key: cord-0754614-mm47i40r
authors: Elkahloun, Abdel G.; Saavedra, Juan M.
title: Candesartan could ameliorate the COVID-19 cytokine storm
date: 2020-08-20
journal: Biomed Pharmacother
DOI: 10.1016/j.biopha.2020.110653
sha: f2d489e9d9317500bf6210b4ecdb7966f117556f
doc_id: 754614
cord_uid: mm47i40r

BACKGROUND: Angiotensin receptor blockers (ARBs) reducing inflammation and protecting lung and brain function, could be of therapeutic efficacy in COVID-19 patients. METHODS: Using GSEA, we compared our previous transcriptome analysis of neurons injured by glutamate and treated with the ARB Candesartan (GSE67036) with transcriptional signatures from SARS-CoV-2 infected primary human bronchial epithelial cells (NHBE) and lung postmortem (GSE147507), PBMC and BALF samples (CRA002390) from COVID-19 patients. RESULTS: Hundreds of genes upregulated in SARS-CoV-2/COVID-19 transcriptomes were similarly upregulated by glutamate and normalized by Candesartan. Gene Ontology analysis revealed expression profiles with greatest significance and enrichment, including proinflammatory cytokine and chemokine activity, the NF-kappa B complex, alterations in innate and adaptive immunity, with many genes participating in the COVID-19 cytokine storm. CONCLUSIONS: There are similar injury mechanisms in SARS-CoV-2 infection and neuronal injury, equally reduced by ARB treatment. This supports the hypothesis of a therapeutic role for ARBs, ameliorating the COVID-19 cytokine storm.

The highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current COVID-19 pandemic, a disease affecting not only the lung but multiple organs with devastating consequences, high mortality, and no available specific therapy. It is imperative to consider repurposing available drugs to treat and prevent SARS-CoV-2-induced multiorgan pathology that are well-tolerated and effective in the elderly, a vulnerable COVID-19 group. Ideal compounds will exert proven potent anti-inflammatory effects with amelioration of the cytokine storm, normalization of p53 pathway, demonstrated reduction of the SARS that follows pneumonia and other coronavirus infections, and protective effects in cardiovascular and metabolic disorders frequently comorbid with COVID-19.

The Angiotensin Receptor Blockers (ARBs) fulfill all these requirements. ARBs block the effects of excessive activation of Angiotensin II AT1 receptors (AT1R), a major injury factor participating in the development of disorders of the brain, the cardiovascular system, the kidney, lipid and glucose metabolism and the immune system, enhancing inflammation and viral injury in the lung and linearly associated with viral load and lung injury in COVID-19 patients [1, 2, 3, 4, 5] .

ARBs, initially developed as antihypertensive compounds, exert multiple pleiotropic protective effects beyond their influence on blood pressure. ARBs reduce excessive inflammation, protect mitochondrial function, maintain insulin sensitivity and energy metabolism, and normalize the coagulation cascade [1, 6, 7] . These compounds are well-tolerated in the elderly and successfully used not only as first-line antihypertensives but also in the treatment of diabetes, kidney disease, congestive heart failure and cerebrovascular disorders, which are frequent COVID-19 comorbidities

ARBs protect the lung from severe injury associated with pneumonia, sepsis, influenza and SARS-CoV [1, 6, 9, 10] . Furthermore, mortality was reduced in patients previously treated with ARBs for cardiovascular disorders and later hospitalized for pneumonia [6] .

In addition, ARBs protect cognition, cerebral blood flow and blood-brain barrier function, reduce brain inflammation, anxiety, and stress [11, 12. 13, 14, 5] . and normalize expression of multiple genes involved in the aging process including p53 signaling [16, 17] . These findings are of interest because cerebrovascular complications are frequent in patients affected by COVID- 19 and their prevalence increases in severe cases and in the elderly [18, 19, 20, 21, 22, 23] .

