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Ann Thorac Surg 1996;62:1586-1587
© 1996 The Society of Thoracic Surgeons
Department of Medicine, Columbia University College of Physicians and Surgeons, 630 W 168th St, New York, NY 10032
After every breath that we take, we exhale a measurable amount of NO [1], evidence for the tremendous capacity of the lungs to synthesize NO from the percursor L-arginine. Recent data even suggest that one of the prime functions of the lungs is to synthesize NO, to be unloaded by hemoglobin in distal tissues [2]. Within the lungs themselves, NO serves important vascular homeostatic functions, which become deranged after ischemia due to the nearly instantaneous quenching of NO by superoxide generated during reperfusion. The plummeting NO levels are associated with a decline in tissue cyclic guanosine monophosphate levels [3], which, in combination with a failure of the cyclic adenosine monophosphate second messenger pathway [4], results in leukosequestration, platelet aggregation, increased permeability, and vasoconstriction. In cardiac or pulmonary models of ischemia and reperfusion, stimulating either proximal or distal components of the nitric oxide/cyclic guanosine monophosphate second messenger pathway ameliorates the vascular dysfunction [3, 5, 6]. Understanding the causes of failed vascular homeostasis and the means by which to normalize it is especially important in the setting of lung transplantation, given the vast vascular bed within the lungs and the extreme vulnerability of the lungs to ischemic injury.
In this regard, this study by Shiraishi and associates is particularly germane. This study confirms the primacy of neutrophil recruitment in postischemic lung injury, and goes further by showing that L-arginine supplementation reduces tissue injury. These studies add to the growing evidence that L-arginine is beneficial in the setting of ischemia and reperfusion. Unfortunately, Shiraishi and associates do not go further in this study to explore the mechanism(s) whereby L-arginine confers benefit. For instance, it is likely that NO generated from L-arginine inhibits leukosequestration after ischemia, which would explain the similar beneficial effects in the leukocyte-depleted and L-arginine–treated groups. It would have been interesting to know whether L-arginine acted synergistically with leukocyte depletion to reduce tissue injury, a result that would suggest that L-arginine has other beneficial properties beyond its effects to inhibit leukocyte adhesion. It is also not clear from this study whether L-arginine–induced inhibition of platelet aggregation and neutrophil/capillary plugging contributed to the observed decrease in pulmonary vascular resistance, or whether this was simply a manifestation of its vasodilator properties.
Finally, an intriguing possibility suggests itself, from both these experiments and those of others [5, 6], in which L-arginine confers postischemic benefits, even though measurable NO levels are low during reperfusion. In studies of brain NO synthase, similar to the endothelial isoform in that both enzymes are Ca2+/calmodulin-dependent, the lack of substrate (L-arginine) is associated with continued electron transport and activity of the enzyme [7, 8]. However, rather than generating NO and L-citrulline, it catalyzes the reduction of molecular oxygen to hydrogen peroxide and superoxide anion. It is possible, therefore, that the beneficial effects of L-arginine during reperfusion may be not only the result of NO generation, but also due to reduced generation of highly reactive oxygen species. This may explain why L-arginine was beneficial in the current experiments even in PGE1-pretreated lungs, which should presumably have augmented levels of cyclic adenosine monophosphate [4], which might otherwise compensate for a loss of cyclic guanosine monophosphate–mediated vascular protection.
Although these hypothetical mechanisms remain to be explored, this study adds to the emerging evidence that L-arginine supplementation and neutrophil depletion are beneficial in the setting of pulmonary reperfusion. Whether or not L-arginine will prove clinically useful remains to be seen, but without an obvious downside, there should be a low threshold for beginning controlled therapeutic trials of its efficacy to improve lung preservation.
References
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