mTOR Overactivation and Compromised Autophagy in the Pathogenesis of Pulmonary Fibrosis

Abstract

The mammalian target of rapamycin (mTOR) signaling pathway in pulmonary fibrosis was investigated in cell and animal models. mTOR overactivation in alveolar epithelial cells (AECs) was achieved in the conditional and inducible Tsc1 knock-down mice SPC-rtTA/TetO-Cre/Tsc1 fx/+ (STT). Doxycycline caused Tsc1 knock-down and consequently mTOR activation in AECs for the STT mice. Mice treated with bleomycin exhibited increased mortality and pulmonary fibrosis compared with control mice. In wild-type C57BL/6J mice, pretreatment with rapamycin attenuated the bleomycin-mediated mortality and fibrosis. Rapamycin-mediated mouse survival benefit was inhibited by chloroquine, an autophagy inhibitor. Autophagosomes were decreased in the lungs after bleomycin exposure. Rapamycin induced the production of autophagosomes and diminished p62. We concluded that mTOR overactivation in AECs and compromised autophagy in the lungs are involved in the pathogenesis of pulmonary fibrosis. The suppression of mTOR and enhancement of autophagy may be used for treatment of pulmonary fibrosis.

Autophagy in Pulmonary Diseases

“…Unlike COPD, LC3-II expression is decreased in lung tissues from patients with IPF compared with lung from normal subjects (30,91,92). In contrast, phosphorylation of S6, an indicator of mTOR activation, is increased in fibroblast foci of IPF lung tissue, suggesting down-regulation of autophagy in IPF (93). In experimental models of IPF, up-regulation of autophagy by rapamycin inhibits transforming growth factor-b-induced fibronectin and a-smooth muscle actin expression in lung fibroblasts (91) and collagen production in lung epithelial cells (94).…”

“…In contrast, deficiency of autophagy genes such as MAP1LC3B, ATG5, and BECN1 or pharmacological inhibition of autophagy promotes transforming growth factorb-induced activation of lung fibroblasts (91,94). Consistently, autophagy inhibition by alveolar epithelial cell-specific knockdown of TSC1 exacerbates bleomycin-mediated lung injury in mice (93). Thus, autophagy is likely to exert beneficial roles on IPF models.…”

mTOR Overactivation in Mesenchymal cells Aggravates CCl4− Induced liver Fibrosis

“…The mTOR pathway plays an important role in cardiac fibrosis and rapamycin is a potential therapeutic treatment that can be used to attenuate cardiac fibrosis12. The rapamycin analogue SDZ RAD was shown to promote dramatic inhibitory effects on collagen accumulation in the lungs in a bleomycin model of pulmonary fibrosis13, thus suppression of mTOR may be a viable treatment for pulmonary fibrosis14. mTORC1 signaling promotes the activation of kidney fibroblasts and contributes to the development of interstitial fibrosis15.…”

Unique and Redundant Functions of p70 Ribosomal S6 Kinase Isoforms Regulate Mesenchymal Cell Proliferation and Migration in Pulmonary Fibrosis

“…In pulmonary disease, Western blot for phosphorylated S6 demonstrated increased expression in three of five idiopathic pulmonary fibrosis (IPF) samples compared with no signal for either nondiseased control subjects or patients with chronic obstructive pulmonary disease (11). In a separate study, immunohistochemical analysis on lung tissues taken at transplantation revealed strong expression of phosphorylated S6 in myofibroblasts from IPF lung tissue compared with little or no expression in healthy lung tissue (12). Together, these findings indicate that the p70S6K pathway is up-regulated in at least a portion of patients with IPF, and emphasize the importance of developing a greater understanding on the relevance of this pathway in mediating fibroproliferative disease.…”