mTOR Overactivation and Compromised Autophagy in the Pathogenesis of Pulmonary Fibrosis

PLoS One. 2015 Sep 18;10(9):e0138625. doi: 10.1371/journal.pone.0138625. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / physiology*
  • Bleomycin
  • Disease Models, Animal
  • Humans
  • Lung / metabolism*
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Pulmonary Alveoli / metabolism
  • Pulmonary Alveoli / pathology
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / metabolism*
  • Pulmonary Fibrosis / pathology
  • Signal Transduction / physiology*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Bleomycin
  • TOR Serine-Threonine Kinases

Grant support

This study was supported by (KFX) the State Key Program of National Natural Science Foundation of China (81430001) and (KFX) the 973 National Basic Research Program of China (2009CB522106).