For these reasons it was reasonable to suggest that ARBs could be beneficial for the treatment of COVID-19 patients, by ameliorating inflammation, hypertension and other comorbidities and directly protecting the lung and other organs from the SARS-CoV-2 infection. Multiple clinical studies are in progress to determine the effect of ARB therapy in COVID-19 patients https://clinicaltrials.gov/ct2/results?cond=COVID-J o u r n a l P r e -p r o o f GSE67036. In this experiment, we treated primary rat cerebellar granule cells (CGC) with either vehicle, candesartan, glutamate, or candesartan and glutamate. Four independent experiments were conducted for each group. Standard procedures such as extraction of total RNA, labeling, hybridization, washing, and staining were as per manufacturer's recommendation (Affymetrix, Santa Clara, CA). The raw data was submitted to GEO under accession GSE67036. Detailed procedures have been described previously [16] .

We used Gene Set Enrichment Analysis (GSEA) [27] (http://www.broadinstitute.org/gsea/) to compare our data to published datasets [26] (GSE147507) downloaded from the National Center for Biotechnology Information (NCBI) GEO database, and [25] , CRA002390 downloaded from their supplemental data and the Genome Sequence Archive in BIG (Beijing Institute of Genomics) Data Center (https://bigd.big.ac.cn/), Chinese Academy of Sciences [28] . A complete description of these data sets is summarized in Table 1 . Data from isolated cells from human fibrotic lung postmortem samples were taken from GSE122960 [29] .

Datasets were imported into Partek Genomics Suite software (Partek, Inc., St. Louis, MI) or analyzed by the GEO2R, an online resource from GEO, that uses GEOquery and limma R packages from the Bioconductor project. We also used the supplemental tables provided by the authors of these two papers. [30, 31, 32] . Ingenuity Pathway Analysis (IPA) (http://www.ingenuity.com) [33] , Gene Ontology (http://geneontology.org/) [34] , Metascape (https://metascape.org/gp/index.html#/main/step1) [35] and Jensen Compartments database (https://compartments.jensenlab.org/) [36] were used to identify gene expression profiles and canonical pathways associated with the differentially expressed genes.

We had previously performed a transcriptome analysis of primary neurons (cerebellar granule cells, CGC) injured by excitotoxic concentrations of glutamate and compared gene expression in injured neurons with and without treatment with the ARB Candesartan (GSE67036), [16, 17] . We have found that glutamate-induced upregulation of hundreds of pro-inflammatory and senescence related genes was normalized by Candesartan, indication of strong anti-inflammatory, anti-aging, and neuroprotective effects of ARB treatment [16, 17] .

Using GSEA, we now asked the question whether this comparison would reveal normalization by Candesartan of gene signatures characteristic of COVID-19. We found a highly statistical positive correlation between the expression of a large number of genes upregulated by glutamate and those genes upregulated in four different SARS-J o u r n a l P r e -p r o o f CoV-2/COVID-19 human transcriptomes: a normal primary human bronchial epithelial (NHBE) cell culture infected with SARS-CoV-2 (Table 1, Figure 1A ), lung tissue post mortem samples from 2 COVID-19 patients and 2 lung biopsies from healthy controls (Table 1 , Figure 1B) , peripheral blood mononuclear cells (PBMC) from 3 COVID-19 patients and 3 healthy controls (Table 1, Figure 1C ) and bronchoalveolar lavage fluid (BALF) from 2 COVID-19 patients and 3 healthy controls (Table 1, Figure 1D ).

Accession number 

To reveal the genes most commonly associated with SARS-CoV-2 infection, we 

The list of the 210 genes was then analyzed using Gene Ontology (GO Molecular

( Some of the Biological Process with highest significance and highest numbers of associated genes were cytokine-mediated signaling pathway, cellular response to type I interferon, type I interferon signaling pathway, cellular response to interferon gamma, cellular response to cytokine stimulus, response to cytokine, response to interferon gamma, inflammatory response, neutrophil mediated immunity, neutrophil degranulation J o u r n a l P r e -p r o o f and neutrophil activation involved in immune response related to the cytokine-mediated signaling pathway, cellular response to type I interferon and type I interferon signaling pathway (Table 3, Supplemental table 3) .

