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Published ahead of print on May 29, 2009, doi:10.1164/rccm.200810-1601OC

Am. J. Respir. Crit. Care Med., Volume 180, Number 4, August 2009, 311-319

A more recent version of this article appeared on August 15, 2009
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Submitted on October 15, 2008
Accepted on May 28, 2009

15-epi-lipoxin A4 Inhibits Myeloperoxidase Signaling and Enhances Resolution of Acute Lung Injury

Driss El Kebir1, Levente Jozsef1, Wanling Pan1, Lili Wang1, Nicos A Petasis2, Charles N Serhan3, and Janos G Filep1*

1 Research Center, Maisonneuve-Rosemont Hospital and Department of Pathology and Cell Biology, University of Montreal, Montréal, QC, Canada, 2 Department of Chemistry, University of Southern California, Los Angeles, California, United States, 3 Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States

* To whom correspondence should be addressed. E-mail: janos.g.filep{at}umontreal.ca.

Rationale: Apoptosis is essential for removal of neutrophils from inflamed tissues and efficient resolution of inflammation. Myeloperoxidase, abundantly expressed in neutrophils, not only generates cytotoxic oxidants, but also signals through the {beta}2 integrin Mac-1 to rescue neutrophils from constitutive apoptosis, thereby prolonging inflammation. Objectives: Since aspirin-triggered 15-epi-lipoxin A4 modulates Mac-1 expression, we investigated the impact of 15-epi-lipoxin A4 on myeloperoxidase suppression of neutrophil apoptosis and myeloperoxidase-mediated neutrophil-dependent acute lung injury. Methods: Human neutrophils were cultured with myeloperoxidase with or without 15-epi-lipoxin A4 to investigate development of apoptosis. Acute lung injury was produced by intratracheal injection of carrageenan plus myeloperoxidase or intraperitoneal injection of live Escherichia coli in mice, and the animals were treated with 15-epi-lipoxin A4 at the peak of inflammation. Main Results: 15-epi-lipoxin A4 through downregulation of Mac-1 expression promoted apoptosis of human neutrophils by attenuating myeloperoxidase-induced activation of ERK and Akt-mediated phosphorylation of Bad and by reducing expression of the anti-apoptotic protein Mcl-1, thereby aggravating mitochondrial dysfunction. The pro-apoptotic effect of 15-epi-lipoxin A4 was dominant over myeloperoxidase-mediated effects even when it was added at 4-hour post-myeloperoxidase. In mice, treatment with 15-epi-lipoxin A4 accelerated the resolution of established carrageenan plus myeloperoxidase-evoked as well as E. coli-induced neutrophil-dependent pulmonary inflammation through redirecting neutrophils to caspase-mediated cell death and facilitating their removal by macrophages. Conclusions: These results demonstrate that aspirin-triggered 15-epi-lipoxin A4 enhances resolution of inflammation by overriding the powerful anti-apoptosis signal from myeloperoxidase, thereby demonstrating a hitherto unrecognized mechanism by which aspirin promotes resolution of inflammation.


Key words: acute lung injury • neutrophils • apoptosis • lipoxins • resolution of inflammation






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