammation post bleomycininduced lung injury which results in improved blood gas exchange.
cord-103496-8tq78p2z	2020	title: RAC1 nitration at Y32 IS involved in the endothelial barrier disruption associated with lipopolysaccharide-mediated acute lung injury Using a molecular modeling approach, we designed a nitration shielding peptide for Rac1, designated NipR2 (nitration inhibitor peptide for the Rho GTPases 2), which attenuated the LPS-induced nitration of Rac1 at Y32, preserves Rac1 activity and attenuates the LPS-mediated disruption of the endothelial barrier in human lung microvascular endothelial cells (HLMVEC). Using a murine model of ALI induced by intratracheal installation of LPS we found that NipR2 successfully prevented Rac1 nitration and Rac1 inhibition, and more importantly attenuated pulmonary inflammation, reduced lung injury and prevented the loss of lung function. We anticipate that a successful clinical efficacy of NipR2 or similar product might require: 1) precision medicine approach to identify patients in the sub-group with satisfactory responsiveness of Rac1 nitration blockade, as not all triggers of ALI (e.g., trauma) will lead to endothelial oxidative stress and peroxynitrite generation; 2) combination therapy with other effective reagents, including suppressor of the cytokine storm and/or neutrophil eliminators; 3)
cord-255440-ls1l2mlg	2020	Besides the approaches described so far, there are a few more approaches used for modeling COVID-19-(i) 3D organoids from bronchospheres and tracheospheres have been established before (Hild and Jaffe, 2016; Rock et al., 2009; Tadokoro et al., 2016) and are now used in apical-out cultures for infection with SARS-COV-2 (Suzuki et al., 2020); (ii) the most common model used for drug screening is the air-liquid interphase (ALI model) in which pseudo-stratified primary bronchial or small airway epithelial cells are used to recreate the multilayered mucociliary epithelium (Mou et al., 2016; Randell et al., 2011) ; (iii) several groups have also generated 3D airway models from iPSCs or tissue-resident stem cells (Dye et al., 2015; Ghaedi et al., 2013; Konishi et al., 2016; McCauley et al., 2017; Miller et al., 2019; Wong et al., 2012) ; (iv) others have generated AT2 cells from iPSCs using closely overlapping protocols of sequential differentiation starting with definitive endoderm, anterior foregut endoderm, and distal alveolar expression (Chen et al., 2017; Gotoh et al., 2014; Huang et al., 2014; Jacob et al., 2017; Jacob et al., 2019; Yamamoto et al., 2017) .
cord-258087-93yfs7ve	2008	CONCLUSIONS: Although the quality of association studies seems to have improved over the years, more and better designed studies, including the replication of previous findings, with larger sample sizes extended to population groups other than those of European descent, are needed for identifying firm genetic modifiers of ALI. This quality assessment of genetic association studies with positive findings in susceptibility or outcome of ALI and ARDS identified a total of 29 articles and 16 genes. ACE, angiotensin-converting enzyme; ALI, acute lung injury; ARDS, acute respiratory distress syndrome; CAP, community-acquired pneumonia; CXCL2, chemokine CXC motif ligand 2; F5, coagulation factor V; IL-6, interleukin-6; IL-10, interleukin-10; MBL2, mannose-binding lectin-2; MIF, macrophage migration inhibitory factor; MV, mechanical ventilation; MYLK, myosin light-chain kinase; NFKB1, nuclear factor kappa light polypeptide gene enhancer in B cells; NFKBIA, nuclear factor kappa light polypeptide gene enhancer in B cells inhibitor alpha; NRF2, nuclear factor erythroid-derived 2 factor; PBEF, pre-B cell-enhancing factor; PLAU, plasminogen activator urokinase; SARS, severe acute respiratory syndrome; SFTPB, surfactant pulmonaryassociated protein B; SIRS, systemic inflammatory response syndrome; SNP, single-nucleotide polymorphism; TNF, tumor necrosis factor; TR, tandem repeat (polymorphism); VEGF, vascular endothelial growth factor. Positive genetic association studies with acute lung injury/acute respiratory distress syndrome susceptibility and/or outcome (by year of publication)
cord-282336-zvc04s39	2020	In contrast, the lung injury in LPS-challenged TTP KO mice was characterized by severe consolidation (>90% of total area of lung section) (Figures 1F,G) that included infiltration of neutrophils, edema, fibrin, and airspace hemorrhage within the airway and alveolar lumen, multifocal loss of bronchiolar epithelium with infiltration of neutrophils and red blood cells within the bronchiolar lumen, and moderate to severe perivascular edema and inflammation (Figures 1F-H) . To determine the cell-specific role of TTP levels in ALI, we modulated TTP levels in hematopoietic progenitor cells (HPCs) and non-HPCs. In order to test whether donor HPCs repopulate the recipient mouse lungs, we first made bone marrow chimeras in which total body irradiated WT mice were transplanted with HPCs from a mouse expressing green fluorescent protein (GFP) in their somatic cells.