From the Jensen Compartments database, we identified 50 highly significant gene expression profiles, and some of the most significant with highest numbers of genes were the NF-kappa B complex, interferon regulatory factor 7, interferon regulatory factor complex, interleukin-12 complex, interleukin-23 complex, S100A9 complex, extracellular space and Bcl-2 family protein complex ( 

Genes Cytokine-mediated signaling pathway (GO:0019221)   ANXA2,BIRC3,CASP1,CD74,CEBPD,ECM1,EREG,F3,FCGR1A,FN1,  CXCL1,CXCL2,IFNGR1,IFNGR2,IL1B,IL1RN,CXCL10,IRF5,IRF7,ISG20,  ITGB2,KRT18,LCN2,MT2A,MX1,MYD88,PLP2,PML,PSMB9,ROBO1,  CCL2,CCL3,CCL4,CXCL6,CXCL11,SOD2,SP100,TRIM21,STAT1,STAT2,  TNF, IL1R2,IFITM1,OASL,CCRL2,ISG15,IRF9,IFITM3,IFITM2,IRAK3,  XAF1,PARP9,IL33,RSAD2  Response to virus  (GO:0009615)   BIRC3,BCL3,IFNGR1,IFNGR2,IL1B,CXCL10,IRF5,IRF7,ISG20,LCN2,  LGALS9,MX1,PML,HTRA1,CCL4,STAT1,STAT2,TNF,FOSL1,IFITM1,  OASL,ISG15,IRF9,IFITM3,IFI44,IFITM2,IRAK3,DDX58,IFIH1,ZC3H12A,  PARP9,IL33,RSAD2,DTX3L Response to interferon-gamma (GO:0034341)   AIF1,ASS1,CASP1,FCGR1A,GCH1,IFNGR1,IFNGR2,IRF5,IRF7,LGALS9,  MT2A,PML,CCL2,CCL3,CCL4,SP100,TRIM21,STAT1,TLR4,IFITM1,OASL,  IRF9,IFITM3,IFITM2,CXCL16 ,PARP9,GBP5,SIRPA There were many genes contributing to regulation of the interferon response or 

We previously showed that Alzheimer's disease, aging, and senescence transcriptomes revealed a striking positive correlation with gene expression upregulated by glutamate and a remarkable negative correlation with gene expression after Candesartan treatment in our neuronal cultures [16, 17] .

Excessive inflammation with a cytokine storm and innate and adaptive immune alterations are hallmarks of COVID-19 [25, 26] , a disorder more severely affecting the elderly and involving not only the lung but many other organs, including the brain [37] .

Because of the above, we asked the question whether the strong anti-inflammatory effects and normalization of the immune response by Candesartan could be in any way related to a relief of the cytokine storm and immune alterations associated with SARS-CoV-2 infection, and we compared, using GSEA, our results with the recently reported gene signature samples obtained from SARS-CoV-2 infected human cells and COVID-19 patients [25, 26] . In all cases, we found striking and highly significative positive correlations between the upregulation of hundreds of genes associated with SARS-CoV-2 infection [25, 26] and those upregulated by neuronal injury, that were negatively correlated with genes normalized by Candesartan in our neuronal cultures [16, 17] .

As expected, because of the different source of the materials examined, each of the datasets studied revealed unique transcriptome signatures when only the top 20 genes with highest rank metric scores in each enrichment dataset were reported ( Table   2 ). The NHBE transcriptome included ICAM1, important for recruitment of inflammatory immune cells and participating in the COVID-19 response [38] , and IL-6, a proinflammatory cytokine associated to poor COVID-19 response [39, 40] . The transcriptome from COVID-19 post mortem samples contained CYBB (NOX2) a superoxide generating enzyme forming excessive reactive oxygen species (ROS) and

involved in SARS-CoV-2 infection [42] and TLR7, a Toll-like receptor essential for antiviral immunity, including the response to SARS-CoV-2 [43, 44, 45] . The PBMC transcriptome revealed HMOX1, with anti-inflammatory properties [46, 47] , and IL18, a proinflammatory cytokine reported to play an important role in COVID-19 [48, 49, 50] .

