PHOSPHATIDIC-ACID SIGNALING MEDIATES LUNG CYTOKINE EXPRESSION AND LUNG INFLAMMATORY INJURY AFTER HEMORRHAGE IN MICE

• Type of Material: Article
• Authors: Edward Abraham, University of Colorado Denver; Stuart Bursten, Cell Therapeutics, Inc; Robert Shenkar, University of Colorado Denver; Janet Allbee, University of Colorado Denver; Rubin Tuder, Cell Therapeutics, Inc; Paul Woodson, Cell Therapeutics, Inc; David Guidot, Emory University; Glenn Rice, Cell Therapeutics, Inc; Jack W. Singer, Cell Therapeutics, Inc; John E. Repine, University of Colorado Denver
• Language: English
• Date: 1995-02-01
• Publisher: Rockefeller University Press
• Publication Version: Final Published Version
• Copyright Statement: © 1995, Rockefeller University Press., All rights reserved.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1084/jem.181.2.569
• Title of Journal or Parent Work: Journal of Experimental Medicine
• ISSN: 0022-1007
• Volume: 181
• Issue: 2
• Start Page: 569
• End Page: 575
• Grant/Funding Information: This work was funded in part by the Swan Foundation, American Heart Association, and the National Institutes of Health (RO1-HL45582, P50 HL40784, GM39102) and a gift from Marc Arnold and Barbara Pfifferling.
• Keywords: Research & Experimental Medicine; RESPIRATORY-DISTRESS SYNDROME; PROTEIN-KINASE-C; INTERLEUKIN-1; TUMOR-NECROSIS-FACTOR; MESSENGER; Life Sciences & Biomedicine; RESUSCITATION; Medicine, Research & Experimental; Immunology; ACTIVATION; Science & Technology; TRAUMA; MESANGIAL CELLS
• Research Categories: Health Sciences, Oncology; Health Sciences, Immunology

Abstract

Because phosphatidic acid (PA) pathway signaling may mediate many basic reactions involving cytokine-dependent responses, we investigated the effects of CT1501R, a functional inhibitor of the enzyme lysophosphatidic acid acyhransferase (LPAAT) which converts lysophosphatidic acid (Lyso-PA) to PA. We found that CT1501R treatment not only prevented hypoxia-induced PA increases and lyso-PA consumption in human neutrophils, but also prevented neutrophil chemotaxis and adherence in vitro, and lung injury and lung neutrophil accumulation in mice subjected to hemorrhage and resuscitation. In addition, CT1501R treatment prevented increases in mRNA levels and protein production of a variety of proinflammatory cytokines in multiple lung cell populations after blood loss and resuscitation. Our results indicate the fundamental role of PA metabolism in the development of acute inflammatory lung injury after blood loss.