Protein S is Protective in Acute Lung Injury by Inhibiting Cell Apoptosis

Acute lung injury is a fatal disease characterized by inflammatory cell infiltration, alveolar-capillary barrier disruption, protein-rich edema, and impairment of gas exchange. Protein S is a vitamin K-dependent glycoprotein that exerts anticoagulant, immunomodulatory, anti-inflammatory, anti-apoptotic, and neuroprotective effects. The aim of this study was to evaluate whether human protein S inhibits cell apoptosis in acute lung injury. Acute lung injury in human protein S transgenic and wild-type mice was induced by intratracheal instillation of lipopolysaccharide. The effect of human protein S on apoptosis of lung tissue cells was evaluated by Western blotting. Inflammatory cell infiltration, alveolar wall thickening, myeloperoxidase activity, and the expression of inflammatory cytokines were reduced in human protein S transgenic mice compared to the wild-type mice after lipopolysaccharide instillation. Apoptotic cells and caspase-3 activity were reduced while phosphorylation of extracellular signal-regulated kinase was enhanced in the lung tissue from human protein S transgenic mice compared to wild-type mice after lipopolysaccharide instillation. The results of this study suggest that human protein S is protective in lipopolysaccharide-induced acute lung injury by inhibiting apoptosis of lung cells.

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Class B Scavenger Receptors BI and BII Protect Against LPS-induced Acute Lung Injury in Mice by Mediating LPS Clearance

Infection and Immunity ◽

10.1128/iai.00301-21 ◽

2021 ◽

Author(s):

Irina N. Baranova ◽

Alexander V. Bocharov ◽

Tatyana G. Vishnyakova ◽

Zhigang Chen ◽

Anna A. Birukova ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Transgenic Mice ◽

Neutrophil Infiltration ◽

Lavage Fluid ◽

Protective Role ◽

Lung Damage ◽

Wild Type ◽

Class B ◽

Anti Inflammatory

Recent studies suggest an anti-inflammatory protective role for class B scavenger receptor BI (SR-BI) in endotoxin-induced inflammation and sepsis. Other data, including ours, provide evidence for an alternative role of SR-BI, facilitating bacterial and endotoxin uptake, and contributing to inflammation and bacterial infection. Enhanced endotoxin susceptibility of SR-BI deficient mice due to their anti-inflammatory glucocorticoid deficiency complicates understanding SR-BI’s role in endotoxemia/sepsis, calling for use of alternative models. In this study, using hSR-BI and hSR-BII transgenic mice, we found that SR-BI and to a lesser extent its splicing variant SR-BII, protects against LPS-induced lung damage. At 20 hours after intratracheal LPS instillation the extent of pulmonary inflammation and vascular leakage was significantly lower in hSR-BI and hSR-BII transgenic mice compared to wild type mice. Higher bronchoalveolar lavage fluid (BALF) inflammatory cell count and protein content as well as lung tissue neutrophil infiltration found in wild type mice was associated with markedly (2-3 times) increased pro-inflammatory cytokine production as compared to transgenic mice following LPS administration. Markedly lower endotoxin levels detected in BALF of transgenic vs. wild type mice along with the significantly increased BODIPY-LPS uptake observed in lungs of hSR-BI and hSR-BII mice 20 hours after the IT LPS injection suggest that hSR-BI and hSR-BII-mediated enhanced LPS clearance in the airways could represent the mechanism of their protective role against LPS-induced acute lung injury.

