To the Editor:—
We read with great interest the recent elegant and important article by Mathru et al. ,1who demonstrated that inhaled nitric oxide attenuates reperfusion injury and inflammatory responses in humans. We would like to add a few comments regarding the possible mechanisms underlying these exciting effects of inhaled nitric oxide.
First, ischemia–reperfusion injury is characterized, in part, by increased tissue oxidative stress, i.e. , the formation of reactive oxygen species, including superoxide.2Nicotine adenine dinucleotide phosphate (NADPH) oxidase has emerged as a major inducible source of superoxide.2In turn, NADPH oxidase expression and activity is rapidly up-regulated by factors associated with ischemia–reperfusion injury. These include hypoxia, cytokines, thromboxane A2, isoprostanes, hydrogen peroxide, and superoxide itself.3Superoxide elicits a battery of proinflammatory effects, such as increased adhesion molecule expression, activation of proinflammatory protein kinases, and vasoconstriction.2
In contrast, endogenous vasculoprotective factors, nitric oxide and prostacyclin (PGI2) are potent inhibitors of NADPH oxidase expression and activity.4–6These effects are mediated by inhibition of Rac1 activation, a key cofactor for activation of NADPH oxidase. However, superoxide negates nitric oxide bioactivity though chemical reactions5,6and reduces PGI2by diverting arachidonic acid into isoprostanes,4effectively rendering tissue more susceptible to an increase of NADPH oxidase expression and activity. Nitric oxide donors and iloprost (stable mimetic of PGI2) are potent inhibitors of NADPH oxidase expression and activity and concomitant superoxide formation in pulmonary artery endothelial and vascular smooth muscle cells.4–6Both inhalational nitric oxide and PGI2have also met with success in treating acute respiratory distress syndrome,7a condition also characterized by aggressive inflammation. This beneficial effect may be due to suppression of NADPH oxidase expression and activity.
It is reasonable to suggest, therefore, that the inhalational nitric oxide may influence the expression and activity of NADPH oxidase within ischemia tissue distal to the lung, which in turn would reduce local superoxide formation. This in turn would conserve the endogenous bioavailability of nitric oxide and PGI2, which in turn may protect against ischemia–reperfusion injury. It is also reasonable to predict that inhalational PGI2may also exert a beneficial effect on peripheral ischemic damage because PGI2not only inhibits NADPH oxidase activity but also exerts the same antiinflammatory effects as nitric oxide.
*Bristol Heart Institute, University of Bristol, Bristol, United Kingdom. firstname.lastname@example.org