Effects of hypoxia on rat airway smooth muscle cell proliferation

Although it is well known that hypoxemia induces pulmonary vasoconstriction and vascular remodeling, due to the proliferation of both vascular smooth muscle cells and fibroblasts, the effects of hypoxemia on airway smooth muscle cells are not well characterized. The present study was designed to assess the in vitro effects of hypoxia (1 or 3% O-2) on rat airway smooth muscle cell growth and response to mitogens (PDGF and 5-HT). Cell growth was assessed by cell counting and cell cycle analysis. Compared with normoxia (21% O-2), there was a 42.2% increase in the rate of proliferation of cells exposed to 3% O-2 (72 h, P = 0.006), as well as an enhanced response to PDGF (13.9% increase; P = 0.023) and to 5-HT (17.2% increase; P = 0.039). Exposure to 1% O-2 (72 h) decreased cell proliferation by 21.0% (P = 0.017) and reduced the increase in cell proliferation induced by PGDF and 5-HT by 16.2 and 15.7%, respectively (P = 0.019 and P = 0.011). A significant inhibition in hypoxia-induced cell proliferation was observed after the administration of bisindolylmaleimide GF-109203X (a specific PKC inhibitor) or downregulation of PKC with PMA. Pretreatment with GF-109203X decreased proliferation by 21.5% (P = 0.004) and PMA by 31.5% (P = 0.005). These results show that hypoxia induces airway smooth muscle cell proliferation, which is at least partially dependent on PKC activation. They suggest that hypoxia could contribute to airway remodeling in patients suffering from chronic, severe respiratory diseases.