Angiotensin-converting enzyme 2 inhibits lung injury induced by respiratory syncytial virus.
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ABSTRACT:
SUBMITTER: Gu H
PROVIDER: S-EPMC4728398 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Since March 2013, the emergence of an avian-origin influenza A (H7N9) virus has raised concern in China. Although most infections resulted in respiratory illness, some severe cases resulted in acute respiratory distress syndrome (ARDS), which is a severe form of acute lung injury (ALI) that further contributes to morbidity. To date, no effective drugs that improve the clinical outcome of influenza A (H7N9) virus-infected patients have been identified. Angiotensin-converting enzyme (ACE) and ACE2 are involved in several pathologies such as cardiovascular functions, renal disease, and acute lung injury. In the current study, we report that ACE2 could mediate the severe acute lung injury induced by influenza A (H7N9) virus infection in an experimental mouse model. Moreover, ACE2 deficiency worsened the disease pathogenesis markedly, mainly by targeting the angiotensin II type 1 receptor (AT1). The current findings demonstrate that ACE2 plays a critical role in influenza A (H7N9) virus-induced acute lung injury, and suggest that might be a useful potential therapeutic target for future influenza A (H7N9) outbreaks.
| S-EPMC4229671 | biostudies-literature
Project description:During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world. A new coronavirus (SARS-CoV) was identified as the SARS pathogen, which triggered severe pneumonia and acute, often lethal, lung failure. Moreover, among infected individuals influenza such as the Spanish flu and the emergence of new respiratory disease viruses have caused high lethality resulting from acute lung failure. In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor. The high lethality of SARS-CoV infections, its enormous economic and social impact, fears of renewed outbreaks as well as the potential misuse of such viruses as biologic weapons make it paramount to understand the pathogenesis of SARS-CoV. Here we provide the first genetic proof that ACE2 is a crucial SARS-CoV receptor in vivo. SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway. These results provide a molecular explanation why SARS-CoV infections cause severe and often lethal lung failure and suggest a rational therapy for SARS and possibly other respiratory disease viruses.
| S-EPMC7095783 | biostudies-literature
Project description:The renin-angiotensin system (RAS) plays a major role in liver fibrosis. Recently, a homolog of angiotensin-converting-enzyme 1 (ACE1), termed ACE2, has been identified that appears to be a negative regulator of the RAS by degrading Ang II to Ang(1-7). The aim of this study was to characterize the long-term effects of gene deletion of ACE2 in the liver, to define the role of ACE2 in acute and chronic liver disease, and to characterize the role of Ang(1-7) in hepatic stellate cell (HSC) activation. Ace2 knockout (KO) mice and wild-type (wt) littermates underwent different models of acute and chronic liver injury. Liver pathology was analyzed by histology, immunohistochemistry, alpha smooth muscle actin (alpha-SMA) immunoblotting, and quantitative polymerase chain reaction (qPCR). Murine HSCs were isolated by collagenase-pronase-perfusion, and density gradient centrifugation. One-year-old ace2 KO mice spontaneously developed an inflammatory cell infiltration and mild hepatic fibrosis that was prevented by treatment with irbesartan. Ace2 KO mice showed increased liver fibrosis following bile duct ligation for 21 days or chronic carbon tetrachloride (CCl(4)) treatment. In contrast, ace2 KO mice subjected to acute liver injury models did not differ from wt littermates. Treatment with recombinant ACE2 attenuated experimental fibrosis in the course of cholestatic and toxic liver injury. HSCs express the Ang(1-7) receptor Mas and Ang(1-7) inhibited Ang II-induced phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 in cultured HSCs.ACE2 is a key negative regulator of the RAS and functions to limit fibrosis through the degradation of Ang II and the formation of Ang(1-7). Whereas loss of ACE2 activity worsens liver fibrosis in chronic liver injury models, administration of recombinant ACE2 shows therapeutic potential.
