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Effects of Bacterial Translocation and Autophagy on Acute Lung Injury Induced by Severe Acute Pancreatitis.

ABSTRACT: Aim:To reveal the role of bacterial translocation (BT) and autophagy in severe acute pancreatitis-induced acute lung injury (SAP-ALI). Methods:Rats were separated into a control (sham-operation) group (n = 10) and a SAP group (n = 10) and a SAP group (. Results:Levels of TNF-?, IL-6, lipase, and amylase in the SAP group were significantly higher than those in the control group (P < 0.01). Histopathological score and W/D ratio of the lung in the SAP-BT(+) group were significantly higher than that in the SAP-BT(-) group (P < 0.01). Histopathological score and W/D ratio of the lung in the SAP-BT(+) group were significantly higher than that in the SAP-BT(-) group (P < 0.01). Histopathological score and W/D ratio of the lung in the SAP-BT(+) group were significantly higher than that in the SAP-BT(-) group (P < 0.01). Histopathological score and W/D ratio of the lung in the SAP-BT(+) group were significantly higher than that in the SAP-BT(-) group (P < 0.01). Histopathological score and W/D ratio of the lung in the SAP-BT(+) group were significantly higher than that in the SAP-BT(-) group (P < 0.01). Histopathological score and W/D ratio of the lung in the SAP-BT(+) group were significantly higher than that in the SAP-BT(-) group (. Conclusions:BT can aggravate SAP-ALI with the increasing oxidative stress level, which may be related to the decrease of autophagy level.

SUBMITTER: Wang H

PROVIDER: S-EPMC7040400 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Effects of Bacterial Translocation and Autophagy on Acute Lung Injury Induced by Severe Acute Pancreatitis.

Wang Hanlin H Li Chang C Jiang Yingjian Y Li Hongbo H Zhang Dianliang D

Gastroenterology research and practice 20200213

<h4>Aim</h4>To reveal the role of bacterial translocation (BT) and autophagy in severe acute pancreatitis-induced acute lung injury (SAP-ALI).<h4>Methods</h4>Rats were separated into a control (sham-operation) group (<i>n</i> = 10) and a SAP group (<i>n</i> = 10) and a SAP group (.<h4>Results</h4>Levels of TNF-<i>α</i>, IL-6, lipase, and amylase in the SAP group were significantly higher than those in the control group (<i>P</i> < 0.01). Histopathological score and W/D ratio of the lung in the S ...[more]

PMID: 32104173

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Project description:BACKGROUND:Acute lung injury (ALI) is a common and life-threatening complication of severe acute pancreatitis (SAP). There are currently limited effective treatment options for SAP and associated ALI. Calycosin (Cal), a bioactive constituent extracted from the medicinal herb Radix Astragali exhibits potent anti-inflammatory properties, but its effect on SAP and associated ALI has yet to be determined. AIM:To identify the roles of Cal in SAP-ALI and the underlying mechanism. METHODS:SAP was induced via two intraperitoneal injections of L-arg (4 g/kg) and Cal (25 or 50 mg/kg) were injected 1 h prior to the first L-arg challenge. Mice were sacrificed 72 h after the induction of SAP and associated ALI was examined histologically and biochemically. An in vitro model of lipopolysaccharide (LPS)-induced ALI was established using A549 cells. Immunofluorescence analysis and western blot were evaluated in cells. Molecular docking analyses were conducted to examine the interaction of Cal with HMGB1. RESULTS:Cal treatment substantially reduced the serum amylase levels and alleviated histopathological injury associated with SAP and ALI. Neutrophil infiltration and lung tissue levels of neutrophil mediator myeloperoxidase were reduced in line with protective effects of Cal against ALI in SAP. Cal treatment also attenuated the serum levels and mRNA expression of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-6, IL-1β, HMGB1 and chemokine (CXC motif) ligand 1 in lung tissue. Immunofluorescence and western blot analyses showed that Cal treatment markedly suppressed the expression of HMGB1 and phosphorylated nuclear factor-kappa B (NF-κB) p65 in lung tissues and an in vitro model of LPS-induced ALI in A549 cells suggesting a role for HGMB1 in the pathogenesis of ALI. Furthermore, molecular docking analysis provided evidence for the direct interaction of Cal with HGMB1. CONCLUSION:Cal protects mice against L-arg-induced SAP and associated ALI by attenuating local and systemic neutrophil infiltration and inflammatory response via inhibition of HGMB1 and the NF-κB signaling pathway.

Project description:Qingyi decoction (QYD) has anti-inflammatory pharmacological properties and substantial therapeutic benefits on severe acute pancreatitis (SAP) in clinical practice. However, its protective mechanism against SAP-associated acute lung injury (ALI) remains unclear. In this study, we screened the active ingredients of QYD from the perspective of network pharmacology to identify its core targets and signaling pathways against SAP-associated ALI. Rescue experiments were used to determine the relationship between QYD and ferroptosis. Then, metabolomics and 16s rDNA sequencing were used to identify differential metabolites and microbes in lung tissue. Correlation analysis was utilized to explore the relationship between core targets, signaling pathways, metabolic phenotypes, and microbial flora, sorting out the potential molecular network of QYD against SAP-associated lung ALI. Inflammatory damage was caused by SAP in the rat lung. QYD could effectively alleviate lung injury, improve respiratory function, and significantly reduce serum inflammatory factor levels in SAP rats. Network pharmacology and molecular docking identified three key targets: ALDH2, AnxA1, and ICAM-1. Mechanistically, QYD may inhibit ferroptosis by promoting the ALDH2 expression and suppress neutrophil infiltration by blocking the cleavage of intact AnxA1 and downregulating ICAM-1 expression. Ferroptosis activator counteracts the pulmonary protective effect of QYD in SAP rats. In addition, seven significant differential metabolites were identified in lung tissues. QYD relatively improved the lung microbiome's abundance in SAP rats. Further correlation analysis determined the correlation between ferroptosis, differential metabolites, and differential microbes. In this work, the network pharmacology, metabolomics, and 16s rDNA sequencing were integrated to uncover the mechanism of QYD against SAP-associated ALI. This novel integrated method may play an important role in future research on traditional Chinese medicine.

Project description:UnlabelledSystems 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.ImportanceSevere 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.

Dataset Information

Effects of Bacterial Translocation and Autophagy on Acute Lung Injury Induced by Severe Acute Pancreatitis.

Publications

Effects of Bacterial Translocation and Autophagy on Acute Lung Injury Induced by Severe Acute Pancreatitis.

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