scholarly journals Genetic inactivation of the phospholipase A2 activity of peroxiredoxin 6 in mice protects against LPS-induced acute lung injury

2019 ◽  
Vol 316 (4) ◽  
pp. L656-L668 ◽  
Author(s):  
José Pablo Vázquez-Medina ◽  
Jian-Quin Tao ◽  
Priyal Patel ◽  
Renata Bannitz-Fernandes ◽  
Chandra Dodia ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Phospholipase A2 ◽  
Oxidant Stress ◽  
Lavage Fluid ◽  
Lung Lavage ◽  
Mutant Mice ◽  
Peroxiredoxin 6 ◽  
Pyrin Domain

Peroxiredoxin 6 (Prdx6) is a multifunctional enzyme that serves important antioxidant roles by scavenging hydroperoxides and reducing peroxidized cell membranes. Prdx6 also plays a key role in cell signaling by activating the NADPH oxidase, type 2 (Nox2) through its acidic Ca2+-independent phospholipase A2 (aiPLA2) activity. Nox2 generation of O2·−, in addition to signaling, can contribute to oxidative stress and inflammation such as during sepsis-induced acute lung injury (ALI). To evaluate a possible role of Prdx6-aiPLA2 activity in the pathophysiology of ALI associated with a systemic insult, wild-type (WT) and Prdx6-D140A mice, which lack aiPLA2 but retain peroxidase activity were administered intraperitoneal LPS. LPS-treated mutant mice had increased survival compared with WT mice while cytokines in lung lavage fluid and lung VCAM-1 expression, nitrotyrosine levels, PMN infiltration, and permeability increased in WT but not in mutant mice. Exposure of mouse pulmonary microvascular endothelial cells in primary culture to LPS promoted phosphorylation of Prdx6 and its translocation to the plasma membrane and increased aiPLA2 activity as well as increased H2O2 generation, nitrotyrosine levels, lipid peroxidation, NF-κB nuclear localization, and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome assembly; these effects were not seen in Nox2 null cells, Prdx6-D140A cells, or WT cells pretreated with MJ33, an inhibitor of aiPLA2 activity. Thus aiPLA2 activity is needed for Nox2-derived oxidant stress associated with LPS exposure. Since inactivation of aiPLA2 reduced mortality and prevented lung inflammation and oxidative stress in this animal model, the aiPLA2 activity of Prdx6 could be a novel target for prevention or treatment of sepsis-induced ALI.

scholarly journals The serpentine path to a novel mechanism-based inhibitor of acute inflammatory lung injury

2014 ◽  
Vol 116 (12) ◽  
pp. 1521-1530 ◽  
Author(s):  
Aron B. Fisher
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Oxidant Stress ◽  
Lung Surfactant ◽  
Phospholipase A ◽  
Peroxiredoxin 6 ◽  
The Past ◽  
Research Activities ◽  
Novel Target ◽  
Nadph Oxidase Activation

The Comroe lecture on which this review is based described my research path during the past 45 years, beginning with studies of oxidant stress (hyperoxia) and eventuating in the discovery of a synthetic inhibitor of phospholipase A2activity (called MJ33) that prevents acute lung injury in mice exposed to lipopolysaccharide. In between were studies of lung ischemia, lung surfactant metabolism, the protein peroxiredoxin 6 and its phospholipase A2activity, and mechanisms for NADPH oxidase activation. These seemingly unrelated research activities provided the nexus for identification of a novel target and a potentially novel therapeutic agent for prevention or treatment of acute lung injury.

scholarly journals Prophylactic treatment with MSC-derived exosomes attenuates traumatic acute lung injury in rats

2019 ◽  
Vol 316 (6) ◽  
pp. L1107-L1117 ◽  
Author(s):  
Qing-Chun Li ◽  
Yun Liang ◽  
Zhen-Bo Su
Keyword(s):  
Oxidative Stress ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Purinergic Receptor ◽  
Dry Weight ◽  
Lavage Fluid ◽  
Inflammatory Factors ◽  
Sprague Dawley ◽  
Stress Injury ◽  
Potential Strategy

