scholarly journals Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury

mBio ◽  
2013 ◽  
Vol 4 (4) ◽  
Author(s):  
Lisa E. Gralinski ◽  
Armand Bankhead ◽  
Sophia Jeng ◽  
Vineet D. Menachery ◽  
Sean Proll ◽  
...  

ABSTRACT Systems biology offers considerable promise in uncovering novel pathways by which viruses and other microbial pathogens interact with host signaling and expression networks to mediate disease severity. In this study, we have developed an unbiased modeling approach to identify new pathways and network connections mediating acute lung injury, using severe acute respiratory syndrome coronavirus (SARS-CoV) as a model pathogen. We utilized a time course of matched virologic, pathological, and transcriptomic data within a novel methodological framework that can detect pathway enrichment among key highly connected network genes. This unbiased approach produced a high-priority list of 4 genes in one pathway out of over 3,500 genes that were differentially expressed following SARS-CoV infection. With these data, we predicted that the urokinase and other wound repair pathways would regulate lethal versus sublethal disease following SARS-CoV infection in mice. We validated the importance of the urokinase pathway for SARS-CoV disease severity using genetically defined knockout mice, proteomic correlates of pathway activation, and pathological disease severity. The results of these studies demonstrate that a fine balance exists between host coagulation and fibrinolysin pathways regulating pathological disease outcomes, including diffuse alveolar damage and acute lung injury, following infection with highly pathogenic respiratory viruses, such as SARS-CoV. IMPORTANCE Severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002 and 2003, and infected patients developed an atypical pneumonia, acute lung injury (ALI), and acute respiratory distress syndrome (ARDS) leading to pulmonary fibrosis and death. We identified sets of differentially expressed genes that contribute to ALI and ARDS using lethal and sublethal SARS-CoV infection models. Mathematical prioritization of our gene sets identified the urokinase and extracellular matrix remodeling pathways as the most enriched pathways. By infecting Serpine1-knockout mice, we showed that the urokinase pathway had a significant effect on both lung pathology and overall SARS-CoV pathogenesis. These results demonstrate the effective use of unbiased modeling techniques for identification of high-priority host targets that regulate disease outcomes. Similar transcriptional signatures were noted in 1918 and 2009 H1N1 influenza virus-infected mice, suggesting a common, potentially treatable mechanism in development of virus-induced ALI.

2020 ◽  
Vol 5 (S1) ◽  
pp. 157-159
Author(s):  
Partha Pratim Medhi ◽  
Shashank Bansal ◽  
Faridha Jane Momin ◽  
Ghritashee Bora

The ongoing pandemic of COVID-19 caused by the Severe Acute Respiratory Syndrome Corona virus 2 (SARS-CoV-2) has affected the healthcare system worldwide to a great extent. Millions of people have succumbed to the disease which might vary from mild febrile illness to severe Acute Lung Injury ultimately resulting in ARDS (Acute Respiratory Distress Syndrome). The mechanism of lung pathology due to SARS CoV-2 infection though unclear, is thought to be due to an imbalance in the inflammatory cascade; leading to a condition called Chemokine Release Syndrome. Low dose Radiotherapy which was historically used to treat Pneumonia, can serve as an approach for this subset of patients; by virtue of its anti-inflammatory response. Thus, in the present time, where a perfect cure is yet to derived all possible interventions should be looked upon with a ray of hope. 


2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Yu-bao Qiu ◽  
Bin-bin Wan ◽  
Gang Liu ◽  
Ya-xian Wu ◽  
Dan Chen ◽  
...  

Abstract Background Ferroptosis is a new type of nonapoptotic cell death model that was closely related to reactive oxygen species (ROS) accumulation. Seawater drowning-induced acute lung injury (ALI) which is caused by severe oxidative stress injury, has been a major cause of accidental death worldwide. The latest evidences indicate nuclear factor (erythroid-derived 2)-like 2 (Nrf2) suppress ferroptosis and maintain cellular redox balance. Here, we test the hypothesis that activation of Nrf2 pathway attenuates seawater drowning-induced ALI via inhibiting ferroptosis. Methods we performed studies using Nrf2-specific agonist (dimethyl fumarate), Nrf2 inhibitor (ML385), Nrf2-knockout mice and ferroptosis inhibitor (Ferrostatin-1) to investigate the potential roles of Nrf2 on seawater drowning-induced ALI and the underlying mechanisms. Results Our data shows that Nrf2 activator dimethyl fumarate could increase cell viability, reduced the levels of intracellular ROS and lipid ROS, prevented glutathione depletion and lipid peroxide accumulation, increased FTH1 and GPX4 mRNA expression, and maintained mitochondrial membrane potential in MLE-12 cells. However, ML385 promoted cell death and lipid ROS production in MLE-12 cells. Furthermore, the lung injury became more aggravated in the Nrf2-knockout mice than that in WT mice after seawater drowning. Conclusions These results suggested that Nrf2 can inhibit ferroptosis and therefore alleviate ALI induced by seawater drowning. The effectiveness of ferroptosis inhibition by Nrf2 provides a novel therapeutic target for seawater drowning-induced ALI.


