© 2007 American Thoracic Society
Detection of Adverse Effects of Endogenous Nitric Oxide in Acute Lung InjuryTo the Editor:McClintock and colleagues in their recent article found that urinary nitric oxide (derived from urinary nitrite) correlated significantly with improved outcomes in patients with acute lung injury (1). Patients subjected to a low tidal volume ventilation strategy had a significantly greater increase of urinary nitric oxide to creatinine ratios compared with patients with traditional tidal volumes (1). The association of increased nitrite levels with a reduced mortality may be related to the fact that nitrite levels not only reflect nitric oxide production but also the effectiveness of oxidation of biologically active nitric oxide to this inactive metabolite. A landmark study demonstrated that mice deficient in S-nitrosoglutathione (GSNO) reductase, which metabolizes GSNO, the dominant form in which biologically active nitric oxide is transported in peripheral blood, had a significantly increased mortality from lipopolysaccharide-induced shock (2). This may also apply to the "GSNO lyase activity" metabolizing GSNO to nitrite (3). Metabolism to nitrite, which is excreted in the urine, may prevent the transfer of NO from GSNO, which does not permeate through cell membranes, to L-cysteine, which carries NO as S-nitrosocysteine through the cell membrane. Increased extracellular metabolism of GSNO may reduce excessive intracellular protein S-nitrosylation, with its associated adverse effects such as apoptosis and ion channel deactivation. This may explain the association of high urinary nitrite levels with better outcome. The greater increase in urinary NO/creatinine ratio in patients with a low tidal volume ventilation strategy, which occurred despite a reduction in interleukin-6 levels, could be related to significantly higher inspired oxygen concentration (FIO2) in this group, which may lead to increased endothelial nitric oxide production (4). Future research into the role of nitric oxide in patients with acute lung injury needs to clarify the role of S-nitrosothiol–metabolizing enzymes in reducing the adverse effects of nitric oxide. Respiratory epithelial cells from bronchoalveolar lavage samples could be screened for proteins inactivated by nitrosylation using antibodies. Such antibodies could be directed against nitrosylation-related new epitopes known to be associated with deactivation of proteins important for lung liquid clearance, including cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels, which showed impaired function in septicemia (5). CFTR function can be down-regulated by direct nitrosylation (6). This together with investigation of the rate of GSNO metabolism could clarify factors important in maintenance of the balance of pathological and physiological S-nitrosylation of vital proteins in the lungs of patients critically ill with acute lung injury.
Luton & Dunstable Hospital NHS Foundation Trust, Luton, United Kingdom FOOTNOTES Conflict of Interest Statement: M.E. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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