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 beta(2) integrin Mac-1 to rescue neutrophils from constitutive apoptosis, thereby prolonging inflammation. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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.
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 beta(2) integrin Mac-1 to rescue neutrophils from constitutive apoptosis, thereby prolonging inflammation. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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.
Authors: Levente József; Christine Zouki; Nicos A Petasis; Charles N Serhan; János G Filep Journal: Proc Natl Acad Sci U S A Date: 2002-09-16 Impact factor: 11.205
Authors: Siobhan Mitchell; Graham Thomas; Killeen Harvey; David Cottell; Keira Reville; Giovanni Berlasconi; Nicos A Petasis; Lars Erwig; Andrew J Rees; John Savill; Hugh R Brady; Catherine Godson Journal: J Am Soc Nephrol Date: 2002-10 Impact factor: 10.121
Authors: Jason P Eiserich; Stephan Baldus; Marie-Luise Brennan; Wenxin Ma; Chunxiang Zhang; Albert Tousson; Laura Castro; Aldons J Lusis; William M Nauseef; C Roger White; Bruce A Freeman Journal: Science Date: 2002-06-28 Impact factor: 47.728
Authors: Raja-Elie E Abdulnour; Jesmond Dalli; Jennifer K Colby; Nandini Krishnamoorthy; Jack Y Timmons; Sook Hwa Tan; Romain A Colas; Nicos A Petasis; Charles N Serhan; Bruce D Levy Journal: Proc Natl Acad Sci U S A Date: 2014-11-04 Impact factor: 11.205
Authors: James Trauer; Stephen Muhi; Emma S McBryde; Shmeylan A Al Harbi; Yaseen M Arabi; Andrew J Boyle; Rodrigo Cartin-Ceba; Wei Chen; Yung-Tai Chen; Marco Falcone; Ognjen Gajic; Jack Godsell; Michelle Ng Gong; Daryl Kor; Wolfgang Lösche; Daniel F McAuley; Hollis R O'Neal; Michael Osthoff; Gordon P Otto; Maik Sossdorf; Min-Juei Tsai; Juan C Valerio-Rojas; Tom van der Poll; Francesco Violi; Lorraine Ware; Andreas F Widmer; Maryse A Wiewel; Johannes Winning; Damon P Eisen Journal: Crit Care Med Date: 2017-11 Impact factor: 7.598
Authors: Daryl J Kor; Jason Erlich; Michelle N Gong; Michael Malinchoc; Rickey E Carter; Ognjen Gajic; Daniel S Talmor Journal: Crit Care Med Date: 2011-11 Impact factor: 7.598
Authors: Fanyong Meng; Isa Mambetsariev; Yufeng Tian; Yvonne Beckham; Angelo Meliton; Alan Leff; Margaret L Gardel; Michael J Allen; Konstantin G Birukov; Anna A Birukova Journal: Am J Respir Cell Mol Biol Date: 2015-02 Impact factor: 6.914