Poldip2 deficiency protects against lung edema and vascular inflammation in a model of acute respiratory distress syndrome

• Authors: Steven J Forrester, Emory University; Qian Xu, Emory University; Daniel S Kikuchi, Emory University; Derick Okwan-Duodu, Emory University; Carolina Ana Campos, Emory University; Elizabeth A Faidley, Emory University; Guogang Zhang, Central South University; Bernard Lassegue, Emory University; Ruxana Sadikot, Emory University; Kathy Griendling, Emory University; Marina S Hernandes, Emory University
• Journal Title: CLINICAL SCIENCE
• Volume: Volume 133, Number 2
• Publisher: PORTLAND PRESS LTD | 2019-01-31, Pages 321-334
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1042/CS20180944
• Subjects: Health Sciences, Public Health; Health Sciences, General
• Keywords: Science & Technology; Life Sciences & Biomedicine; Medicine, Research & Experimental; Research & Experimental Medicine; DELTA-INTERACTING PROTEIN-2; ENDOTHELIAL-CELLS; EXPRESSION; PERMEABILITY; NEUTROPHILS; MIGRATION; LFA-1; VLA-4; SITE

Abstract

Acute respiratory distress syndrome (ARDS) in a deadly disease that can be brought on by endotoxins such as lipopolysaccharide (LPS). ARDS is characterized by vascular permeability, a severe inflammatory response, lung leukocyte infiltration, and resultant lung edema. Polymerase δ-interacting protein 2 (Poldip2) is a novel regulator of blood–brain barrier permeability; however, its role in regulating lung permeability and vascular inflammation is unknown. Here, the role of Poldip2 in regulating vascular permeability and inflammation in a mouse model of ARDS was assessed. Heterozygous deletion of Poldip2 was found to reduce LPS-induced mortality within 20 h, lung inflammatory signaling, and leukocyte infiltration. Moreover, reduced Poldip2-suppressed LP-induced vascular cell adhesion molecule (VCAM)-1 induction, leukocyte recruitment, and mitochondrial reactive oxygen species (ROS) production in vitro. These data indicate that Poldip2 is an important regulator of the debilitating consequences of ARDS, potentially through the regulation of mitochondrial ROS-induced inflammatory signaling. Consequently, inhibition of Poldip2 may be a viable option for therapeutic discovery moving forward.