The mesenchymal stem cell (MSC) is a potential strategy in the pretreatment of traumatic acute lung injury (ALI), a disease that causes inflammation and oxidative stress. This study aimed to investigate whether MSC-exosomal microRNA-124-3p (miR-124-3p) affects traumatic ALI. Initially, a traumatic ALI rat model was established using the weight-drop method. Then, exosomes were obtained from MSCs of Sprague-Dawley rats, which were injected into the traumatic ALI rats. We found that miR-124-3p was abundantly-expressed in MSCs-derived exosomes and could directly target purinergic receptor P2X ligand-gated ion channel 7 (P2X7), which was overexpressed in traumatic ALI rats. After that, a loss- and gain-of-function study was performed in MSCs and traumatic ALI rats to investigate the role of miR-124-3p and P2X7 in traumatic ALI. MSC-derived exosomal miR-124-3p or silenced P2X7 was observed to increase the survival rate of traumatic ALI rats and enhance the glutathione/superoxide dismutase activity in their lung tissues. However, the wet/dry weight of lung tissues, activity of methylenedioxyamphetamine and H2O2, and levels of inflammatory factors (TNF-a, IL-6, and IL-8) were reduced. Similarly, the numbers of total cells, macrophages, neutrophils, and lymphocytes in bronchoalveolar lavage fluid were also reduced when treated with exosomal miR-124-3p or silenced P2X7. In conclusion, the results provide evidence that miR-124-3p transferred by MSC-derived exosomes inhibited P2X7 expression, thus improving oxidative stress injury and suppressing inflammatory response in traumatic ALI, highlighting a potential pretreatment for traumatic ALI.

Attenuation of Lung Inflammation by Adrenergic Agonists in Murine Acute Lung Injury

2001 ◽  
Vol 95 (4) ◽  
pp. 947-953 ◽  
Author(s):  
Vinay K. Dhingra ◽  
Ari Uusaro ◽  
Cheryl L. Holmes ◽  
Keith R. Walley
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Response ◽  
Interleukin 6 ◽  
Lavage Fluid ◽  
Lung Lavage ◽  
Adrenergic Agonists ◽  
Beta Adrenergic ◽  
Beta Adrenergic Agonists ◽  
Inflammatory Protein

Background Acute lung injury leading to a systemic inflammatory response greatly increases mortality in critically ill patients. Cardiovascular management of these patients frequently involves beta-adrenergic agonists. These agents may alter the inflammatory response. Therefore, the authors tested the hypothesis that beta-adrenergic agonists alter the pulmonary inflammatory response during acute lung injury in mice. Methods Five-week-old CD-1 mice received continuous infusions of 10 microg x kg(-1) x min(-1) dobutamine, 6 microg x kg(-1) x min(-1) dopexamine, or vehicle via intraperitoneal mini osmotic pumps, followed immediately by intratracheal instillation of approximately 2 microg/kg endotoxin (or phosphate-buffered saline control). Six hours later the mice were killed, and lung lavage was performed. Interleukin-6 and -10 concentrations in lung homogenates were measured using enzyme-linked immunosorbent assay. Interleukin-6 and macrophage inflammatory protein-2 mRNA was measured using reverse-transcription polymerase chain reaction. Results Interleukin-6 protein and mRNA significantly increased after intratracheal endotoxin (P < 0.001), and the fraction of neutrophils in lung lavage fluid increased in endotoxin-treated (41 +/- 25%) versus control mice (2 +/- 4%, P < 0.05). Treatment of endotoxic mice with dobutamine significantly decreased interleukin-6 protein (P < 0.05) and mRNA (P < 0.05) expression. Dopexamine had similar but less pronounced effects. Dobutamine decreased interleukin-10 expression, whereas dopexamine did not. In endotoxemic mice, both dobutamine and dopexamine decreased induction of macrophage inflammatory protein-2 mRNA (P < 0.05) and reduced the fraction of neutrophils in lung lavage fluid (P < 0.05). Conclusions In endotoxin-induced acute lung injury, beta-adrenergic agonists can significantly decrease proinflammatory cytokine expression, decrease induction of chemokine mRNA, and decrease the resultant neutrophil infiltrate in the lung.

scholarly journals Anti-inflammatory Role of Trilobatin on Lipopolysaccharide-induced Acute Lung Injury through Activation of AMPK/GSK3β-Nrf2 Pathway