cord-284332-p4c1fneh	2012	[47] Although both of these studies were conducted prior to the 1994 AECC definition, ARDS was strictly defined in the aforementioned studies, including a PaO 2 /FiO 2 ratio <150 or intrapulmonary shunt >20% in patients requiring mechanical ventilation and who had diffuse infiltrates on chest radiograph without clinical evidence of heart failure as pulmonary arterial occlusion pressures were <18 mmHg. Building on the results of these two studies, Sinuff and colleagues [48] developed practice guidelines for prophylactic ketoconazole use, and tested the implementation and efficacy of these guidelines in two ICUs (one control and one active comparator). [119] A phase II study enrolling 98 patients with ALI compared an antioxidant enteral feeding formula containing eicosapentaenoic acid, g-linolenic acid and antioxidant vitamins with placebo, and observed improved oxygenation, reduced pulmonary inflammation, fewer days of mechanical ventilation and fewer non-pulmonary organ failures in the treatment arm, although there was no difference in mortality between this approach and the control group.
cord-291076-p350i54m	2015	Unregulated complement activation is likely to play a crucial role in the pathogenesis of acute lung injury (ALI) induced by highly pathogenic virus including influenza A viruses H5N1, H7N9, and severe acute respiratory syndrome (SARS) coronavirus. [1] [2] [3] In addition, the complement system has been implicated in the development of acute lung diseases induced by highly pathogenic viruses including influenza A virus H1N1, 4 H5N1, 5 H7N9, 6 severe acute respiratory syndrome coronavirus (SARS-Cov), 7 Middle East respiratory syndrome coronavirus (MERS-Cov). C5a-mediated release of reactive oxygen species C5a is a strong chemoattractant for neutrophils and monocytes; it then activates these cells to generate oxidative burst with release of 10 A study demonstrated that ROS are primary pathogenic molecules in pneumonia from mice infected with influenza virus. Inhibition of Complement Activation Alleviates Acute Lung Injury Induced by Highly Pathogenic Avian Influenza H5N1 Virus Infection
cord-305173-95o5z685	2008	In the complex inflammatory response initiated by HCl in the lungs, one might expect that TLR4 would be activated by several different endogenous stimuli; however, mice lacking TLR4, TRIF, or TRAF6 all resisted HClas well as OxPAPC-induced inflammation, supporting a role for OxPAPC as an important stimulus of TLR4 activation in this model. As in the HCl injury model, immunohistochemical analysis identified OxPAPC in the lungs, but mice lacking TLR4 or TRIF had lung inflammation that was much less severe. Mice lacking the Ncf1 protein, which lack an active NADPH oxidase complex, were protected from viral lung inflammation and did not form OxPAPC in the airspaces, further supporting a key role for oxidation of phospholipids in the pathogenic pathway. OxPAPC activates TLR4 expressed by myeloid cells (an alveolar macrophage is shown), and the intracellular signal is transduced by the adaptor proteins TRIF and TRAF6, leading to interleukin 6 (IL-6) production, inflammation, and alveolar damage.
cord-306835-juitltpi	2020	The keywords used for the search were as follows: coronavirus-19, COVID-19, SARS-CoV-2, curcumin, Curcuma longa, turmeric, curcumin and antiviral, curcumin and anti-inflammatory, curcumin and antipyretic, curcumin and lung, curcumin and acute lung injury, curcumin and fatigue, curcumin and antioxidant, curcumin and ARDS, curcumin and bradykinin, curcumin and fibrosis, curcumin and Interleukin-6 (IL-6), curcumin and tumor necrosis factor-alpha (TNF-α), curcumin and NF-κB, curcumin and Toll-like receptors (TLRs), curcumin and antiapoptotic. AA: arachidonic acid, ALI: acute lung injury, AP-1: activator protein 1, BK: bradykinin, ACE2: angiotensin-converting enzyme 2, Ang II: angiotensin II, ARDS: acute respiratory distress syndrome, Cas-3: caspase 3, COX: cyclooxygenase, CXCL: chemokine (C-X-C motif) ligand, 12-HPETE: 12-hydroperoxyeicosatetraenoic acid, JNK: c-Jun N-terminal kinase, 12 LOX: 12-lipoxygenase, MMP: matrix metalloproteinase NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells, MAPK: mitogen-activated protein kinase, PAI-1: plasminogen activator inhibitor-1, PLA2: phospholipase A2, PG: prostaglandin, SMAD3: mothers against decapentaplegic homolog 3, TGF-β1: transforming growth factor-beta 1, TNF-α: tumor necrosis factor-α, TLR: Toll-like receptor, TRPA1: transient receptor potential channel subfamily vanilloid member 1, TRPV1: transient receptor potential channel subfamily A member 1 mechanisms that curcumin may be useful to prevent or treat the ARDS.
