Mechanical strain-induced proliferation and signaling in pulmonary epithelial H441 cells

Pulmonary epithelial cells are exposed to mechanical strain during physiolo gical breathing and mechanical ventilation. Strain regulates pulmonary grow th and development and is implicated in volutrauma-induced fibrosis. The me chanisms of strain-induced effects are not well understood. It was hypothes ized that mechanical strain induces proliferation of pulmonary epithelial c ells and that this is mediated by signals initiated within seconds of strai n. To test this hypothesis, human pulmonary adenocarcinoma H441 cells were strained in vitro. Cyclic as well as tonic strain resulted in increased cel lular proliferation. Western blot analysis of strained cells demonstrated t hree newly phosphorylated tyrosine residues within 30 s of strain. Phosphor ylation of mitogen-activated protein kinases p42/44 increased, electrophore tic mobility shift assay demonstrated activation of transcription factor ac tivating protein-1, and immunohistochemistry demonstrated increased phospho rylation of c-jun in response to strain. The tyrosine kinase inhibitor geni stein blocked the strain-induced proliferation. We conclude that strain ind uces proliferation in pulmonary epithelial cells and that tyrosine kinase a ctivity is necessary to signal the proliferative response to mechanical str ain.