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Preventing cleavage of Mer promotes efferocytosis and suppresses acute lung injury in bleomycin treated mice
- Preventing cleavage of Mer promotes efferocytosis and suppresses acute lung injury in bleomycin treated mice
- Lee Y.-J.; Lee S.-H.; Youn Y.-S.; Choi J.-Y.; Song K.-S.; Cho M.-S.; Kang J.L.
- Ewha Authors
- 이지희; 조민선
- SCOPUS Author ID
- 이지희; 조민선
- Issue Date
- Journal Title
- Toxicology and Applied Pharmacology
- Toxicology and Applied Pharmacology vol. 263, no. 1, pp. 61 - 72
- SCIE; SCOPUS
- Document Type
- 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.
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