title: Apoptotic cell instillation after bleomycin attenuates lung injury through hepatocyte growth factor induction.
abstract: Apoptotic cell clearance by macrophages and neighbouring tissue cells induces hepatocyte growth factor (HGF) secretion. HGF plays a key role in alveolar epithelial regeneration and reconstruction after lung injury. Direct in vivo exposure to apoptotic cells enhances HGF production, resulting in attenuation of pulmonary injury. We investigated the direct effect of in vivo exposure to apoptotic cells in bleomycin-stimulated lungs (2 days old) on HGF induction. Furthermore, sequential changes of bleomycin-induced HGF production following apoptotic cell instillation related to the changes in inflammatory and fibrotic responses were assessed. At 2 h after apoptotic cell instillation into bleomycin-stimulated lungs, the levels of HGF mRNA and protein production, and apoptotic cell clearance by alveolar macrophages were enhanced. Furthermore, HGF induction persistently increased following apoptotic cell instillation up to 21 days after bleomycin treatment. Apoptotic cell instillation attenuated bleomycin-induced pro-inflammatory mediator production, inflammatory cell recruitment and total protein levels. Apoptotic cell instillation also induced antiapoptotic and antifibrotic effects. These anti-inflammatory and antiapoptotic effects could be reversed by co-administration of HGF-neutralising antibody. These findings indicate that in vivo exposure to apoptotic cells enhances transcriptional HGF production in bleomycin-stimulated lungs, resulting in attenuation of lung injury and fibrosis.
authors.affiliation: Dept of Physiology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, 911-1 Mok-6-dong, Yangcheon-gu, Seoul 158-056, Korea.
authors.forename: Ye-Ji
authors.initials: YJ
authors.lastname: Lee
authors.forename: Changsuk
authors.initials: C
authors.lastname: Moon
authors.forename: Seung Hae
authors.initials: SH
authors.lastname: Lee
authors.forename: Hyun-Jeong
authors.initials: HJ
authors.lastname: Park
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Seoh
authors.forename: Min-Sun
authors.initials: MS
authors.lastname: Cho
authors.forename: Jihee Lee
authors.initials: JL
authors.lastname: Kang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D001761:Bleomycin / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D019169:Jurkat Cells; D008168:Lung / Q000473:pathology; D055370:Lung Injury / Q000188:drug therapy*; D008264:Macrophages / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
chemical_list: D000903:Antibiotics, Antineoplastic; D012333:RNA, Messenger; D001761:Bleomycin; D017228:Hepatocyte Growth Factor; D053148:Caspase 3; D053453:Caspase 9