HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Wang, Z. Articles by Kvietys, P. R. Search for Related Content PubMed PubMed Citation Articles by Wang, Z. Articles by Kvietys, P. R.

Alveolar Macrophages from Septic Mice Promote Polymorphonuclear Leukocyte Transendothelial Migration via an Endothelial Cell Src Kinase/NADPH Oxidase Pathway¹

Critical Illness Research, Lawson Health Research Institute, London Health Sciences Centre, London, Ontario, Canada

Alveolar macrophages (AM) have been implicated in the polymorphonuclear leukocyte (PMN) recruitment to the lungs during sepsis. Using an in vivo murine model of sepsis (feces in the peritoneum), we show that peritonitis leads to increased activation of AM and PMN migration into pulmonary alveoli. To assess cellular mechanisms, an in vitro construct of the pulmonary vascular-interstitial interface (murine AM, pulmonary endothelial cells, and PMN) and a chimera approach were used. Using immunologic (Abs) and genetic blockade (CXCR2-deficient AM), we show that CXC chemokines in septic plasma are responsible for the activation of AM. The activated AM can promote PMN transendothelial migration, even against a concentration gradient of septic plasma, by generating platelet-activating factor and H₂O₂. Platelet-activating factor/H₂O₂ induce an oxidant stress in the adjacent endothelial cells, an event that appears to be a prerequisite for PMN transendothelial migration, since PMN migration is abrogated across Cu/Zn-superoxide dismutase overexpressing endothelial cells. Using gp91-deficient endothelial cells, we show that NADPH oxidase plays an important role in the AM-induced PMN transendothelial migration. Pharmacologic/small interfering RNA blockade of Src kinase inhibits AM-induced endothelial NADPH oxidase activation and PMN migration. Collectively, our findings indicate that the PMN transendothelial migration induced by septic AM is dependent on the generation of superoxide in endothelial cells via the Src kinase/NADPH oxidase signaling pathway.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Canadian Institutes for Health Research Grants MOP-37758, MGC-12816, and MOP-81303.

² Address correspondence and reprint requests to Dr. Peter Kvietys, Critical Illness Research, Lawson Health Research Institute, London Health Sciences Centre, WC, 800 Commissioners Road E, London, Ontario N6A 4G4, Canada. E-mail address: peter.kvietys{at}lhsc.on.ca

³ Abbreviations used in this paper: ALI, acute lung injury; AM, alveolar macrophage; ARDS, acute respiratory distress syndrome; CLP, cecal ligation and perforation; DHR, dihydrorhodamine; EB, Evans blue; FIP, feces in the peritoneum; KC, keratinocyte-derived chemokine; LIX, LPS-inducible CXC chemokine; PAF, platelet-activating factor; PEC, pulmonary endothelial cell; PMN, polymorphonuclear leukocyte; PP2, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine; siRNA, small interfering RNA; SOD, superoxide dismutase; WT, wild type.