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 three weeks of hypoxia (PB ~380 Torr, inspired PO2 ~ 68-70 Torr) rats showed no evidence of inflammation; however, treatment with the inducible NO synthase (iNOS) inhibitor L-N6-(1-Iminoethyl) lysine dihydrochloride (L-NIL) 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 (LNMMA) or the selective iNOS inhibitor N-(3-(Aminomethyl) benzyl) acetamidine (1400W) restored the effect of MCP-1. Inducible NO synthase (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.
- systemic inflammation
- ROS/NO balance
- Copyright © 2016, Journal of Applied Physiology