2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Weifeng Yao ◽  
Gangjian Luo ◽  
Guosong Zhu ◽  
Xinjin Chi ◽  
Ailan Zhang ◽  
...  

Objective. This study aimed to investigate whether propofol pretreatment can protect against liver transplantation-induced acute lung injury (ALI) and to explore whether Nrf2 pathway is involved in the protections provided by propofol pretreatment.Method. Adult male Sprague-Dawley rats were divided into five groups based on the random number table. Lung pathology was observed by optical microscopy. Lung water content was assessed by wet/dry ratio, and PaO2was detected by blood gas analysis. The contents of H2O2, MDA, and SOD activity were determined by ELISA method, and the expression of HO-1, NQO1, Keap1, and nuclear Nrf2 was assayed by western blotting.Results. Compared with saline-treated model group, both propofol and N-acetylcysteine pretreatment can reduce the acute lung injury caused by orthotopic autologous liver transplantation (OALT), decrease the lung injury scores, lung water content, and H2O2and MDA levels, and improve the arterial PaO2and SOD activity. Furthermore, propofol (but not N-acetylcysteine) pretreatment especially in high dose inhibited the expression of Keap1 and induced translocation of Nrf2 into the nucleus to further upregulate the expression of HO-1 and NQO1 downstream.Conclusion. Pretreatment with propofol is associated with attenuation of OALT-induced ALI, and the Nrf2 pathway is involved in the antioxidative processes.


2012 ◽  
Vol 40 (4) ◽  
pp. 1309-1316 ◽  
Author(s):  
Robinder G. Khemani ◽  
Neal J. Thomas ◽  
Vani Venkatachalam ◽  
Jason P. Scimeme ◽  
Ty Berutti ◽  
...  

2021 ◽  
Vol 2021 ◽  
pp. 1-22
Author(s):  
Yiru Shao ◽  
Zhifeng Jiang ◽  
Daikun He ◽  
Jie Shen

Phosgene exposure can cause acute lung injury (ALI), for which there is no currently available effective treatment. Mesenchymal stem cells (MSCs) which have been proven to have therapeutic potential and be helpful in the treatment of various diseases, but the mechanisms underlying the function of MSCs against phosgene-induced ALI are still poorly explored. In this study, we compared the expression profiles of mRNAs, lncRNAs, and circRNAs in the lung tissues from rats of three groups—air control (group A), phosgene-exposed (group B), and phosgene + MSCs (group C). The results showed that 389 mRNAs, 198 lncRNAs, and 56 circRNAs were differently expressed between groups A and B; 130 mRNAs, 107 lncRNAs, and 35 circRNAs between groups A and C; and 41 mRNAs, 88 lncRNAs, and 18 circRNAs between groups B and C. GO and KEGG analyses indicated that the differentially expressed RNAs were mainly involved in signal transduction, immune system processes, and cancers. In addition, we used a database to predict target microRNAs (miRNAs) interacting with circRNAs and the R network software package to construct a circRNA-targeted miRNA gene network map. Our study showed new insights into changes in the RNA expression in ALI, contributing to explore the mechanisms underlying the therapeutic potential of MSCs in phosgene-induced ALI.


2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
Jian-Yu Liu ◽  
Ying-Xiao Jiang ◽  
Meng-Yu Zhang ◽  
Chen Huo ◽  
Yi-Can Yang ◽  
...  

Background. Acute lung injury (ALI) is a fatal syndrome frequently induced by lipopolysaccharide (LPS) released from the bacterial cell wall. LPS could also trigger autophagy of lung bronchial epithelial cell to relieve the inflammation, while the overwhelming LPS would impair the balance of autophagy consequently inducing serious lung injury. Methods. We observed the autophagy variation of 16HBE, human bronchial epithelial cell, under exposure to different concentrations of LPS through western blot, immunofluorescence staining, and electron microscopy. Eight strands of 16HBE were divided into two groups upon 1000 ng/ml LPS stimulation or not, which were sent to be sequenced at whole transcriptome. Subsequently, we analyzed the sequencing data in functional enrichment, pathway analysis, and candidate gene selection and constructed a hsa-miR-663b-related competing endogenous RNA (ceRNA) network. Results. We set a series of concentrations of LPS to stimulate 16HBE and observed the variation of autophagy in related protein expression and autophagosome count. We found that the effective concentration of LPS was 1000 ng/ml at 12 hours of exposure and sequenced the 1000 ng/ml LPS-stimulated 16HBE. As a result, a total of 750 differentially expressed genes (DEGs), 449 differentially expressed lncRNAs (DElncRNAs), 76 differentially expressed circRNAs (DEcircRNAs), and 127 differentially expressed miRNAs (DEmiRNAs) were identified. We constructed the protein-protein interaction (PPI) network to visualize the interaction between DEGs and located 36 genes to comprehend the core discrepancy between LPS-stimulated 16HBE and the negative control group. In combined analysis of differentially expressed RNAs (DERNAs), we analyzed all the targeted relationships of ceRNA in DERNAs and figured hsa-miR-663b as a central mediator in the ceRNA network to play when LPS induced the variation of autophagy in 16HBE. Conclusion. Our research indicated that the hsa-miR-663b-related ceRNA network may contribute to the key regulatory mechanism in LPS-induced changes of autophagy and ALI.


