# mTOR Overactivation and Compromised Autophagy in the Pathogenesis of Pulmonary Fibrosis

## TL;DR

This study shows that overactive mTOR and reduced autophagy in lung cells contribute to pulmonary fibrosis, and targeting these processes may help treat the disease.

## Contribution

The study reveals a novel role of mTOR overactivation and impaired autophagy in alveolar epithelial cells in causing pulmonary fibrosis.

## Key findings

- mTOR overactivation in alveolar epithelial cells worsens bleomycin-induced pulmonary fibrosis in mice.
- Rapamycin reduces fibrosis and mortality by enhancing autophagy, which is blocked by the autophagy inhibitor chloroquine.
- Bleomycin exposure decreases autophagosomes in the lungs, and rapamycin restores their levels.

## 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.