Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia

Chronic hypoxia causes pulmonary hypertension with smooth muscle cell proli feration and matrix deposition in the wall of the pulmonary arterioles, We demonstrate here that hypoxia also induces a pronounced inflammation in the lung before the structural changes of the vessel wall. The proinflammatory action of hypoxia is mediated by the induction of distinct cytokines and c hemokines and is independent of tumor necrosis factor-cu signaling, We have previously proposed a crucial role for heme oxygenase-l (HO-1) in protecti ng cardiomyocytes from hypoxic stress, and potent anti-inflammatory propert ies of HO-1 have been reported in models of tissue injury, We thus establis hed transgenic mice that constitutively express HO-1 in the lung and expose d them to chronic hypoxia, HO-1 transgenic mice were protected from the dev elopment of both pulmonary inflammation as well as hypertension and vessel wall hypertrophy induced by hypoxia. Significantly, the hypoxic induction o f proinflammatory cytokines and chemokines was suppressed in HO-1 transgeni c mice. Our findings suggest an important protective function of enzymatic products of HO-1 activity as inhibitors of hypoxia-induced vasoconstrictive and proinflammatory pathways.