mTOR Overactivation and Compromised Autophagy in the Pathogenesis of Pulmonary Fibrosis

Area of Science:

• Pulmonology
• Molecular Biology
• Cell Biology

Background:

• Pulmonary fibrosis is a progressive lung disease with limited treatment options.
• The mammalian target of rapamycin (mTOR) pathway plays a role in cellular processes relevant to fibrosis.

Purpose of the Study:

• To investigate the role of mTOR signaling in the pathogenesis of pulmonary fibrosis.
• To explore the potential of targeting mTOR and autophagy for treating pulmonary fibrosis.

Main Methods:

• Utilized conditional and inducible Tsc1 knock-down mice (STT) to achieve mTOR overactivation in alveolar epithelial cells (AECs).
• Induced pulmonary fibrosis using bleomycin in mice.
• Administered rapamycin (mTOR inhibitor) and chloroquine (autophagy inhibitor) to assess their effects on mortality and fibrosis.

Main Results:

• mTOR overactivation in AECs was successfully induced in STT mice.
• Bleomycin treatment led to increased mortality and pulmonary fibrosis.
• Rapamycin pretreatment attenuated bleomycin-induced mortality and fibrosis.
• Rapamycin's protective effect was diminished by chloroquine, indicating an autophagy-dependent mechanism.
• Bleomycin exposure decreased autophagosomes, while rapamycin increased them and reduced p62 levels.

Conclusions:

• mTOR overactivation in AECs and impaired autophagy contribute to pulmonary fibrosis development.
• Suppressing mTOR and enhancing autophagy represent potential therapeutic strategies for pulmonary fibrosis.