The BALF transcriptome included upregulated CFH, reported to increase pathogen virulence [51] , and PMAIP1 (Noxa) proapoptotic member of the Bcl-2 protein family, involved in p53-mediated apoptosis [52] . However, when the entire lists of enriched genes were compared (Table 1 and Supplemental table 2 

Individual analysis of the 210-gene list revealed many genes playing major roles in COVID-19 pathology. There were several commonly upregulated genes associated with viral entry, such as TLR4, MyD88, DDX58 (RIG-I) [53] . TLR4, encoding for the PRR TLR4, a Toll-like receptor 4 [54] , recognizes molecular patterns from SARS-CoV-2 J o u r n a l P r e -p r o o f to induce inflammatory responses [55] . TLR4 and MyD88 are major components of the

inflammatory cytokine production such as TNF-α, and IL-1, and activating the innate immune system [56] . MyD88 plays an important role in IL-6 induction during COVID-19 [57] . RIG-I is a PRR sensing RNA virus, upregulated by viral infection [58] and has been implicated in the induction of early antiviral immune responses in COVID-19 [59] .

Many genes are associated to the COVID-19 cytokine storm. IL1B is markedly increased during SARS-CoV-2 infection associated with rapid activation of the innate immune response, epithelial and endothelial apoptosis and vascular leakage [60, 61, 62 ] CASP1, encoding for Caspase-1/interleukin-1 converting enzyme (ICE) forms part of the inflammasome complex activating IL-1β and IL-18 [63, 64] . CXCL6, CXCL1, and CXCL2 encode for pro-inflammatory chemokines, attracting neutrophils, monocytes, [65, 66, 67] . They activate oxidative and endoplasmic reticulum stress, amplify acute lung injury and SARS, subsequently triggering innate immune responses [67, 68] . CXCL10 is a chemokine attracting macrophages and promoting T cell adhesion in response to interferon [69] and is part of the COVID-19 cytokine storm [70] .

CCL2 encodes MCP1,recruiting monocytes, memory T cells, and dendritic cells to the sites of inflammation and is part of the distinct host inflammatory cytokine profile to SARS-CoV-2 infection [25, 44] . CCL2 activates apoptosis and the p53 J o u r n a l P r e -p r o o f signaling pathway that may cause patient's lymphopenia [25] . CCL4 and CCL7 are chemokines attracting macrophages and with major proinflammatory properties [71, 72] , CXCL16 is induced by interferon gamma and TNF-α [73] , that interacts with SARS-CoV N protein in and out of the cell [74] . CCL2 stimulates neuroinflammatory processes [66] . CD74 encodes the HLA class II histocompatibility antigen gamma chain (CD74) mediating the macrophage migration inhibitory factor proinflammatory effects, viral replication and IFN-γ production during the acute phase of brain SARS-CoV.

STAT1 is activated by interferon and IL-6, polarizing the immune response specifically in macrophages, resulting in a worsened COVID-19 outcome [75, 76, 77, 78] . TNF is produced by activated macrophages, promoting the acute inflammatory response.

Increased TNFα production and release, associated with IL-1α and IL-β and inversely correlated with lymphopenia and decreased IFN-γ expression, is characteristic of severe COVID-19 [79, 80, 81, 82] . PTGS2, encoding COX2, plays an important role in SARS-CoV infections. SARS-CoV N protein causes lung inflammation by activating COX2 and stimulating multiple COX2 inflammatory cascades [83] .

CF2 is a subunit of the NADPH oxidase complex and produces a burst of ROS in neutrophils [84] . IRAK3, an interleukin-1 receptor associated kinase, is involved in excessive production of reactive oxygen species [85] . SOD2 is a crucial regulator of antiviral signaling, clearing mitochondrial reactive oxygen species (ROS), protecting against cell death, [86] inhibiting the RIG-I-like receptor induction of innate immune responses, and activating interferon regulatory factor-3 [87] . CN2/NGAL, encoding lipocalin-2, is a biomarker of systemic inflammation [88, 89] .

Other genes, such as IFITM1 and IFITM3 encoding interferon-induced transmembrane protein 1 and 3, respectively, have been previously associated with SARS-CoV infections. They are restriction factors for virus, including SARS-CoV [90, 91, 92, 93, 94] . MX1 encodes interferon-induced GTP-binding proteins Mx1 (MxA) and

is prominently induced by interferon-beta after SARS-CoV infection [95] . PLP2 encodes for proteolipid protein 2, a coronavirus protease increasing virulence factors and antagonizing the host innate immune response, inhibiting the p53-IRF7-mediated antiviral response including that to SARS-CoV [96, 97, 98, 99] . HTRA1 encodes serine protease HTRA1; its overexpression enhances papilloma virus cell proliferation [100] .

