title: Rapamycin Regulates Bleomycin-Induced Lung Damage in SP-C-Deficient Mice.
abstract: Injury to the distal respiratory epithelium has been implicated as an underlying cause of idiopathic lung diseases. Mutations that result in SP-C deficiencies are linked to a small subset of spontaneous and familial cases of interstitial lung disease (ILD) and interstitial pulmonary fibrosis (IPF). Gene-targeted mice that lack SP-C (Sftpc(-/-)) develop an irregular ILD-like disease with age and are a model of the human SP-C related disease. In the current study, we investigated whether rapamycin could ameliorate bleomycin-induced fibrosis in the lungs of Sftpc(-/-) mice. Sftpc(+/+) and -/- mice were exposed to bleomycin with either preventative administration of rapamycin or therapeutic administration beginning eight days after the bleomycin injury. Rapamycin-treatment increased weight loss and decreased survival of bleomycin-treated Sftpc(+/+) and Sftpc(-/-) mice. Rapamycin did not reduce the fibrotic disease in the prophylactic or rescue experiments of either genotype of mice. Further, rapamycin treatment augmented airway resistance and reduced lung compliance of bleomycin-treated Sftpc(-/-) mice. Rapamycin treatment was associated with an increased expression of profibrotic Th2 cytokines and reduced expression of INF-γ. These findings indicate that novel therapeutics will be required to treat individuals with SP-C deficient ILD/IPF.
authors.affiliation: Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
authors.forename: Satish K
authors.initials: SK
authors.lastname: Madala
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Maxfield
authors.forename: Cynthia R
authors.initials: CR
authors.lastname: Davidson
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Schmidt
authors.forename: Daniel
authors.initials: D
authors.lastname: Garry
authors.forename: Machiko
authors.initials: M
authors.lastname: Ikegami
authors.forename: William D
authors.initials: WD
authors.lastname: Hardie
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Glasser