2020 ◽  
Keyword(s):  
Oxidative Stress ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Interleukin 1 ◽  
Dry Weight ◽  
Lavage Fluid ◽  
Pathological Process ◽  
Lung Edema ◽  
Necrosis Factor Alpha ◽  
Induce Lung Injury

Inflammation is essential for the pathological process of acute lung injury (ALI). Trilo-batin, a glycosylated dihydrochalcone can show anti-oxidative and anti-inflammation properties. This study aimed to explore whether trilobatin could suppress inflammation in lipopolysaccharide (LPS)-induced ALI. Firstly, mice were injected with trilobatin intraperitoneally, and then LPS was administered intranasally to induce lung injury. Data from analysis of lung edema and pathologic histology of lung tissues indicated that pretreatment with trilobatin alleviated LPS-induced histopathological changes and decreased wet-to-dry weight (W/D) ratio. Moreover, LPS-induced lung injury was attenuated post trilobatin treatment with reduced protein concentration, cell numbers, neutrophils and macrophages in BALF (bronchoalveolar lavage fluid). Secondly, trilobatin treatment decreased the protein level of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) thereby suppressing LPS-induced inflammation. LPS-induced oxidative stress was ameliorated following trilobatin treatment with decreased malondialdehyde (MDA) and increased glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). Lastly, trilobatin decreased NF-κB phosphorylation and increased Nrf2 through up-regulation of AMPK and GSK3β phosphorylation. In conclusion, trilobatin repressed oxidative stress and inflammatory damage by ameliorating LPS-induced ALI through activation of AMPK/GSK3β-Nrf2 and inhibition of NF-κB.

scholarly journals Group V Phospholipase A2 Mediates Endothelial Dysfunction and Acute Lung Injury Caused by Methicillin-Resistant Staphylococcus aureus

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1731
Author(s):  
Yu Maw Htwe ◽  
Huashan Wang ◽  
Patrick Belvitch ◽  
Lucille Meliton ◽  
Mounica Bandela ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Acute Lung Injury ◽  
Endothelial Dysfunction ◽  
Lung Injury ◽  
Phospholipase A2 ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Group V ◽  
Methicillin Resistant

Lung endothelial dysfunction is a key feature of acute lung injury (ALI) and clinical acute respiratory distress syndrome (ARDS). Previous studies have identified the lipid-generating enzyme, group V phospholipase A2 (gVPLA2), as a mediator of lung endothelial barrier disruption and inflammation. The current study aimed to determine the role of gVPLA2 in mediating lung endothelial responses to methicillin-resistant Staphylococcus aureus (MRSA, USA300 strain), a major cause of ALI/ARDS. In vitro studies assessed the effects of gVPLA2 inhibition on lung endothelial cell (EC) permeability after exposure to heat-killed (HK) MRSA. In vivo studies assessed the effects of intratracheal live or HK-MRSA on multiple indices of ALI in wild-type (WT) and gVPLA2-deficient (KO) mice. In vitro, HK-MRSA increased gVPLA2 expression and permeability in human lung EC. Inhibition of gVPLA2 with either the PLA2 inhibitor, LY311727, or with a specific monoclonal antibody, attenuated the barrier disruption caused by HK-MRSA. LY311727 also reduced HK-MRSA-induced permeability in mouse lung EC isolated from WT but not gVPLA2-KO mice. In vivo, live MRSA caused significantly less ALI in gVPLA2 KO mice compared to WT, findings confirmed by intravital microscopy assessment in HK-MRSA-treated mice. After targeted delivery of gVPLA2 plasmid to lung endothelium using ACE antibody-conjugated liposomes, MRSA-induced ALI was significantly increased in gVPLA2-KO mice, indicating that lung endothelial expression of gVPLA2 is critical in vivo. In summary, these results demonstrate an important role for gVPLA2 in mediating MRSA-induced lung EC permeability and ALI. Thus, gVPLA2 may represent a novel therapeutic target in ALI/ARDS caused by bacterial infection.

LPS-Induced Oxidative Stress And Microtubule-Dependent Signaling In Acute Lung Injury

2012 ◽  
Author(s):  
Xinyong Tian ◽  
Eric Kratzer ◽  
Tinghuai Wu ◽  
Yufeng Tian ◽  
Nicolene Sarich ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Lung Injury ◽  
Lung Injury
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