Apoptotic cell instillation after bleomycin attenuates lung injury through hepatocyte growth factor induction

• Published in: The European respiratory journal Vol. 40; no. 2; pp. 424 - 435
• Main Authors: LEE, Ye-Ji, MOON, Changsuk, SEUNG HAE LEE, PARK, Hyun-Jeong, SEOH, Ju-Young, CHO, Min-Sun, JIHEE LEE KANG
• Format: Journal Article
• Language: English
• Published: Leeds Maney 01-08-2012
• Subjects: Animals; Antibiotics, Antineoplastic - pharmacology; Apoptosis; Biological and medical sciences; Bleomycin - pharmacology; Caspase 3 - metabolism; Caspase 9 - metabolism; Cell Proliferation; Epithelial Cells - cytology; Hepatocyte Growth Factor - metabolism; Humans; Inflammation - metabolism; Jurkat Cells; Lung - pathology; Lung Injury - drug therapy; Macrophages - metabolism; Macrophages, Alveolar - metabolism; Male; Medical sciences; Mice; Mice, Inbred C57BL; Models, Biological; Pneumology; Respiratory system : syndromes and miscellaneous diseases; RNA, Messenger - metabolism; Time Factors; apoptotic cell clearance; Lung disease; Respiratory disease; Hepatocyte growth factor; Induction; Lung; Inflammation; Clearance; Alveolar macrophages; lung fibrosis; Bleomycin; Pulmonary fibrosis; Cell; Macrophage; Pneumology; lung inflammation
• ISSN: 0903-1936; 1399-3003
• DOI: 10.1183/09031936.00096711

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.