Abstract-Pulmonary hypertension (PH) is a common complication of chronic hypoxic lung diseases, which increase morbidity and mortality. Hypoxic PH has previously been attributed to structural changes in the pulmonary vasculature including narrowing of the vascular lumen and loss of vessels, which produce a fixed increase in resistance. Using quantitative stereology, we now show that chronic hypoxia caused PH and remodeling of the blood vessel walls in rats but that this remodeling did not lead to structural narrowing of the vascular lumen. Sustained inhibition of the RhoA/Rho-kinase pathway throughout the period of hypoxic exposure attenuated PH and prevented remodeling in intra-acinar vessels without enlarging the structurally determined lumen diameter. In chronically hypoxic lungs, acute Rho kinase inhibition markedly decreased PVR but did not alter the alveolar to arterial oxygen gap. In addition to increased vascular resistance, chronic hypoxia induced Rho kinase-dependent capillary angiogenesis. Thus, hypoxic PH was not caused by fixed structural changes in the vasculature but by sustained vasoconstriction, which was largely Rho kinase dependent. Importantly, this vasoconstriction had no role in ventilation-perfusion matching and optimization of gas exchange. Rho kinase also mediated hypoxia-induced capillary angiogenesis, a previously unrecognized but potentially important adaptive response. S ustained pulmonary hypertension (PH) is a common complication of chronic hypoxic lung diseases that is strongly associated with increased morbidity and reduced survival. Moreover, the presence of cor pulmonale is an independent predictor of increased mortality, suggesting that PH contributes directly to mortality (reviewed in Hopkins et al 1 ). The increase in pulmonary vascular resistance (PVR) caused by chronic hypoxia has previously been attributed to structural changes in the vasculature, in particular encroachment of the remodeled arteriolar walls into the vascular lumen and loss of blood vessels, although recent reports have cast doubt on this paradigm. [1][2][3] In particular, we have recently shown for the first time that hypoxia induces angiogenesis in the adult pulmonary circulation, a potentially beneficial adaptation, and does not cause vessel loss as previously believed. 2 The small G-protein RhoA and its downstream effector Rho-kinase (ROCK) play a central role in diverse cellular functions including smooth muscle contraction, cytoskeletal rearrangement, cell migration, cell proliferation, and gene expression. 4 -8 Given these important functions, it is not surprising that disturbances of this pathway have been identified as important pathogenetic mechanisms in many diseases of the cardiovascular system, including systemic hypertension, arteriosclerosis, and ischemic heart disease. 9 -11 Blockade of the RhoA/ROCK pathway effectively corrects blood pressure in a number of animal models of systemic hypertension 8,11 and is a key regulator of vascular smooth muscle proliferation and migration in disea...

Deliberate induction of prophylactic hypercapnic acidosis protects against lung injury after in vivo ischemia-reperfusion and ventilation-induced lung injury. However, the efficacy of hypercapnic acidosis in sepsis, the commonest cause of clinical acute respiratory distress syndrome, is not known. We investigated whether hypercapnic acidosis--induced by adding CO2 to inspired gas--would be protective against endotoxin-induced lung injury in an in vivo rat model. Prophylactic institution of hypercapnic acidosis (i.e., induction before endotoxin instillation) attenuated the decrement in arterial oxygenation, improved lung compliance, and attenuated alveolar neutrophil infiltration compared with control conditions. Therapeutic institution of hypercapnic acidosis, that is, induction after endotoxin instillation, attenuated the decrement in oxygenation, improved lung compliance, and reduced alveolar neutrophil infiltration and histologic indices of lung injury. Therapeutic hypercapnic acidosis attenuated the endotoxin-induced increase in the higher oxides of nitrogen and nitrosothiols in the lung tissue and epithelial lining fluid. Lung epithelial lining fluid nitrotyrosine concentrations were increased with hypercapnic acidosis. We conclude that hypercapnic acidosis attenuates acute endotoxin-induced lung injury, and is efficacious both prophylactically and therapeutically. The beneficial actions of hypercapnic acidosis were not mediated by inhibition of peroxynitrite-induced nitration within proteins.