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MiR-574-5p alleviates sepsis-induced acute lung injury by regulating TRAF6/NF-κB pathway

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v19i4.1 ◽

2020 ◽

Vol 19 (4) ◽

pp. 676-682

Author(s):

Changfu Xu ◽

Lei Chong ◽

Gang Yu ◽

Hailin Zhang

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Cell ◽

Inflammatory Responses ◽

Cecal Ligation ◽

Cytokine Expression ◽

Inflammatory Cell Infiltration ◽

Luciferase Assay ◽

Cell Infiltration ◽

Mice Model

Purpose: To investigate the protective effect of miR-574-5p pretreatment against acute lung injury (ALI) induced by sepsis.Methods: A male C57BL/6 mouse model of sepsis-induced ALI was established by cecal ligation and puncture (CLP) and treated with miR-574-5p agomir (intravenous injection, 80 mg/kg per day, 3 days). After that, blood and lung samples were obtained for histopathological observation. Myeloperoxidase (MPO) activity, inflammatory cell infiltration, and cytokine expression were analyzed. The target gene of miR-574-5p was predicted using TargetScan prediction, and verified by luciferase assay and western blot.Results: In sepsis-induced ALI mice model, downregulation of miR-574-5p was observed. Pretreatment of miR-574-5p significantly alleviated ALI by suppressing histological damage, and reducing MPO activity and inflammatory cell infiltration, as well as decreasing cytokine expression. The underlying mechanism was that miR-574-5p targeted TNF receptor associated factor 6 (TRAF6) and suppressed the downstream NF-κB pathway. Moreover, TRAF6 overexpression reversed the effects of miR-574-5p on ALI.Conclusion: MiR-574-5p pretreatment suppresses inflammatory responses, thus reducing lung injury induced by sepsis in mice, partly via the regulation of TRAF6 and NF-κB pathway. Therefore, this approach can potentially be used for the clinical management of ALI in humans Keywords: Sepsis, Acute lung injury, MiR-574-5p, TRAF6, NF-κB pathway

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Intratracheal Transplantation of Trophoblast Stem Cells Attenuates Acute Lung Injury in Mice

10.21203/rs.3.rs-63519/v1 ◽

2020 ◽

Author(s):

Junwen Han ◽

Gu Li ◽

Minmin Hou ◽

Min-Young Kwon ◽

Kevin Xiong ◽

...

Keyword(s):

Stem Cells ◽

Acute Lung Injury ◽

Epithelial Cells ◽

Lung Injury ◽

Lung Tissue ◽

Cell Apoptosis ◽

Type I ◽

Trophoblast Stem Cells ◽

Alveolar Epithelial ◽

Trophoblast Stem

Abstract BackgroundAcute lung injury (ALI) is a common lung disorder that affects millions of people every year. The infiltration of inflammatory cells into the lungs and death of the alveolar epithelial cells are key factors to trigger a pathological cascade. Trophoblast stem cells (TSCs) have been shown to possess immune privilege, immunomodulation, and the potential of self-renewal and multipotency with differentiation into three germ layers. We hypothesized that intratracheal transplantation of TSCs may alleviate ALI.MethodsALI was induced by intratracheal delivery of Bleomycin (BLM) in mice. At day 3 after exposure to BLM, pre-labeled TSCs or Fibroblasts (FBs) were intratracheally administered into the lungs. At day 7 after exposure to BLM, histological analyses of the lungs were performed for inflammatory infiltrates, cell apoptosis, and engraftment of TSCs. Pro-inflammatory cytokines/chemokines of lung tissue and in bronchoalveolar lavage fluid (BALF) were also assessed by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assays , respectively. Flow cytometry was utilized to assess engraftment of TSCs and cell apoptosis.Results Histological analyses of the lungs displayed a reduction in cellularity and less thickening of the alveolar walls in ALI mice that received TSCs compared with ALI mice receiving PBS or FBs. TSCs decreased infiltration of neutrophils and macrophages, and the expression of interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) and keratinocyte-derived chemokine in the injured lungs. The levels of IL-6 and MCP-1 in BALF were decreased in ALI mice receiving TSCs, compared with ALI mice that received PBS or FBs. Terminal deoxynucleotidyl transferase dUTP nick end labeling confirmed that TSCs significantly reduced BLM-induced apoptosis of lung tissue in vivo and epithelial cells in vitro . Transplanted TSCs integrated into the alveolar walls and expressed aquaporin 5 and prosurfactant protein C, markers for alveolar epithelial type I and II cells, respectively. ConclusionIntratracheal transplantation of TSCs into the lungs of mice after acute exposure to BLM reduced pulmonary inflammation and cell death. Furthermore, TSCs engrafted into the alveolar walls to form alveolar epithelial type I and II cells. These data support the use of TSCs for the treatment of ALI.