Genes part of the complement complex, such as CFB and F5, stimulate recruitment and infiltration of inflammatory cells, contributing to lung injury [101] and predisposing to thrombosis [102] . Their upregulation may play a role in the high risk of thrombosis of COVID-19 patients [103, 104] .

The anti-inflammatory effects of ARB treatment have been extensively documented in the literature, and ARBs normalize the upregulation of expression of several genes in our 210-gene selected list. LCN2/NGAL is increased in hypertensive patients and downregulated by ARB treatment [105] . ARB blockade reduces STAT1 phosphorylation induced by inflammation and IL-1β, leading to a predominant M2 J o u r n a l P r e -p r o o f macrophage phenotype [106] . ARBs downregulate TLR4, MyD88 and NF-kappa B expression [107, 108] as well as the inflammasome [109, 110] .

There is extensive evidence for a reduction of inflammatory cytokines such IL-1β, encoded by IL-1B after ARB treatment, both in the periphery and in the brain [13, 111] .

Beneficial effects of ARB treatment, reducing inflammation including TNFα production and release have been extensively documented in disorders where excessive inflammation and increased AT1R receptor activity play a fundamental role, including but not limited to diabetes [112] , cerebral ischemia [113] , hypertension [114] and cardiovascular disease [115] . COX2, a powerful proinflammatory enzyme, is inhibited by ARBs [116, 117] .

ARB treatment reduced the effects of CXCL1 and CXCL2 upregulation and increased oxidative stress [118, 119, 120] . CXCL16 is involved in Angiotensin II associated metabolic disorders and atherosclerosis, and its secretion is blocked by ARBs [121, 122] . ARB treatment reduces MCP-1 upregulation during lung injury, inhibits monocyte recruitment and reduces lung fibrosis development [123, 124] . ARBs downregulate the proinflammatory chemokines CCL4, CCL7 and CXCL10 [125, 126, 127, 128] .

The beneficial effect of ARB treatment may not be limited to acute SARS-CoV-2 infection and COVID-19 severity but may extend to ameliorate long-term consequences of the disease. Pulmonary fibrosis leading to pulmonary arterial hypertension and irreversible respiratory failure is likely to occur in patients recovered from acute J o u r n a l P r e -p r o o f respiratory distress syndrome (ARDS) associated with critically severe COVID-19 [57, 129, 130] . We found highly significant negative correlations between genes upregulated by glutamate and normalized by Candesartan in our neuronal cultures with transcriptome signatures of alveolar cells, fibroblasts and macrophages from post mortem human fibrotic lungs, indicative of alterations in mitochondrial biogenesis and enhanced oxidative stress, inflammation and senescence [29] (Supplemental Table 4 ).

It has been previously established that Angiotensin II increases lung fibrosis and chronic obstructive pulmonary disease [131] in animal models, and this is suppressed by ARB treatment [123, 132, 133, 134, 135] . Examples of genes from our 210-gene list and previously reported to play a role in the development of lung fibrosis include SOX2, [75, 76, 77, 78, 136] and HTRA1, a gene repressing signaling by TGF-β family members, preventing vascular fibrosis and extracellular matrix protein synthesis, effects similar to those of ARB treatment [137] .

Old age is a major risk factor for COVID-19 progression and death [5, 18, 138] .

As we previously reported, ARBs normalize expression of multiple genes involved in the aging process [16, 17] , and ARB blockade prevents the premature senescence produced by excessive Angiotensin II activation [139, 140] . It has been recently shown that one Alzheimer's risk gene correlates with risk for severe COVID-19 [141] . Within our 210-gene list, a genetic variant of IFITM3 has been recently associated with agedependent COVID-19 severity [142] , and ADAP2 has been proposed to participate in Alzheimer's disease progression [143] . Downregulation of SOD2, a gene with antiaging J o u r n a l P r e -p r o o f effects that ameliorates DNA damage and protects against cellular senescence [144] is normalized by ARB treatment in a rodent model of Alzheimer's disease [145] .

Genes highly expressed in the brain, and effects of ARB treatment on brain disorders.