cord-308892-5gbjdr0u	2020	title: Acute liver injury and its association with death risk of patients with COVID-19: a hospital-based prospective case-cohort study The aim of this study was to analyze SARS-CoV-2-induced acute liver injury (ALI), its association with death risk and prognosis after discharge. Despite of no difference on serum TBA, alkaline phosphatase and glutamyl transferase, two markers of cholestasis, were higher in critically ill patients than those of common cases. The present study aimed to analyze SARS-CoV-2-induced ALI, its association with death risk and the prognosis after discharge. The major findings of this study include: (1) ALI is more common in the critically ill COVID-19 patients; (2) Accumulating data demonstrated that SARS-CoV-2 infection caused multiple organ injuries, including myocardial dysfunction, lymphopenia and even acute renal These results provide evidence that ALI on admission is associated with the severity of COVID-19 patients.
cord-309301-ai84el0j	2020	The mini-gut culture approach has been applied to the generation of organoids derived from the epithelial compartments of a variety of murine and human tissues of ecto-, meso-and endodermal origin, and promotes the study of stem cell biology of other tissues except for intestine. For translational research, tumorderived organoids can be used for biobanking, genetic repair and drug screening studies, both for personalized medicine (to choose the most effective treatment for a specific patient) and drug development (to test a compound library on a specific set of tumor organoids), as well as immunotherapy research similar in liver, small intestine, and colon stem cells, regardless of the large variation in cancer incidence of these organs. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell-and patient-derived tumor organoids
cord-313091-ksrxsdpp	2017	Studies using the ATCC isolate suggest that HCoV-229E enters cells via the late endosome using cathepsin L to cleave S protein, although it can enter cells via the cell surface or early endosome in the presence of transmembrane protease serine 2 (TMPRSS2) or trypsin (Bertram et al., 2013; Kawase et al., 2009) . In the present study, we found that field isolates of HCoV-OC43 and HCoV-HKU1 could be isolated using HBTE-ALI cell culture, and we then used these clinical isolates to assess whether the mode of virus entry found in HCoV-229E was also in play in other HCoVs. For isolation of HCoVs, nasal swabs were collected from outpatients who showed respiratory infection as a cardinal symptom when assessed at a hospital in Tokyo, Japan. To evaluate the entry routes of clinical isolates of HCoVs, viruses were inoculated onto HBTE-ALI in the presence of EST or camostat (10 μM) and the amounts virus that entered were estimated by detecting subgenomic mRNAs using real-time RT-PCR (Fig. 2) .
cord-317993-012hx4kc	2020	SIMPLE SUMMARY: This commentary focuses on the methods currently available to test the efficacy and safety of new orally inhaled drugs for the treatment of uncurable respiratory diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis or lung cancer, prior to entering human experimentation. Inhalation is the preferred administration method for treating respiratory diseases [13] , as: (i) it delivers the drug directly at the site of action, resulting in a rapid therapeutic onset with considerably lower drug doses, (ii) it is painless and minimally invasive thus improving patients'' compliance, and (iii) it avoids first-pass metabolism, providing optimal pharmacokinetic conditions for drug absorption and reducing systemic side effects [14] [15] [16] . In the context of OID preclinical testing, lung organoids can be used for modeling respiratory diseases and, therefore, as a platform for screening the efficacy of inhalation therapies [115, 116] .
