Tài liệu Báo cáo khoa học: Bacterial-induced hepoxilin A3 secretion as a pro-inflammatory mediator

MINIREVIEW

Bacterial-induced hepoxilin A3 secretion as

a pro-inflammatory mediator

Beth A. McCormick

Department of Pediatric Gastroenterology, Massachusetts General Hospital, and Department of Microbiology and Molecular Genetics,

Harvard Medical School, Charlestown, MA, USA

Introduction

Recent studies suggest that 8S⁄ R-hydroxy-11,12-

epoxyeicosa-5Z,9E,14Z-trienoic acid (hepoxilin A3;

HXA3) plays a central role in the directed migration of

neutrophils across mucosal surfaces infected with

pathogenic bacteria. This review will discuss recent

advances made in understanding the complex molecu￾lar events that orchestrate the directional movement of

neutrophils across the mucosal surface during bacterial

infection of the intestinal tract and lung and will, in

particular, emphasize the important role played by the

eicosanoid HXA3.

HXA3 is secreted from epithelial cells

during bacterial infection and is a

potent neutrophil chemoattractant

Bacterial pathogens continually confront epithelial bar￾riers of the body, such as those of the gastrointestinal,

respiratory and reproductive tracts. Although mucosal

surfaces are generally impermeable to most foreign

entities, many microorganisms have developed sophis￾ticated strategies to breach or alter this barrier. In gen￾eral, microbial pathogens have evolved the capacity to

engage their host cells in very complex interactions

commonly involving the exchange of biochemical

Keywords

arachidonic acid; chemotaxis; eicosanoid;

hepoxolin A3; inflammation; intestine; lung;

neutrophils; Pseudomonas aeruginosa;

Salmonella typhimurium

Correspondence

B. A. McCormick, Department of Pediatric

Gastroenterology, Massachusetts General

Hospital, Harvard Medical School, CNY 114

16th Street (114–3503), Charlestown,

MA 02129, USA

Fax: +1 617 7264172

Tel: +1 617 7264168

E-mail: mccormic@helix.mgh.harvard.edu

(Received 13 Oct 2006, accepted 23 May

2007)

doi:10.1111/j.1742-4658.2007.05911.x

Bacterial infections at epithelial surfaces, such as those that line the gut

and the lung, stimulate the migration of neutrophils through the co-ordi￾nated actions of chemoattractants secreted from pathogen-stimulated epi￾thelial cells. One such factor involved in attracting polymorphonuclear

leukocytes across the epithelium and into the lumen has until recently

remained elusive. In 2004, we identified the eicosanoid, hepoxilin A3, to be

selectively secreted from the apical surface of human intestinal or lung epi￾thelial cells stimulated with Salmonella enterica serotype Typhimurium or

Pseudomonas aeruginosa, respectively. In this role, the function of hepoxilin

A3 is to guide neutrophils, via the establishment of a gradient, across the

epithelial tight junction complex. Interestingly, interruption of the synthetic

pathway of hepoxilin A3 blocks the apical release of hepoxilin A3 in vitro

and the transmigration of neutrophils induced by S. typhimurium both in

in vitro and in vivo models of inflammation. Such results have led to the

discovery of a completely novel pathway that is not only critical for

responses to bacterial pathogens but also has broad implications for

inflammatory responses affecting mucosal surfaces in general. Thus, the

objective of this review was to highlight the recent findings that implicate

hepoxilin A3 as a key regulator of mucosal inflammation.

Abbreviations

AA, arachidonic acid; HpETE, hydroperoxy-eicosatetraenoic acid; HXA3, 8S ⁄ R-hydroxy-11,12-epoxyeicosa-5Z,9E,14Z-trienoic acid

(hepoxilin A3); IL-8, interleukin-8; LOX, lipoxygenase; PKC, protein kinase C; PLA2, phospholipase A2.

FEBS Journal 274 (2007) 3513–3518 ª 2007 The Author Journal compilation ª 2007 FEBS 3513