SARS-CoV-2 infection not only affects the lung but extends to many other organs, including the brain, and age-related cerebrovascular disorders such as cerebral hemorrhage and stroke are not only frequent comorbidities but also novel and critical events in the presentation, progress and prognosis of COVID-19 [18, 19, 21, 22, 23, 146, 147] . It has also been established that ARB administration is strongly neuroprotective, regulating cerebral blood flow, blood-brain barrier function, reducing brain inflammation and protecting cognition in hypertensive patients and in the elderly [5, 11, 12, 13, 15, 17] . Some of the genes included in our 210-gene list are widely expressed in brain, such as SLC43A3, encoding the solute carrier family 22 member 3 and a biomarker of sensitivity to DNA damage [148] , specifically expressed in the microvasculature [149, 150] . Increased CXCL1 expression in the brain was associated with increased mortality and demyelination [151] .

Our IPA upstream regulator analysis identified many factors that may downregulate COVID-19 upregulated genes in our study, including dexamethasone, immunoglobulin, beta-estradiol, and simvastatin. Dexamethasone has been proposed for acutely ill COVID-19 patients, but its use carries severe risks and needs to be J o u r n a l P r e -p r o o f carefully evaluated [152] . Immunoglobulin was reported to be effective in severely ill COVID-19 patients [153] . The use of beta-estradiol and simvastatin is currently being evaluated in interventional clinical trials [154] . Not surprisingly, many proinflammatory cytokines (TNF, IL1B, IL6, IL13), PRRs such as TLR4 and TLR7, and inflammationinducing drugs such as lipopolysaccharide were found to positively correlate with COVID-19 upregulated genes.

It could be argued that given that cells and tissues analyzed here are very different from neurons, Candesartan inhibition of neuronal inflammation does not necessarily correlate with similar effects of this compound in the lung and PBMC.

However, there is convincing literature demonstrating a role for AT1R in lung function [155, 156, 157, 158] , lung injury as a result of excessive AT1 receptor activation [133, 159, 160, 161, 162, 163, 164, 165] and protective effects of ARB treatment in lung injury [10, 135, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175] .

It has also been reported that ARBs ameliorate pneumonia in COVID-19 patients [176, 177, 178, 179] , after viral infections [6, 180, 181, 182, 183, 184, 185, 186] , in diabetic patients [187] and in chronic obstructive pulmonary disease [188, 189, 190] .

Improved clinical outcome after ARB treatment of COVID-19 patients is associated with reduced IL-6 in peripheral blood, increased CD3 and CD8 T cell counts and reduced peak viral load [178] and lower concentrations of high-sensitivity C-reactive protein (hs-CRP) and procalcitonin (PCT) [24] . In addition, Candesartan decreases the innate immune response to endotoxin administration in human monocytes, including reduction of gene expression of CD14, the pro-inflammatory cytokines TNF-alpha, IL-1beta, IL-6, and the lectin-like oxidized low-density lipoprotein receptor, and well as a reduction of NF-kappaB activation, TNFalpha and IL-6 secretion and oxygen radical production [192] . These findings support the present correlation of our neuronal transcriptome with that of PBMC in COVID-19

patients. AT1R inhibition by ARBs may activate counterbalance mechanisms such as Ang II AT2 receptor stimulation. Activation of AT2 receptors was reported to produce antiinflammatory effects in an animal model [193] . However, the role of AT2 receptor activation in COVID-19 patients has not been studied.

In summary, the present results and those of the literature, strongly suggest that ARB treatment, by amelioration of excessive inflammation, oxidative stress, lung fibrosis, and expression of pro-senesce genes, normalization of mitochondrial function, interferon production and innate and adaptive immunity, could be beneficial for the treatment of acute SARS-CoV-2 infection and its long-term complications, be particularly effective in the elderly and protect not only lung function but that of the brain as well.

Our goal was to test the hypothesis of common mechanisms leading to infection, but also to perform carefully designed data analysis and conclusive clinical studies to establish whether these compounds may be considered as additional therapeutic tools in COVID-19 patients.

AGE performed and interpreted the bioinformatic analysis, wrote the analytical methods and contributed to write the manuscript.

JMS conceived of the presented idea, described the role of the genes involved, and wrote the manuscript.

