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Preventing cleavage of Mer promotes efferocytosis and suppresses acute lung injury in bleomycin treated mice

Title
Preventing cleavage of Mer promotes efferocytosis and suppresses acute lung injury in bleomycin treated mice
Authors
Lee Y.-J.Lee S.-H.Youn Y.-S.Choi J.-Y.Song K.-S.Cho M.-S.Kang J.L.
Ewha Authors
이지희조민선
SCOPUS Author ID
이지희scopus; 조민선scopus
Issue Date
2012
Journal Title
Toxicology and Applied Pharmacology
ISSN
0041-008XJCR Link
Citation
vol. 263, no. 1, pp. 61 - 72
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Mer receptor tyrosine kinase (Mer) regulates macrophage activation and promotes apoptotic cell clearance. Mer activation is regulated through proteolytic cleavage of the extracellular domain. To determine if membrane-bound Mer is cleaved during bleomycin-induced lung injury, and, if so, how preventing the cleavage of Mer enhances apoptotic cell uptake and down-regulates pulmonary immune responses. During bleomycin-induced acute lung injury in mice, membrane-bound Mer expression decreased, but production of soluble Mer and activity as well as expression of disintegrin and metalloproteinase 17 (ADAM17) were enhanced Treatment with the ADAM inhibitor TAPI-0 restored Mer expression and diminished soluble Mer production. Furthermore, TAPI-0 increased Mer activation in alveolar macrophages and lung tissue resulting in enhanced apoptotic cell clearance in vivo and ex vivo by alveolar macrophages. Suppression of bleomycin-induced pro-inflammatory mediators, but enhancement of hepatocyte growth factor induction were seen after TAPI-0 treatment. Additional bleomycin-induced inflammatory responses reduced by TAPI-0 treatment included inflammatory cell recruitment into the lungs, levels of total protein and lactate dehydrogenase activity in bronchoalveolar lavage fluid, as well as caspase-3 and caspase-9 activity and alveolar epithelial cell apoptosis in lung tissue. Importantly, the effects of TAPI-0 on bleomycin-induced inflammation and apoptosis were reversed by coadministration of specific Mer-neutralizing antibodies. These findings suggest that restored membrane-bound Mer expression by TAPI-0 treatment may help resolve lung inflammation and apoptosis after bleomycin treatment. © 2012 Elsevier Inc.
DOI
10.1016/j.taap.2012.05.024
Appears in Collections:
의학전문대학원 > 의학과 > Journal papers
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