Discovery of Specialized Lung Cells Accelerates Repair After Smoke and Virus Exposure in Mice

Recent research from Stanford Medicine has uncovered a rare type of neuroendocrine cell in the lining of the lungs that plays a critical role in rapid tissue repair following exposure to harmful toxins like wildfire smoke or respiratory viruses. These cells initiate a biological signaling cascade that activates repair and regeneration processes across the lung tissue, a mechanism previously understood in the pancreas, where similar cells help protect insulin-producing beta cells from damage.

Published in the journal Cell, the study demonstrates that treating mice with an experimental drug activating this repair pathway significantly protected their airways from damage caused by influenza and COVID-19. Conversely, blocking the pathway resulted in severe airway injury.

The research highlights that activating this pathway in humans could potentially enhance resilience in firefighters, individuals with respiratory illnesses, and those at risk for metabolic disorders. The pathway involves neuroendocrine cells—less than 1% of airway epithelial cells—that produce Desert hedgehog, a signaling protein crucial for tissue repair. This protein travels into the underlying mesenchyme, stimulating cells through Gli1 to produce IL-6, which prompts stem cells to divide and replace damaged cells.

This epithelial-mesenchymal feedback loop rapidly amplifies airway defense within hours of toxin exposure, restoring critical cell populations like ciliated and secretory cells responsible for clearing particles and mucus. Disruption of this signaling cascade leads to increased vulnerability, with greater cell loss and failed regeneration.

Further insights revealed that the same regenerative signaling occurs in the pancreas, where insulin-producing cells also make Desert hedgehog to safeguard against damage. The findings suggest potential therapeutic strategies—such as targeted activation of this pathway using aerosols or other delivery methods—to prevent lung damage and metabolic decline. However, researchers caution against long-term activation, emphasizing the need for precise control.

This groundbreaking work opens avenues for future treatments aimed at boosting the body's natural repair mechanisms to combat respiratory toxins and metabolic diseases.