Inhibition of Peroxiredoxin 6 PLA2 Activity Decreases Oxidative Stress and the Severity of Acute Lung Injury in the Mouse Cecal Ligation and Puncture Model

The use of agents to inhibit the production of reactive oxygen species (ROS) has been proposed for the treatment of Acute Lung Injury (ALI). However, this approach also inhibits the bactericidal activity of polymorphonuclear leucocytes (PMN) and other cells, raising the possibility of aggravating lu...

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Autores principales:	Aron B. Fisher, Chandra Dodia, Jian-Qin Tao, Sheldon I. Feinstein, Shampa Chatterjee
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	acute lung injury peroxiredoxin 6 phospholipase A2 NADPH oxidase oxidative lung injury rac1 and 2 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/0aaab728e31c4525a5c31b9e2ea3864d
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spelling	oai:doaj.org-article:0aaab728e31c4525a5c31b9e2ea3864d2021-11-25T16:25:51ZInhibition of Peroxiredoxin 6 PLA2 Activity Decreases Oxidative Stress and the Severity of Acute Lung Injury in the Mouse Cecal Ligation and Puncture Model10.3390/antiox101116762076-3921https://doaj.org/article/0aaab728e31c4525a5c31b9e2ea3864d2021-10-01T00:00:00Zhttps://www.mdpi.com/2076-3921/10/11/1676https://doaj.org/toc/2076-3921The use of agents to inhibit the production of reactive oxygen species (ROS) has been proposed for the treatment of Acute Lung Injury (ALI). However, this approach also inhibits the bactericidal activity of polymorphonuclear leucocytes (PMN) and other cells, raising the possibility of aggravating lung injury in ALI associated with bacterial infection. We used the cecal ligation and puncture (CLP) model of ALI associated with sepsis to investigate the effect of inhibiting NADPH oxidase 2 (NOX2)-derived ROS production, the main source of ROS in lungs. A phospholipase A<sub>2</sub> inhibitor called peroxiredoxin 6 inhibitory peptide-2 (PIP-2) was used to inhibit NOX2 activation; the peptide prevents liberation of Rac, a necessary NOX2 co-factor. At 18 h after intravenous treatment with 2 µg PIP-2 /gram body weight (wt), the number of colony-forming bacteria in lungs and peritoneal fluid of mice with CLP was approximately doubled as compared to untreated mice. Treatment with 10 µg PIP-2/g body wt resulted in 100% mortality within 18 h. Antibiotic treatment abolished both the increase in lung bacteria with low dose PIP-2 and the increased mortality with high dose PIP-2. Treatment with PIP-2 plus antibiotics resulted in significantly improved lung histology, decreased PMN infiltration, decreased lung fluid accumulation, and decreased oxidative lung injury compared to antibiotics alone. We conclude that the administration of PIP-2 provides partial protection against lung injury in a model of ALI due to bacterial infection, while concurrent antibiotic treatment abolishes the deleterious effects of PIP-2 on lung bacterial clearance. These results suggest that addition of PIP-2 to the antibiotic regimen is beneficial for treatment of ALI associated with bacterial infection.Aron B. FisherChandra DodiaJian-Qin TaoSheldon I. FeinsteinShampa ChatterjeeMDPI AGarticleacute lung injuryperoxiredoxin 6phospholipase A2NADPH oxidaseoxidative lung injuryrac1 and 2Therapeutics. PharmacologyRM1-950ENAntioxidants, Vol 10, Iss 1676, p 1676 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	acute lung injury peroxiredoxin 6 phospholipase A2 NADPH oxidase oxidative lung injury rac1 and 2 Therapeutics. Pharmacology RM1-950
spellingShingle	acute lung injury peroxiredoxin 6 phospholipase A2 NADPH oxidase oxidative lung injury rac1 and 2 Therapeutics. Pharmacology RM1-950 Aron B. Fisher Chandra Dodia Jian-Qin Tao Sheldon I. Feinstein Shampa Chatterjee Inhibition of Peroxiredoxin 6 PLA2 Activity Decreases Oxidative Stress and the Severity of Acute Lung Injury in the Mouse Cecal Ligation and Puncture Model
description	The use of agents to inhibit the production of reactive oxygen species (ROS) has been proposed for the treatment of Acute Lung Injury (ALI). However, this approach also inhibits the bactericidal activity of polymorphonuclear leucocytes (PMN) and other cells, raising the possibility of aggravating lung injury in ALI associated with bacterial infection. We used the cecal ligation and puncture (CLP) model of ALI associated with sepsis to investigate the effect of inhibiting NADPH oxidase 2 (NOX2)-derived ROS production, the main source of ROS in lungs. A phospholipase A<sub>2</sub> inhibitor called peroxiredoxin 6 inhibitory peptide-2 (PIP-2) was used to inhibit NOX2 activation; the peptide prevents liberation of Rac, a necessary NOX2 co-factor. At 18 h after intravenous treatment with 2 µg PIP-2 /gram body weight (wt), the number of colony-forming bacteria in lungs and peritoneal fluid of mice with CLP was approximately doubled as compared to untreated mice. Treatment with 10 µg PIP-2/g body wt resulted in 100% mortality within 18 h. Antibiotic treatment abolished both the increase in lung bacteria with low dose PIP-2 and the increased mortality with high dose PIP-2. Treatment with PIP-2 plus antibiotics resulted in significantly improved lung histology, decreased PMN infiltration, decreased lung fluid accumulation, and decreased oxidative lung injury compared to antibiotics alone. We conclude that the administration of PIP-2 provides partial protection against lung injury in a model of ALI due to bacterial infection, while concurrent antibiotic treatment abolishes the deleterious effects of PIP-2 on lung bacterial clearance. These results suggest that addition of PIP-2 to the antibiotic regimen is beneficial for treatment of ALI associated with bacterial infection.
format	article
author	Aron B. Fisher Chandra Dodia Jian-Qin Tao Sheldon I. Feinstein Shampa Chatterjee
author_facet	Aron B. Fisher Chandra Dodia Jian-Qin Tao Sheldon I. Feinstein Shampa Chatterjee
author_sort	Aron B. Fisher
title	Inhibition of Peroxiredoxin 6 PLA2 Activity Decreases Oxidative Stress and the Severity of Acute Lung Injury in the Mouse Cecal Ligation and Puncture Model
title_short	Inhibition of Peroxiredoxin 6 PLA2 Activity Decreases Oxidative Stress and the Severity of Acute Lung Injury in the Mouse Cecal Ligation and Puncture Model
title_full	Inhibition of Peroxiredoxin 6 PLA2 Activity Decreases Oxidative Stress and the Severity of Acute Lung Injury in the Mouse Cecal Ligation and Puncture Model
title_fullStr	Inhibition of Peroxiredoxin 6 PLA2 Activity Decreases Oxidative Stress and the Severity of Acute Lung Injury in the Mouse Cecal Ligation and Puncture Model
title_full_unstemmed	Inhibition of Peroxiredoxin 6 PLA2 Activity Decreases Oxidative Stress and the Severity of Acute Lung Injury in the Mouse Cecal Ligation and Puncture Model
title_sort	inhibition of peroxiredoxin 6 pla2 activity decreases oxidative stress and the severity of acute lung injury in the mouse cecal ligation and puncture model
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/0aaab728e31c4525a5c31b9e2ea3864d
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Inhibition of Peroxiredoxin 6 PLA2 Activity Decreases Oxidative Stress and the Severity of Acute Lung Injury in the Mouse Cecal Ligation and Puncture Model

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