Both authors discussed the results and contributed to the final manuscript.

The authors have no financial interests to declare. J o u r n a l P r e -p r o o f

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Angiotensin II AT1 receptor blockade ameliorates brain inflammation

Inflammation and the etiology of type 2 diabetes

Angiotensin II type 1 receptors in cerebral ischaemiareperfusion: initiation of inflammation

Is hypertension an inflammatory process?

Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease

Sex differences in angiotensin II responses contribute to a differential regulation of coxmediated vascular dysfunction during aging

Telmisartan inhibits Ang II-induced MMP-9 expression in macrophages in stabilizing atheromatous plaque

Comparison between single and combined treatment with candesartan and pioglitazone following transient focal ischemia in rat brain

Olmesartan, a novel angiotensin II type 1 receptor antagonist, reduces severity of atherosclerosis in apolipoprotein E deficient mice associated with reducing superoxide production

Mechanisms of the anti-inflammatory actions of the angiotensin type 1 receptor antagonist losartan in experimental models of arthritis

Angiotensin receptor 1 blockade reduces secretion of inflammation associated cytokines from cultured human carotid atheroma and vascular cells in association with reduced extracellular signal regulated kinase expression and activation

Functional role of endothelial CXCL16/CXCR6-platelet-leucocyte axis in angiotensin II-associated metabolic disorders

Preventive effect of irbesartan on bleomycin-induced lung injury in mice

The Angiotensin Receptor Blocker Losartan Suppresses Growth of Pulmonary Metastases via AT1R-Independent Inhibition of CCR2 Signaling and Monocyte Recruitment

Sanz -J. CXCR2 blockade impairs angiotensin II-induced CC chemokine synthesis and mononuclear leukocyte infiltration

Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system

Hepatic expression of serum amyloid A1 is induced by traumatic brain injury and modulated by telmisartan

Therapeutic Effect of

Rehabilitation management of patients with COVID-19. Lessons learned from the first experiences in China

Lung transplantation as therapeutic option in acute respiratory distress syndrome for COVID-19-related pulmonary fibrosis

Renin-angiotensin system blockade: a novel therapeutic approach in chronic obstructive pulmonary disease

Reduction of bleomycin induced lung fibrosis by candesartan cilexetil, an angiotensin II type 1 receptor antagonist

Effects of angiotensin on the expression of fibrosis-associated cytokines, growth factors, and matrix proteins in human lung fibroblasts

Angiotensin II facilitates fibrogenic effect of TGF-β1 through enhancing the downregulation of BAMBI caused by LPS: a new pro-fibrotic mechanism of angiotensin II

Valsartan attenuates bleomycin-induced pulmonary fibrosis by inhibition of NF-κB expression and regulation of Th1/Th2 cytokines

Ectopic respiratory epithelial cell differentiation in bronchiolised distal airspaces in idiopathic pulmonary fibrosis

Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan

Losartan inhibits STAT1 activation and protects human glomerular mesangial cells from angiotensin II induced premature senescence

Angiotensin II Regulates Th1 T Cell Differentiation Through Angiotensin II Type 1 Receptor-PKA-Mediated Activation of Proteasome

APOE e4 genotype predicts severe COVID-19 in the UK Biobank community cohort

Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with disease severity in COVID-19

Functions of the neuron-specific protein ADAP1 (centaurin-α1) in neuronal differentiation and neurodegenerative diseases, with an overview of structural and biochemical properties of ADAP1

The Differential Expression of Mitochondrial Function-Associated Proteins and Antioxidant Enzymes during Bovine Herpesvirus 1 Infection: A Potential Mechanism for Virus Infection-Induced Oxidative

Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer's disease model

Angiotensin receptor blockers and COVID-19

Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China

SLC43A3 Is a Biomarker of Sensitivity to the Telomeric DNA Damage Mediator 6-Thio-2'-Deoxyguanosine

Identification of a core set of 58 gene transcripts with broad and specific expression in the microvasculature

Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain

Inducible Expression of CXCL1 within the Central Nervous System Amplifies Viral-Induced Demyelination

Dexamethasone for COVID-19? Not so fast

Recovery of severely ill COVID-19 patients by intravenous immunoglobulin (IVIG) treatment: A case series