2020 ◽  
Author(s):  
Yu-bao Qiu ◽  
Bin-bin Wan ◽  
Gang Liu ◽  
Ya-xian Wu ◽  
Dan Chen ◽  
...  

Abstract Background: Ferroptosis is a new type of nonapoptotic cell death model that was closely related to reactive oxygen species (ROS) accumulation. Seawater drowning-induced acute lung injury (ALI) which is caused by severe oxidative stress injury, has been a major cause of accidental death worldwide. The latest evidences indicate nuclear factor (erythroid-derived 2)-like 2 (Nrf2) suppress ferroptosis and maintain cellular redox balance. Here, we test the hypothesis that activation of Nrf2 pathway attenuates seawater drowning-induced ALI via inhibiting ferroptosis.Methods: we performed studies using Nrf2-specific agonist (dimethyl fumarate), Nrf2 inhibitor (ML385), Nrf2-knockout mice and ferroptosis inhibitor (Ferrostatin-1) to investigate the potential roles of Nrf2 on seawater drowning-induced ALI and the underlying mechanisms.Results: Our data shows that Nrf2 activator dimethyl fumarate could increase cell viability, reduced the levels of intracellular ROS and lipid ROS, prevented glutathione depletion and lipid peroxide accumulation, increased FTH1 and GPX4 mRNA expression, and maintained mitochondrial membrane potential in MLE-12 cells. However, ML385 promoted cell death and lipid ROS production in MLE-12 cells. Furthermore, the lung injury became more aggravated in the Nrf2-knockout mice than that in WT mice after seawater drowning.Conclusions: These results suggested that Nrf2 can inhibit ferroptosis and therefore alleviate ALI induced by seawater drowning. The effectiveness of ferroptosis inhibition by Nrf2 provides a novel therapeutic target for seawater drowning-induced ALI.


2011 ◽  
Vol 85 (9) ◽  
pp. 4234-4245 ◽  
Author(s):  
S. L. Smits ◽  
J. M. A. van den Brand ◽  
A. de Lang ◽  
L. M. E. Leijten ◽  
W. F. van IJcken ◽  
...  

2005 ◽  
Vol 73 (3) ◽  
pp. 1754-1763 ◽  
Author(s):  
Samithamby Jeyaseelan ◽  
Hong Wei Chu ◽  
Scott K. Young ◽  
Mason W. Freeman ◽  
G. Scott Worthen

ABSTRACT Acute lung injury (ALI) induced by lipopolysaccharide (LPS) is a major cause of mortality among humans. ALI is characterized by microvascular protein leakage, neutrophil influx, and expression of proinflammatory mediators, followed by severe lung damage. LPS binding to its receptors is the crucial step in the causation of these multistep events. LPS binding and signaling involves CD14 and Toll-like receptor 4 (TLR4). However, the relative contributions of CD14 and TLR4 in the induction of ALI and their therapeutic potentials are not clear in vivo. Therefore, the aim of the present study was to compare the roles of CD14 and TLR4 in LPS-induced ALI to determine which of these molecules is the more critical target for attenuating ALI in a mouse model. Our results show that CD14 and TLR4 are necessary for low-dose (300-μg/ml) LPS-induced microvascular leakage, NF-κB activation, neutrophil influx, cytokine and chemokine (KC, macrophage inflammatory protein 2, tumor necrosis factor alpha, interleukin-6) expression, and subsequent lung damage. On the other hand, when a 10-fold-higher dose of LPS (3 mg/ml) was used, these responses were only partially dependent on CD14 and they were totally dependent on TLR4. The CD14-independent LPS response was dependent on CD11b. A TLR4 blocking antibody abolished microvascular leakage, neutrophil accumulation, cytokine responses, and lung pathology with a low dose of LPS but only attenuated the responses with a high dose of LPS. These data are the first to demonstrate that LPS-induced CD14-depdendent and -independent (CD11b-dependent) signaling pathways in the lung are entirely dependent on TLR4 and that blocking TLR4 might be beneficial in lung diseases caused by LPS from gram-negative pathogens.


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