Genetic inactivation of the phospholipase A2activity of peroxiredoxin 6 in mice protects against LPS-induced acute lung injury
| Autor: | José Pablo Vázquez-Medina, Sheldon I. Feinstein, Jian-Quin Tao, Priyal Patel, Chandra Dodia, Aron B. Fisher, Shampa Chatterjee, Renata Bannitz-Fernandes, Elena M. Sorokina |
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| Rok vydání: | 2019 |
| Předmět: |
Lipopolysaccharides
0301 basic medicine Pulmonary and Respiratory Medicine Antioxidant Phospholipase A2 Inhibitors Physiology medicine.medical_treatment Acute Lung Injury Cell Mice Transgenic Lung injury Peroxiredoxin 6 Mice 03 medical and health sciences 0302 clinical medicine Phospholipase A2 Catalytic Domain Physiology (medical) medicine Animals chemistry.chemical_classification biology Chemistry Cell Biology Mice Mutant Strains Recombinant Proteins Cell biology Mice Inbred C57BL Disease Models Animal Phospholipases A2 030104 developmental biology medicine.anatomical_structure Enzyme Membrane Amino Acid Substitution NADPH Oxidase 2 Mutagenesis Site-Directed biology.protein 030217 neurology & neurosurgery Research Article Peroxiredoxin VI |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 316:L656-L668 |
| ISSN: | 1522-1504 1040-0605 |
| DOI: | 10.1152/ajplung.00344.2018 |
| Popis: | 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-aiPLA2activity in the pathophysiology of ALI associated with a systemic insult, wild-type (WT) and Prdx6-D140A mice, which lack aiPLA2but 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 aiPLA2activity as well as increased H2O2generation, 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 aiPLA2activity. Thus aiPLA2activity is needed for Nox2-derived oxidant stress associated with LPS exposure. Since inactivation of aiPLA2reduced mortality and prevented lung inflammation and oxidative stress in this animal model, the aiPLA2activity of Prdx6 could be a novel target for prevention or treatment of sepsis-induced ALI. |
| Databáze: | OpenAIRE |
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