Repurposing current therapeutics for treating COVID-19: A vital role of prescription records data mining

Angiotensin-II receptor subtypes in fetal tissue of the rat: autoradiography, guanine nucleotide sensitivity, and association with phosphoinositide hydrolysis

Expression and regulation of AT1 receptor in rat lung microvascular endothelial cell

Increased angiotensin II AT1 receptor mRNA and binding in spleen and lung of AT2 receptor gene disrupted mice

The Role of Angiotensin II and Cyclic AMP in Alveolar Active Sodium Transport

Distribution of type-1 and type-2 angiotensin receptors in the normal human lung and in lungs from patients with chronic obstructive pulmonary disease

Angiotensin receptor subtype AT(1) mediates alveolar epithelial cell apoptosis in response to ANG II

LPS induces permeability injury in lung microvascular endothelium via AT(1) receptor

The involvement of type 1a

angiotensin II receptors in the regulation of airway inflammation in a murine model of allergic asthma

The synergistic induction of cyclooxygenase-2 in lung fibroblasts by angiotensin II and pro-inflammatory cytokines

The effect of endogenous angiotensin II on alveolar fluid clearance in rats with acute lung injury

Losartan, a selective inhibitor of subtype AT1 receptors for angiotensin II, inhibits neutrophil recruitment in the lung triggered by fMLP

Nonpeptide antagonists of AT1 receptor for angiotensin II delay the onset of acute respiratory distress syndrome

Effects of olmesartan, an AT1 receptor antagonist, on hypoxia-induced activation of ERK1/2 and pro-inflammatory signals in the mouse lung

Losartan attenuates ventilator-induced lung injury

Losartan, an antagonist of AT1 receptor for angiotensin II, attenuates lipopolysaccharide-induced acute lung injury in rat

Losartan prevents sepsis-induced acute lung injury and decreases activation of nuclear factor kappaB and mitogen-activated protein kinases

Angiotensin II type-1 receptor antagonist attenuates LPS-induced acute lung injury

Amelioration of systemic fibrosis in mice by angiotensin II receptor blockade

Losartan attenuated lipopolysaccharide-induced lung injury by suppression of lectin-like oxidized low-density lipoprotein receptor-1

Cardiovascular and antacid treatment and mortality in oxygen-dependent pulmonary fibrosis: A population-based longitudinal study

Angiotensin II Receptors -Impact for COVID-19

Evidence That Renin-Angiotensin System Inhibitors Should Not Be Discontinued Due to the COVID-19 Pandemic

Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension

ARM IN SARS-COV-2 RELATED LUNG INJURY

Population-based study of statins, angiotensin II receptor blockers, and angiotensin-converting enzyme inhibitors on pneumonia-related outcomes

Treating influenza with statins and other immunomodulatory agents

Potential mechanisms of AT1 receptor blockers on reducing pneumonia-related mortality

Risk of hospitalization for community acquired pneumonia with renin-angiotensin blockade in elderly patients: a population-based study

Comparing individual angiotensin-converting enzyme inhibitors with losartan in the risk of hospitalization for pneumonia and related mortality: a nationwide cohort study

Do outpatient statins and

ACEIs/ARBs have synergistic effects in reducing the risk of pneumonia? A populationbased case-control study

Clinician-initiated research on treating the host response to pandemic influenza

Influence of Renin-Angiotensin System Inhibitors on Lower-Respiratory Tract Infections in Type 2 Diabetes: The Fremantle Diabetes Study Phase II

The association of renin-angiotensin system blockades and pneumonia requiring admission in patients with COPD

Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on the risk of pneumonia and severe exacerbations in patients with COPD

Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: A Promising Medication for Chronic Obstructive Pulmonary Disease?

Losartan prevents sepsis-induced acute lung injury and decreases activation of nuclear factor kappaB and mitogen-activated protein kinases

Candesartan reduces the innate immune response to lipopolysaccharide in human monocytes

Role of the Backbenchers of the Renin-Angiotensin System ACE2 and AT2 Receptors in COVID-19: Lessons From SARS

AGE was supported by the Intramural grant HG200365-09 from the National Human Genome Research Institute, National Institutes of Health.JMS did not receive any support during the preparation of this manuscript.