15-epi-lipoxin A4 inhibits myeloperoxidase signaling and enhances resolution of acute lung injury.
BACKGROUND
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 beta(2) integrin Mac-1 to rescue neutrophils from constitutive apoptosis, thereby prolonging inflammation.


OBJECTIVE
Because aspirin-triggered 15-epi-lipoxin A(4) (15-epi-LXA(4)) modulates Mac-1 expression, we investigated the impact of 15-epi-LXA(4) 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-LXA(4) 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-LXA(4) at the peak of inflammation.


RESULTS
15-Epi-LXA(4) 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-LXA(4) was dominant over MPO-mediated effects even when it was added at 4 hours post MPO. In mice, treatment with 15-epi-LXA(4) 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-LXA(4) 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.
El Kebir
Driss
D
Research Center, Maisonneuve-Rosemont Hospital, Montréal, Quebec.
József
Levente
L
Pan
Wanling
W
Wang
Lili
L
Petasis
Nicos A
NA
Serhan
Charles N
CN
Filep
János G
JG
D055371:Acute Lung Injury / Q000276:immunology* / Q000473:pathology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D018821:CD18 Antigens / Q000097:blood; D053148:Caspase 3 / Q000097:blood; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D007958:Leukocyte Count; D044045:Lipoxins / Q000097:blood / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D009195:Peroxidase / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018821:CD18 Antigens; D015850:Interleukin-6; D044045:Lipoxins; C040527:lipoxin A4; D009195:Peroxidase; D053148:Caspase 3; D001241:Aspirin