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Paeoniflorin protects against lipopolysaccharide-induced acute lung injury in mice by alleviating inflammatory cell infiltration and microvascular permeability

Inflammation Research ◽

10.1007/s00011-011-0359-9 ◽

2011 ◽

Vol 60 (10) ◽

pp. 981-990 ◽

Cited By ~ 36

Author(s):

Haiqiang Zhou ◽

Difei Bian ◽

Xiaolan Jiao ◽

Zhifeng Wei ◽

Haofang Zhang ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Cell ◽

Microvascular Permeability ◽

Inflammatory Cell Infiltration ◽

Cell Infiltration

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Long non-coding RNA OIP5-AS1 aggravates acute lung injury by promoting inflammation and cell apoptosis via regulating the miR-26a-5p/TLR4 axis

BMC Pulmonary Medicine ◽

10.1186/s12890-021-01589-1 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Qingsong Sun ◽

Man Luo ◽

Zhiwei Gao ◽

Xiang Han ◽

Weiqin Wu ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Response ◽

Cell Apoptosis ◽

Quantitative Polymerase Chain Reaction ◽

Luciferase Reporter ◽

Enzyme Linked Immunosorbent Assay ◽

Interacting Protein ◽

Wide Range

Abstract Background Acute lung injury (ALI) is a pulmonary disorder that leads to acute respiration failure and thereby results in a high mortality worldwide. Increasing studies have indicated that toll-like receptor 4 (TLR4) is a promoter in ALI, and we aimed to explore the underlying upstream mechanism of TLR4 in ALI. Methods We used lipopolysaccharide (LPS) to induce an acute inflammatory response in vitro model and a murine mouse model. A wide range of experiments including reverse transcription quantitative polymerase chain reaction, western blot, enzyme linked immunosorbent assay, flow cytometry, hematoxylin–eosin staining, RNA immunoprecipitation, luciferase activity and caspase-3 activity detection assays were conducted to figure out the expression status, specific role and potential upstream mechanism of TLR4 in ALI. Result TLR4 expression was upregulated in ALI mice and LPS-treated primary bronchial/tracheal epithelial cells. Moreover, miR-26a-5p was confirmed to target TLR4 according to results of luciferase reporter assay. In addition, miR-26a-5p overexpression decreased the contents of proinflammatory factors and inhibited cell apoptosis, while upregulation of TLR4 reversed these effects of miR-26a-5p mimics, implying that miR-26a-5p alleviated ALI by regulating TLR4. Afterwards, OPA interacting protein 5 antisense RNA 1 (OIP5-AS1) was identified to bind with miR-26a-5p. Functionally, OIP5-AS1 upregulation promoted the inflammation and miR-26a-5p overexpression counteracted the influence of OIP5-AS1 upregulation on cell inflammatory response and apoptosis. Conclusion OIP5-AS1 promotes ALI by regulating the miR-26a-5p/TLR4 axis in ALI mice and LPS-treated cells, which indicates a promising insight into diagnostics and therapeutics in ALI.

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Effect of Qinbai Qingfei Concentrated Pellets on substance P and neutral endopeptidase of rats with post-infectious cough

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-020-03081-5 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Weigang Jia ◽

Wei Wang ◽

Rui Li ◽

Quanyu Zhou ◽

Ying Qu ◽

...

