Leucine and its transporter provide protection against cigarette smoke-induced cell death: A potential therapy for emphysema

• CS downregulates Lat1, transporter of leucine, in alveolar epithelial cells.
• Lat1 downregulation leads to mTOR inactivation and cell death in A549.
• Dietary leucine supplementation prevents CS-induced mTOR inactivation in animals.
• Leucine ameliorates CS-induced pre-existing emphysematous changes in animals.
• Leucine can be a potential therapeutic agent for CS-induced lung damage.

Cigarette smoke (CS) is a major risk factor for emphysematous changes in the lungs and the underlying mechanism involves CS-induced cell death. In the present study we investigated the ability of nutrients to rescue CS-induced cell death. We observed that pre-treatment with excess leucine can partially rescue CS extract-induced cell death in Saccharomyces cerevisiae and alveolar epithelial A549 cells. Excess dietary leucine was also effective in alleviating effects of CS in guinea pig lungs. Further investigation to understand the underlying mechanism showed that CS exposure causes downregulation of leucine transporter that results in inactivation of mTOR, which is a positive regulator of protein synthesis and cell proliferation. Notably, leucine supplemented diet ameliorated even existing CS-induced emphysematous changes in guinea pig lung, a condition hitherto thought to be irreversible. Thus the current study documents a new mechanism by which CS affects cellular physiology wherein leucine transporter is a key target.