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PMID: 16565483 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Lipoxin A(4) regulates bronchial epithelial cell responses to acid injury.

The American journal of pathology ·Vol. 168 ·No. 4 ·2006-04-00 ·Pages 1064-72

Bonnans C, Fukunaga K, Levy MA, Levy BD

Abstract

Aspiration of gastric acid commonly injures airway epithelium and, if severe, can lead to respiratory failure from acute respiratory distress syndrome. Recently, we identified cyclooxygenase-2 (COX-2)-derived prostaglandin E(2) (PGE(2)) and lipoxin A(4) (LXA(4)) as pivotal mediators in vivo for resolution of acid-initiated acute lung injury. To examine protective mechanisms for these mediators in the airway, we developed an in vitro model of acid injury by transiently exposing well-differentiated normal human bronchial epithelial cells to hydrochloric acid. Transmission electron microscopy revealed selective injury to superficial epithelial cells with disruption of cell attachments and cell shedding. The morphological features of injury were substantially resolved within 6 hours. Acid triggered and early marked increases in COX-2 expression and PGE(2) production, and acid-induced PGE(2) significantly increased epithelial LXA(4) receptor (ALX) expression. LXA(4) is generated in vivo during acute lung injury, and we observed that nanomolar quantities increased basal epithelial cell proliferation and potently blocked acid-triggered interleukin-6 release and neutrophil transmigration across well-differentiated normal human bronchial epithelial cells. Expression of recombinant human ALX in A549 airway epithelial cells uncovered ALX-dependent inhibition of cytokine release by LXA(4). Together, these findings indicate that injured bronchial epithelial cells up-regulate ALX in a COX-2-dependent manner to promote LXA(4)-mediated resolution of airway inflammation.

MeSH Terms
Bronchi/metabolism,ultrastructure Cell Adhesion Cell Proliferation Cells, Cultured Cyclooxygenase 2/biosynthesis Dinoprostone/biosynthesis Epithelial Cells/drug effects,physiology,ultrastructure Gastric Acid/physiology Humans Hydrochloric Acid/toxicity Lipoxins/physiology Membrane Proteins/antagonists & inhibitors,biosynthesis Microscopy, Electron, Transmission Nitrobenzenes/pharmacology Receptors, Formyl Peptide/biosynthesis Receptors, Lipoxin/biosynthesis Respiratory Mucosa/metabolism,ultrastructure Sulfonamides/pharmacology
Chemicals
FPR2 protein, human Lipoxins Membrane Proteins Nitrobenzenes Receptors, Formyl Peptide Receptors, Lipoxin Sulfonamides lipoxin A4 N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide Cyclooxygenase 2 PTGS2 protein, human Dinoprostone Hydrochloric Acid
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Bonnans Caroline
Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115, USA.
Fukunaga Koichi
Levy Marilyn A
Levy Bruce D
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Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.2353/ajpath.2006.051056
Published
2006-04-00
Pages
1064-72
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1606555
Subset
IM
Grants
NHLBI NIH HHS · R01 HL068669 · United States
NIDCR NIH HHS · P50 DE016191 · United States
NIDCR NIH HHS · DE016191 · United States
NIAID NIH HHS · AI0608084 · United States
NHLBI NIH HHS · HL68669 · United States
Corrections
CommentIn
PMID: 16565482
External Links
PubMed source DOI: 10.2353/ajpath.2006.051056 PMC Full Text View journal details
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