Keyword(s):

Substance P ◽

Inflammatory Cytokines ◽

Lung Tissue ◽

Inflammatory Cell ◽

Neutral Endopeptidase ◽

Inflammatory Cell Infiltration ◽

Lung Damage ◽

Cell Infiltration ◽

Cough Frequency ◽

Post Infectious

Abstract Background In recent years, it has been reported that Qinbai Qingfei Concentrated Pellet (QQCP) has the effect of relieving cough and reducing sputum. However, the therapeutic potentials of QQCP on post-infectious cough (PIC) rat models has not been elucidated. So the current study was aimed to scientifically validate the efficacy of QQCP in post infectious cough. Methods All rats were exposed to sawdust and cigarette smokes for 10 days, and intratracheal lipopolysaccharide (LPS) and capsaicin aerosols. Rats were treated with QQCP at dose of 80, 160, 320 mg/kg. Cough frequency was monitored twice a day for 10 days after drug administration. Inflammatory cell infiltration was determined by ELISA. Meanwhile, the histopathology of lung tissue and bronchus in rats were evaluated by hematoxylin-eosin staining (H&E). Neurogenetic inflammation were measured by ELISA and qRT-PCR. Results QQCP dose-dependently decreased the cough frequency and the release of pro-inflammatory cytokines TNF-α, IL-1β, IL-6 and IL-8, but exerted the opposite effects on the secretion of anti-inflammatory cytokines IL-10 and IL-13 in BALF and serum of PIC rats. The oxidative burden was effectively ameliorated in QQCP-treated PIC rats as there were declines in Malondialdehyde (MDA) content and increases in Superoxide dismutase (SOD) activity in the serum and lung tissue. In addition, QQCP blocked inflammatory cell infiltration into the lung as evidenced by the reduced number of total leukocytes and the portion of neutrophils in the broncho - alveolar lavage fluid (BALF) as well as the alleviated lung damage. Furthermore, QQCP considerable reversed the neurogenetic inflammation caused by PIC through elevating neutral endopeptidase (NEP) activity and reducing Substance P (SP) and Calcitonin gene related peptide (CGRP) expression in BALF, serum and lung tissue. Conclusions Our study indicated that QQCP demonstrated a protective role of PIC and may be a potential therapeutic target of PIC.

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Gut Lymph Purification in Rats With Acute Lung Injury Caused By Gut Ischemia Reperfusion Injury

10.21203/rs.3.rs-606735/v1 ◽

2021 ◽

Author(s):

Can Jin ◽

Shucheng Zhang ◽

Linlin Wu ◽

Bohan Li ◽

Meimei Shi ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Reperfusion Injury ◽

Lung Tissue ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Mononuclear Phagocyte ◽

Alveolar Epithelial Cells ◽

Expression Level ◽

Tissue Samples

Abstract Rationale: It is unclear whether removing the danger-associated molecular patterns (DAMPs) of gut lymph (GL) in the rats of gut ischemia-reperfusion injury (GIRI) model may reduce the distant organ lung injury.Objective: To determine whether oXiris gut lymph purification (GLP) may remove the DAMPs of GL in the rats’ model of acute lung injury (ALI) caused by GIRI.Methods: The experimental rats were divided into four groups: Sham group, GIRI group, GIRI + gut lymph drainage (GLD) group, and GIRI + GLP group. After successful modeling, the lung tissue samples of rats in each group were taken for hematoxylin-eosin (HE) staining and detection of expression levels of apoptotic indexes. The level of DAMPs was detected in blood and lymph. We observed its microstructure of type II alveolar epithelial cells (AECⅡ), and detected the expression level of apoptosis indexes.Measurements and Main Results: GIRI-induced destruction of alveolar structure, thickened alveolar walls, inflammatory cell infiltration emerged in the GIRI group, HMGB-1 and IL-6 levels significantly increased, and HSP70 and IL-10 levels reduced in lymph and serum. Compared with GIRI group, the lung tissue damage in GIRI + GLP group significantly improved, the expression level of HMGB-1 and IL-6 in the lymph and serum reduced, and HSP70 and IL-10 increased. The organelle structure of AECII in GIRI + GLP group was significantly improved compared with the GIRI group. Conclusions: oXiris GLP blocks the key link between DAMPs and mononuclear phagocyte system to inhibit inflammation and cell apoptosis, thereby reducing ALI induced by GIRI.

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