| S-EPMC4734904 | biostudies-literature
Project description:Cadmium (Cd) is a naturally occurring environmental toxicant that disrupts mitochondrial function at occupational exposure levels. The impacts of Cd exposure at low levels through dietary intake remain largely uncharacterized. Human respiratory syncytial virus (RSV) causes severe morbidity, which can require hospitalization and result in death in young children and elderly populations. The impacts of environmental Cd exposure on the severity of RSV disease are unknown. Herein, we used a mouse model to examine whether Cd pre-exposure at a level of dietary intake potentiates pulmonary inflammation on subsequent infection with RSV. Mice were given Cd or saline in drinking water for 28 days. Subsets of these mice were infected with RSV at 5 days before the end of the study. Cd pre-exposure caused relatively subtle changes in lung; however, it elevated the IL-4 level and altered metabolites associated with fatty acid metabolism. After RSV infection, mice pre-exposed to Cd had elevated lung RSV titer and increased inflammation, as measured by histopathology, immune cell infiltration, cytokines, and chemokines. RSV infection after Cd pre-exposure also caused widespread perturbation in metabolism of glycerophospholipids and amino acids (Trp, Met, and Cys, branched-chain amino acids), as well as carnitine shuttle associated with mitochondrial energy metabolism. The results show that Cd burden by dietary intake potentiates RSV infection and severe disease with associated mitochondrial metabolic disruption.
| S-EPMC6717913 | biostudies-literature
Project description:Angiotensin converting enzyme (ACE) is well known for its dual actions to convert inactive Ang I to active Ang II, and degrades active bradykinin (BK), which plays an important role in controlling blood pressure. Because it is the bottleneck step for the production of pressor Ang II, it was targeted pharmacologically in the 1970s. Successful ACE inhibitors such as captopril were produced to treat hypertension. Studies on domain-specific ACE inhibitors are continuing to produce effective hypertension-controlling drugs with fewer side effects. ACE2 was discovered in 2000 and it converts Ang II into Ang(1–7), thereby reducing the concentration of Ang II as well as increasing that of Ang(1–7), an important enzyme for Ang(1–7)/Mas receptor signaling. ACE2 also acts as the receptor in the lung for the coronavirus, causing the infamous severe acute respiratory syndrome (SARS) in 2003.
| S-EPMC8361046 | biostudies-literature
Project description:BackgroundNanoparticles have become a key technology in multiple industries. However, there are growing reports of the toxicity of nanomaterials to humans. In particular, nanomaterials have been linked to lung diseases. The molecular mechanisms of nanoparticle toxicity are largely unexplored.MethodsAcute lung injury was induced in wild-type mice and angiotensin-coverting enzyme 2 (ACE2) knockout mice by the intratracheal instillation of cationic polyamidoamine dendrimer (PAMAM) nanoparticles. For rescue experiments, losartan (15 mg/kg in PBS) was injected intraperitoneally 30 min before nanoparticle administration.ResultsSome PAMAM nanoparticles, but not anionic PAMAM nanoparticles or carbon nanotubes, triggered acute lung failure in mice. Mechanistically, cationic nanoparticles can directly bind ACE2, decrease its activity and down-regulate its expression level in lung tissue, resulting in deregulation of the renin-angiotensin system. Gene inactivation of Ace2 can exacerbate lung injury. Importantly, the administration of losartan, which is an angiotensin II type I receptor antagonist, can ameliorate PAMAM nanoparticle-induced lung injury.ConclusionsOur data provide molecular insight into PAMAM nanoparticle-induced lung injury and suggest potential therapeutic and screening strategies to address the safety of nanomaterials.
