Abstract
Apoptotic cell clearance by macrophages and neighboring tissue cells induces hepatocyte growth factor (HGF) secretion. HGF plays a key factor involved in alveolar epithelial regeneration and reconstruction after lung injury. Direct in vivo exposure to apoptotic cells would enhance HGF production, resulting in attenuation of pulmonary injury.
We investigated the direct effect of in vivo exposure to apoptotic cells into bleomycin-stimulated lungs (2 days old) on the 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 proinflammatory mediator production, inflammatory cell recruitment, and total protein levels. Apoptotic cell instillation also induced the effects of anti-apoptosis and anti-fibrosis. These anti-inflammatory, and anti-apoptotic effects could be reversed by coadministration of HGF neutralizing 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.
- ERS
