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

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

Correspondence and requests for reprints should be addressed to Dr. János G. Filep, M.D., Research Center, Maisonneuve-Rosemont Hospital, University of Montreal, 5415 blvd de l'Assomption, Montreal, QC, Canada H1T 2M4. 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 (MPO), abundantly expressed in neutrophils, not only generates cytotoxic oxidants but also signals through the β₂ integrin Mac-1 to rescue neutrophils from constitutive apoptosis, thereby prolonging inflammation.

Objectives: Because aspirin-triggered 15-epi-lipoxin A₄ (15-epi-LXA₄) modulates Mac-1 expression, we investigated the impact of 15-epi-LXA₄ on MPO suppression of neutrophil apoptosis and MPO-mediated neutrophil-dependent acute lung injury.

Methods: Human neutrophils were cultured with MPO with or without 15-epi-LXA₄ to investigate development of apoptosis. Acute lung injury was produced by intratracheal injection of carrageenan plus MPO or intraperitoneal injection of live Escherichia coli in mice, and the animals were treated with 15-epi-LXA₄ at the peak of inflammation.

Measurements and Main Results: 15-Epi-LXA₄ through down-regulation of Mac-1 expression promoted apoptosis of human neutrophils by attenuating MPO-induced activation of extracellular signal–regulated kinase and Akt-mediated phosphorylation of Bad and by reducing expression of the antiapoptotic protein Mcl-1, thereby aggravating mitochondrial dysfunction. The proapoptotic effect of 15-epi-LXA₄ was dominant over MPO-mediated effects even when it was added at 4 hours post MPO. In mice, treatment with 15-epi-LXA₄ accelerated the resolution of established carrageenan plus MPO-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-LXA₄ enhances resolution of inflammation by overriding the powerful antiapoptosis signal from MPO, thereby demonstrating a hitherto unrecognized mechanism by which aspirin promotes resolution of inflammation.

Key Words: acute lung injury • neutrophil • apoptosis • lipoxins • resolution of inflammation

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Myeloperoxidase (MPO) signals through the β2-integrin Mac-1 to suppress neutrophil apoptosis, thereby prolonging inflammation. Aspirin-triggered 15-epi-lipoxin A4 (15-epi-LXA4) modulates Mac-1 expression, but it is not known whether it could affect MPO signaling. What This Study Adds to the Field Our results demonstrate that aspirin-triggered 15-epi-LXA4 overrides MPO suppression of neutrophil apoptosis by blocking β2 integrin–mediated outside-in signaling and enhances resolution of MPO-sustained acute lung injury. These observations identify a new mechanism by which aspirin promotes resolution of inflammation in which neutrophils play a central role.