| S-EPMC4395934 | biostudies-literature
Project description:Evolution of glomerulonephritis (GN) to tubulointerstitial disease is a universal antecedent to the development of chronic kidney disease (CKD). There is also evidence that angiotensin converting enzyme (ACE) inhibition may attenuate the development of CKD in some forms of glomerulonephritis. We tested the role of ACE inhibition in a model of GN in which complement-dependent tubulointerstitial disease develops. GN was induced in C57BL/6 mice with intraperitoneal injections of horse spleen apoferritin (HSA) using lipopolysaccharide (LPS) as an adjuvant. Four groups of six animals were studied: saline-injected control mice treated with captopril or water, and GN mice treated with captopril or water. GN developed in all HSA-treated animals. In those receiving captopril, however, proteinuria (albumin/creatinine ratio) was significantly reduced by captopril treatment. Array screening was used to examined the expression of collagen-related genes and determine if these effects could be mediated by regulation of collagen genes. Six genes were identified for further analysis by quantitative RT-PCR. This model demonstrates that tubulointerstitial disease can be attenuated by ACE inhibition, with clinical, histologic, and gene expression measures. All protocols were approved by the Institutional Animal Care and Use Committee at SUNY Upstate Medical University. We employed four groups of six mice each: saline-injected control mice with and without captopril, and GN with and without captopril. C57BL/6 mice were purchased from The Jackson Laboratories (Bar Harbor, ME). Glomerulonephritis (GN) was induced by intraperitoneal (i.p.) injection of 10 mg of apoferritin from horse spleen (HSA, Sigma, St. Louis, MO) five days per week, with i.p. injection of 100 micrograms lipopolysaccharide (LPS, from Salmonella minnesota; EMD Biosciences, La Jolla, CA), as adjuvant, three times per week. Control animals received equal volumes of 0.15 M NaCl by i.p. injection. Injections were begun when the mice were approximately eight weeks of age and were continued for six weeks. Captopril, at 100 mg/kg/day was given in the drinking water. After 9 weeks, the animals were euthanized and kidneys were removed for RNA purification and analysis.
2013-07-30 | E-GEOD-49323 | biostudies-arrayexpress
Project description:BACKGROUND: A previous meta-analysis reported a positive association between an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) and the risk of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Here, we updated this meta-analysis and additionally assessed the association of this polymorphism with ALI/ARDS mortality. METHODS: We searched electronic databases through October 2011 for the terms "angiotensin-converting enzyme gene", "acute lung injury", and "acute respiratory distress syndrome," and reviewed all studies that reported the relationship of the I/D polymorphism in ACE with ALI/ARDS in humans. Seven studies met the inclusion criteria, comprising 532 ALI/ARDS patients, 3032 healthy controls, and 1432 patients without ALI/ARDS. We used three genetic models: the allele, dominant, and recessive models. RESULTS: The ACE I/D polymorphism was not associated with susceptibility to ALI/ARDS for any genetic model. However, the ACE I/D polymorphism was associated with the mortality risk of ALI/ARDS in Asian subjects ( P(allele) < 0.0001, P(dominant) = 0.001, P(recessive) = 0.002). This finding remained significant after correction for multiple comparisons. CONCLUSIONS: There is a possible association between the ACE I/D polymorphism genotype and the mortality risk of ALI/ARDS in Asians.
| S-EPMC3459791 | biostudies-other
Project description:Respiratory syncytial virus (RSV) is the most common cause of hospitalization for respiratory tract infection in young children. It is also a significant cause of morbidity and mortality in elderly individuals and in persons with asthma and chronic obstructive pulmonary disease. Currently, no reliable vaccine or simple RSV antiviral therapy is available. Recently, we determined that the minor pulmonary surfactant phospholipid, palmitoyl-oleoyl-phosphatidylglycerol (POPG), could markedly attenuate inflammatory responses induced by lipopolysaccharide through direct interactions with the Toll-like receptor 4 (TLR4) interacting proteins CD14 and MD-2. CD14 and TLR4 have been implicated in the host response to RSV. Treatment of bronchial epithelial cells with POPG significantly inhibited interleukin-6 and -8 production, as well as the cytopathic effects induced by RSV. The phospholipid bound RSV with high affinity and inhibited viral attachment to HEp2 cells. POPG blocked viral plaque formation in vitro by 4 log units, and markedly suppressed the expansion of plaques from cells preinfected with the virus. Administration of POPG to mice, concomitant with viral infection, almost completely eliminated the recovery of virus from the lungs at 3 and 5 days after infection, and abrogated IFN-gamma (IFN-gamma) production and the enhanced expression of surfactant protein D (SP-D). These findings demonstrate an important approach to prevention and treatment of RSV infections using exogenous administration of a specific surfactant phospholipid.
| S-EPMC2806703 | biostudies-literature
Project description:This study examined the role of local complement synthesis in a mouse model of glomerulonephritis, which evolves into progressive tubulointerstitial disease. The model was used to quantitate clinical, histologic, and transcriptomic outcomes, and assess the role of angiotensin conversting enzyme (ACE) inhibition in modifying these measures. We also comprehensively explored the biological pathways and networks exhibiting alterations in gene expression to provide further insight into the role of ACE inhibition in the model.
2018-08-01 | GSE117917 | GEO