Chronic hypoxia induces constitutive p38 mitogen-activated protein kinase activity that correlates with enhanced cellular proliferation in fibroblasts from rat pulmonary but not systemic arteries

Pulmonary hypertension occurs commonly in patients with chronic hypoxic lun g disease and is characterized by the remodeling of the pulmonary artery wa lls. The molecular mechanisms underlying such remodeling are unknown but we have recently shown that the stress-activated (Jnk and p38) mitogen-activa ted protein (MAP) kinases are activated in pulmonary artery fibroblasts fol lowing acute hypoxia. We now show that Erk and p38 MAP kinases are constitu tively activated in fibroblasts derived from the remodeled pulmonary, but n ot the systemic circulation from rats exposed to chronically hypoxic condit ions. Moreover, we find that such fibroblasts show sustained enhanced proli ferative capacities relative to pulmonary artery fibroblasts derived from n ormoxic rats or to aortic fibroblasts from either normoxic or hypoxic rats. Finally, abrogation of p38, but not Erk MAP kinase activity by use of spec ific inhibitors, prevents the enhanced proliferative capacity exhibited by pulmonary artery fibroblasts. Taken together, these data suggest that enhan ced p38 MAP kinase activity provides a molecular mechanism to explain the p roliferation of pulmonary artery fibroblasts required for remodeling of the pulmonary vasculature.