cord-319936-5uze06rp	2008	INTRODUCTION: Animal studies of acute lung injury (ALI) suggest nebulised heparin may limit damage from fibrin deposition in the alveolar space and microcirculation. Studies in animal models of ALI have demonstrated that nebulised heparin improved the PaO 2 /FiO 2 ratio and reduced histological ALI = acute lung injury; APTT = activated partial thromboplastin time; BAL = bronchoalveolar lavage; ELISA = enzyme-linked immunosorbent assay; PaO 2 /FiO 2 = arterial oxygen partial pressure to inspired oxygen fraction ratio; PTF = prothrombin fragments; TCT = thrombin clotting time; t-PA = tissue plasminogen activator. Analysis of variance was used to compare the effect of heparin dose on the P a O 2 /F i O 2 ratio, lung compliance, the alveolar dead space fraction, the APTT, the TCT and intrapulmonary PTF and t-PA levels. We found administration of nebulised heparin to mechanically ventilated patients with ALI was feasible, was not associated with serious adverse events, and increased APTT levels at higher doses.
cord-320681-b3ui95vx	2020	Based on clinical features, pathology, the pathogenesis of acute respiratory disorder induced by either highly homogenous coronaviruses or other pathogens, the evidence suggests that excessive inflammation, oxidation, and an exaggerated immune response very likely contribute to COVID-19 pathology. Herein, we review the evidence indicating that melatonin will have supportive adjuvant utility in treating COVID-19 induced pneumonia, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In SARS-CoV and MERS-CoV infected animal model, marked inflammatory and immune responses may activate a "cytokine storm", and apoptosis of epithelial cells and endothelial cells; subsequently, vascular leakage, abnormal T cell and macrophages responses ensue and induce ALI/ARDS or even death [13] . The amplification of the inflammatory response would promote cellular apoptosis or We postulated that lungs infected by SARS-CoV-2, and a suppressed immune response, elevated inflammation and excessive oxidation stress proceed unabated, this results in the activation of the cytokine storm.
cord-331887-kagggou1	2020	Compared with those in ALI, the expression of CXCL2, CXCL1, CXCL6, NFKBIA, IFNG, IL6, IL17A, IL17F, IL17C, MMP9 and TNFAIP3, which are involved in the IL-17 signalling pathway, were significantly decreased in the LJF group according to the qRT-PCR analyses. CONCLUSIONS: In view of the network pharmacology and RNA-Seq results, the study identified the main active ingredient and potential targets of LJF involved in protecting against ALI, which suggests directions for further research on LJF. LJF significantly inhibited CXCL2, CXCL1, CXCL6, NFKBIA, IFNG, IL6, IL17A, 290 IL17F, IL17C, MMP9, and TNFAIP3 mRNA expression in lung tissue homogenates according to 291 RNA-Seq, which indicates that the IL-17 signalling pathway is critical for treatment of 292 LPS-induced ALI with LJF (Fig.S4) . Consistent with the RNA-Seq data, the expression of CXCL2, CXCL1, CXCL6, 295 NFKBIA, IFNG, IL6, IL17A, IL17F, IL17C, MMP9 and TNFAIP3 in lung tissue was 296 significantly decreased compared with that in the ALI and LJF groups according to the qRT-PCR 297 analyses (P<0.05) (Fig.8) .
cord-333520-v2sb90rc	2020	Exosomes derived from mesenchymal stem cells (MSCs) are being explored for the management of a number of diseases that currently have limited or no therapeutic options, thanks to their anti-inflammatory, immunomodulatory, and pro-angiogenic properties. Next, we describe some of the most significant clinical evidence of the successful use of MSC-derived exosomes in animal models of lung and heart injuries, which might strengthen our hypothesis in terms of their utility for also treating critically ill COVID-19 patients. Recently, MSC-derived exosomes have been demonstrated to have comparable and even greater effects than cells themselves in improving inflammation and injury in a variety of pre-clinical lung disease models, including ALI/ARDS (Table 1) . From the studies discussed above, it emerged that the rationale for using MSC-derived exosomes, MVs, or EVs in ALI/ARDS is based on several processes, many of which are shared with those identified in the parent MSCs. These include immunomodulation and anti-inflammatory properties on host tissue, reduction of the permeability of alveolar epithelium and endothelium, improvement of alveolar fluid clearance, enhancement of macrophage phagocytosis, and tissue repair through direct mitochondrial transfer with host cells (Figure 2 ).
