Acclimatization of the systemic microcirculation to alveolar hypoxia is mediated by an iNOS-dependent increase in nitric oxide availability

Rats breathing 10% O₂ show a rapid and widespread systemic microvascular inflammation that results from nitric oxide (NO) depletion secondary to increased reactive O₂ species (ROS) generation. The inflammation eventually resolves, and the microcirculation becomes resistant to more severe hypoxia. These experiments were directed to determine the mechanisms underlying this microvascular acclimatization process. Intravital microscopy of the mesentery showed that after 3 wk of hypoxia (barometric pressure ∼380 Torr; partial pressure of inspired O₂ ∼68-70 Torr), rats showed no evidence of inflammation; however, treatment with the inducible NO synthase (iNOS) inhibitor L-N6-(1-iminoethyl) lysine dihydrochloride led to ROS generation, leukocyte-endothelial adherence and emigration, and increased vascular permeability. Mast cells harvested from normoxic rats underwent degranulation when exposed in vitro to monocyte chemoattractant protein-1 (MCP-1), the proximate mediator of mast cell degranulation in acute hypoxia. Mast cell degranulation by MCP-1 was prevented by the NO donor spermine-NONOate. MCP-1 did not induce degranulation of mast cells harvested from 6-day hypoxic rats; however, pretreatment with either the general NOS inhibitor L-NG-monomethyl arginine citrate or the selective iNOS inhibitor N-[3-(aminomethyl) benzyl] acetamidine restored the effect of MCP-1. iNOS was demonstrated in mast cells and alveolar macrophages of acclimatized rats. Nitrate ± nitrite plasma levels decreased significantly in acute hypoxia and were restored after 6 days of acclimatization. The results support the hypothesis that the microvascular acclimatization to hypoxia results from the restoration of the ROS/NO balance mediated by iNOS expression at key sites in the inflammatory cascade. NEW &NOTEWORTHY The study shows that the systemic inflammation of acute hypoxia resolves via an inducible nitric oxide (NO) synthase-induced restoration of the reactive O₂ species/NO balance in the systemic microcirculation. It is proposed that the acute systemic inflammation may represent the first step of the microvascular acclimatization process.