Pulmonary fibrosis is a progressive and often fatal condition characterized pathologically by mesenchymal cell proliferation in the lung, expansion of the extracellular matrix, and extensive remodeling of the lung parenchyma [1
]. Lung fibrosis occurs in interstitial lung diseases and idiopathic interstitial pneumonias, as part of several systemic connective tissue diseases and childhood interstitial lung disease syndromes, and in response to many types of lung injury, including radiation and some chemotherapeutic drugs. Idiopathic pulmonary fibrosis (IPF) is perhaps the most intractable form of lung fibrogenesis where the molecular origins are unclear. Recent evidence indicates that the prevalence and mortality of IPF are growing in the U.S. and elsewhere [2
Currently, there are no approved medical antifibrotic therapies for pulmonary fibrosis. Initial therapies focused on aggressive anti-inflammatory treatment; however, this approach has not improved loss of lung function or survival. Pulmonary fibrosis remains a significant public health burden with no proven therapies that prevent or reverse disease progression. As pulmonary fibrosis is likely heterogeneous in molecular etiology, identification of common downstream pathways where signals converge may provide optimal therapeutic targets that will allow treatment of fibrosis regardless of the upstream initiating events.
Chronic exposures to inhaled particles, infections, and genetic mutations or deficiencies that modify lung function are responsible for persistent inflammation and fibrotic lung diseases. Alveolar type II epithelial cells produce and secrete surfactant lipids and surfactant-associated proteins SP-A, SP-B, SP-C, and SP-D that enhance alveolar compliance and host defense [3
]. Recent studies demonstrated a strong association between surfactant protein C gene mutations and familial idiopathic pulmonary fibrosis [4
]. SP-C is a small 34 amino acid hydrophobic, alpha-helical protein that is selectively synthesized type II epithelial cells in the lung and secreted into the airspace along with other surfactant lipids. Genetic mutations that can cause misfolding or amyloid fibril formation of SP-C are often associated with interstitial lung disease [5
]. In particular, L188Q mutation in SP-C has been shown to associate with human lung disease and found cytotoxic when overexpressed in mouse lung epithelial cells [7
]. SP-C-deficiencies are also associated with human lung disease. SP-C deficient mice (Sftpc−/−
) also developed heterogeneous interstitial lung disease with age [8
]. However, molecular mechanisms or pathways that mediate pulmonary inflammation and fibrosis in SP-C deficient mice remained unidentified.
The mammalian target of rapamycin (mTOR) has been shown to influence tissue fibrosis and is considered a potential control point for pharmacological intervention [9
]. In support, inhibition of mTOR with rapamycin has been shown to prevent the initiation and propagation in a mouse model of TGFα
-driven pulmonary fibrosis [11
]. The antifibrotic affects of mTOR inhibition have recently been reported in several rat models of chronic kidney disease, including diabetic nephropathy, chronic glomerulosclerosis, and tubulointerstitial fibrosis [15
]. In rat models of established liver cirrhosis, rapamycin reduced fibrosis and attenuated disease progression [18
]. Together, these studies support rapamycin as a potential novel therapy in the treatment of pulmonary fibrosis. Recent recommendations regarding minimal preclinical criteria to be applied before embarking on clinical trials of novel agents in patients with IPF includes demonstration of the antifibrotic effects of the agent in at least two different animal models of lung fibrosis, with drug being delivered during the postinflammatory, fibrogenic phase of lung injury [19
]. In this study, we evaluated if rapamycin was effective in reducing bleomycin-induced inflammation and pulmonary fibrosis in the SP-C deficient mice that exhibit an increased response to profibrotic stimuli.