cord-334528-xenq90xj	2011	This literature review includes a brief historical retrospective of ALI/ARDS, the neurogenic pulmonary edema due to head injury, the long-term experimental studies and clinical investigations from our laboratory, the detrimental role of NO, the risk factors, and the possible pathogenetic mechanisms as well as therapeutic regimen for ALI/ARDS. [33, 34] In addition to the aforementioned animal experimentations and clinical observations that NO production through the iNOS may be involved in the lung injury due to various causes, our research team demonstrated that endotoxemia produced in anesthetized rats by intravenous administration of lipopolysaccharide (LPS, endotoxin) provoked systemic hypotension, endothelial damage and ALI accompanied by increased plasma nitrate/nitrite and expression of iNOS mRNA, TNF α and IL-1 β . The detrimental role of inducible nitric oxide synthase in the pulmonary edema caused by hypercalcemia in conscious rats and isolated lungs
cord-337973-djqzgc1k	2020	title: Long Period Modeling SARS-CoV-2 Infection of in Vitro Cultured Polarized Human Airway Epithelium We also identified that SARS-CoV-2 does not infect HAE from the basolateral side, and the dominant SARS-CoV-2 permissive epithelial cells are ciliated cells and goblet cells, whereas virus replication in basal cells and club cells was not detectable. Our observation that SARS-CoV-2 was unable to infect epithelial cells from the 299 basolateral side supports that the viral entry receptor ACE2 is polarly expressed at the apical 300 side 30, 31 . We 332 determined that 1 pfu of SARS-CoV-2 in Vero-E6 cells has a particle (viral genome copy) 333 number of 820, suggesting that a load of 2.46 x 10 5 particles is required to productively infect 1 334 cm 2 of the airway epithelium, which is much higher than the small DNA virus parvovirus human 335 bocavirus 1 (HBoV1) we studied 55 .
cord-340865-sut3nf2a	2015	LPS administration increased P2X7 expression in the lung parenchyma and P2X7 −/− mice showed decreased polymorphonuclear cell infiltration, less inflammatory cytokine production and reduced collagen deposition [8] . In this study, we demonstrated that pharmacological blockade of P2X7 by using selective antagonists effectively ameliorated ALI in mice via inhibiting NLRP3 inflammasome pathway. Enhanced protein expression of P2X7, NLRP3, and ASC was observed in the lungs from LPS-induced lung injury mice compared with control mice treated by PBS (Fig. 1) . Coincident with the cell counts, the total protein level was also elevated in the LPS-induced lung injury group, which was significantly reduced by A438079 treatment (Fig. 3d) . In this study, P2X7 expression was significantly enhanced at the protein level in the lung tissues from ALI mice, paralleled with alveolar damage and inflammatory cytokine production. We found that blockage of P2X7 inhibited the activation of NLRP3 inflammasome pathway, neutrophil accumulation and production of proinflammatory cytokines, resulting in reduction of lung damage.
cord-349201-d88g5toc	2020	title: Exploring the biomarkers associated with different host inflammation of acute respiratory distress syndrome (ARDS) from lung metabolomics in mice RATIONALE: The aim of this study was to analyze the metabolomics of lung with different host inflammation of acute respiratory distress syndrome (ARDS) for the identification of biomarkers for predicting severity under different inflammatory conditions. RF analysis of lung-targeted metabolomics data defined a set of 15 metabolites that constitute the best predictors of differences in host inflammation status: in particular, increased 4hydroxyphenylacetic acid, 1-aminocyclopentanecarboxylic acid (ACPC), and cis-aconitic acid, Tridecane and hydroxybenzoic acid were strong predictors of the hyper-inflammatory subgroup in CLP-induced ALI ( Figure 3B ). Interestingly, RF analysis of lung-targeted metabolomics data showed that the metabolic biomarker group with 5 products was a strong predictor of the hyper-inflammatory subgroup in CLP-induced ALI ( Figure 3B ).
cord-354829-god79qzw	2020	title: Identification of robust genetic signatures associated with lipopolysaccharide-induced acute lung injury onset and astaxanthin therapeutic effects by integrative analysis of RNA sequencing data and GEO datasets Here we performed a statistical meta-analysis of five publicly available gene expression datasets from LPS-induced ALI mouse models, conducted RNA-sequencing (RNA-seq) to screen differentially expressed genes (DEGs) in response to LPS administration and AST treatment, and integrative analysis to determine robust genetic signatures associated with LPS-induced ALI onset and AST administration. We subsequently integrated the RNA-seq and microarray meta-analysis data, and 11 core DEGs (Timp1, Ly6i, Cxcl13, Irf7, Cxcl5, Ccl7, Isg15, Saa3, Saa1, Tgtp1, and Gbp11) that were upregulated in ALI models and downregulated significantly after AST treatment were identified ( Table 2) . To further identify the robust expression signature related to LPS-induced ALI and investigate the transcriptional changes in response to the treatment of ALI by AST, we performed RNA-seq on three groups of mice and integrated the data with the results of the above mentioned meta-analysis.