Role of nitric oxide in lung ischemia and reperfusion injury

Abstract

We studied the effects of nitric oxide synthase (NOS) inhibitors and nitric oxide (NO.) donors on ischemia-reperfusion (I/R)-induced microvascular permeability increase in isolated buffer-perfused rat lungs. Microvascular permeability (Kf,c) was significantly increased in lungs subjected to 45 min of ischemia followed by 30 min of reperfusion. Lungs that were pretreated with 300 and 600 microM N omega-nitro-L-arginine methyl ester (L-NAME), 1, 300, and 600 microM NG-monomethyl-L-arginine (L-NMMA), or 600 microM L-N6-(1-iminoethyl) ornithine (L-NIO) still showed significant increases in Kf,c after I/R. Lungs that were pretreated with 5 mM L-NAME or 5 mM N omega-nitro-D-arginine methyl ester showed no increase in Kf,c after I/R. However, both compounds at these concentrations produced significant decreases in perfusate pH. The decreased pH was responsible for the protective effects, since lungs pretreated with 5 mM L-NAME and supplemented with NaHCO3 to prevent the perfusate pH decrease still showed a significant elevation in Kf,c after I/R. In additional experiments, NO.donors were administered to isolated lungs at the onset of reperfusion. Spermine-NO (100 microM) and S-nitroso-N-acetylpenacillamine (300 microM) both prevented the increase in Kf,c associated with I/R. We conclude from these studies that peroxynitrite does not mediate microvascular permeability increase after lung I/R injury in this model, and exogenous NO. does not exacerbate injury; rather, it prevents microvascular damage.

Lung ischemia-reperfusion injury: a molecular and clinical view on a complex pathophysiological process

“…However, this is only the case on the vascular side of the lung: several papers have suggested that inhaling NO is beneficial in preventing LIRI (139,204). However, it should be noted that none of these studies provide, nor prove, a mechanism of action for these effects.…”

Nitric oxide in gingival crevicular fluid and nitric oxide synthase expression in the gingiva of patients with sickle cell disease

“…During NO synthesis by NOS, if L-arginine levels decrease or consumption of NO increases via cell-free plasma hemoglobin and ROS, then oxidative damage occurs, HbS denatures, and superoxide production increases. It was shown that iNOS inhibition significantly limits tissue ischemiareperfusion injury in the liver and kidneys [10][11]; however, inhibition of iNOS attenuated ischemiareperfusion injury in the rat heart [12], but not in the rat lung [13]. Increased iNOS expression was reported in the kidneys of transgenic mice [9], but Nath et al [14] reported the lack of iNOS upregulation in intrarenal vasculature and increased iNOS expression in the glomeruli and distal tubules of sickle mice.…”

“…Increased iNOS expression and a consequent increase in tissue nitrite and nitrate production have been observed in the kidneys and liver of SCD patients [8], mice [2,3,8,9], and pigs [4]. Additionally, it was shown that iNOS inhibition significantly limits tissue ischemia-reperfusion injury in the liver and kidneys [10,11]; however, inhibition of iNOS attenuated ischemia-reperfusion injury in the rat heart [12] and did not affect ischemia-reperfusion injury in the rat lung [13]. Increased levels of iNOS expression were shown in the kidneys of transgenic mice [9], but Nath et al [14] reported the lack of upregulation of iNOS in the intrarenal vasculature and increased expression of iNOS in the [15][16][17] and in vitro [18].…”

Potential Benefits of Peroxynitrite

“…At nanomolar concentrations, NO modulates a number of physiologic processes related to vascular reactivity and platelet function [228,269], leukocyte-endothelial cell interactions [270], vascular permeability [271,272], and is cytoprotective in ischemia-reperfusion injury [273,274]. However, at higher micromolar concentrations, NO as well as PN, participates in cellular injury as seen in the lung [243], following the development of ischemia-reperfusion injury, endotoxic and hypovolemic shock [7,275].…”