Cyclic stretch induces PlGF expression in bronchial airway epithelial cells via nitric oxide release

Mechanical strain of lung tissue is an important stimulus for the production of growth factors that are critical for lung growth and development. However, excessive mechanical strain, as may occur during mechanical ventilation, may produce an increase in growth factors that may contribute to lung injury. We hypothesized that mechanical strain of primary bronchial airway epithelial cells (BAEpCs) induced the production of placental growth factor (PlGF), a member of the VEGF family. BAEpCs were cultured on a deformable silicoelastic membrane and exposed to different magnitudes of stretch. Stretch induced PlGF and nitric oxide (NO) production that increased with increasing magnitude of stretch. Stretch also induced PlGF and inducible NO synthase (iNOS) gene expression. The stretch-induced PlGF production and NO synthesis were attenuated by PD98059, a specific mitogen-activated protein kinase kinase-1 and -2 inhibitor. Inhibition of NO generation by l-NAME or l-NMMA or scavenging NO by carboxy-PTIO prevented stretch-mediated erk1/2 activation. In addition, in unstretched BAEpCs, exogenous NO enhanced erk1/erk2 activation. Our data suggest that mechanical stretch of BAEpCs induces iNOS expression and induces PlGF release in an erk1/2 activation-dependent manner.