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Aspirin‐triggered lipoxins enhance resolution of myeloperoxidase‐mediated lung inflammation by promoting neutrophil apoptosis
Author(s) -
Filep Janos G,
Jozsef Levente,
Pan Wanling,
Wang Lili,
Petasis Nicos A,
Serhan Charles N,
El Kebir Driss
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.235.1
Subject(s) - myeloperoxidase , lipoxin , inflammation , apoptosis , chemistry , bronchoalveolar lavage , lucigenin , aspirin , lung , immunology , pharmacology , medicine , biochemistry , superoxide , enzyme
We have reported that myeloperoxidase (MPO) prolongs carrageenan‐induced lung injury parallel with suppression of neutrophil apoptosis in a mouse model of inflammation. Since aspirin‐triggered 15‐epi‐lipoxin A 4 (15‐epi‐LXA 4 ) overrides MPO signaling in neutrophils in vitro, we investigated the impact of 15‐epi‐LXA 4 on the resolution of lung inflammation. Treatment of mice with 15‐epi‐LXA 4 accelerated the resolution of established inflammation when administered intravenously at the peak of inflammation evoked by carrageenan plus MPO. 15‐epi‐LXA 4 produced decreases in bronchoalveolar neutrophil accumulation and increased the number of monocytes/macrophages. 15‐epi‐LXA 4 reduced lung injury, tissue MPO content, attenuated edema formation and IL‐6 release. 15‐epi‐LXA 4 augmented DNA fragmentation and caspase‐3 activity in bronchoalveolar neutrophils. Decreases in neutrophil number occurred parallel with increases in the percentage of apoptotic neutrophils and the percentage of macrophages containing apoptotic bodies. Co‐treatement with the pan‐caspase inhibitor zVAD‐fmk fully abolished the beneficial actions of 15‐epi‐LXA 4. Our results indicate that aspirin‐triggered 15‐epi‐LXA 4 overrides the anti‐apoptosis signal of MPO in neutrophils, thereby demonstrating a hitherto unrecognized mechanism by which aspirin could promote resolution of inflammation. (Support: CIHR MOP‐64283).