Reactive oxidant species and emerging therapies in clinical medicine

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Nitric oxide (NO) is a dynamic and reactive molecule that impacts a wide range of disease. It reversibly alters the expression of specific genes, activity of proteins and signaling pathways, regulating both physiologic processes and disease states. NO has a basic role in regulating vascular tone of the pulmonary circulation, and recent animal models have suggested a key role on peritoneal lung development. Inhaled nitric oxide (inhaled NO) is a well tolerated and effective treatment for newborns with pulmonary hypertension and hypoxemic respiratory failure and bronchopulmonary dysplasia (BPD). The success of inhaled NO therapy in infants has led to active investigations of its potential role in treating adults. The effect of inhaled NO in human infectious diseases is being evaluated; pulmonary tuberculosis is a likely candidate in which inhaled NO may be of therapeutic benefits. Red blood cells (RBCs) both scavenge NO and carry it in form of S-nitrosothiols (SNOs). It has been postulated that lack of vasodilatation in diabetes and sickle cell disease (SCD) may be a consequence of hypoxia-induced defects in NO processing by RBCs. In management of patients with airway diseases who are treated with inhaled corticosteroids, exhaled NO (FENO) and exhaled breath condensate (EBC) are widely utilized to determine the appropriate dose of the drug. Also, low concentrations of Snitrosoglutathione (GSNO) compared to normal in patients with cystic Fibrosis (CF) or asthma is associated with decreased pulmonary function. Treatments with GSNO have shown to stimulate chloride ion secretion in CF or enhance bronchodilation in asthmatic patients. There is growing evidence that arginine is beneficial for conditions of endothelial dysfunction such as CF or SCD. Inhaled arginine therapy improved pulmonary functions in CF, and combined treatments of inhaled arginine and hydroxyurea proved effective for the vaso-occlusive crisis. Although many advances have been made in vascular gene therapy, translation of preclinical research to the clinic has been slower than expected. The key barriers to the translation of this research are suitable vectors and adequate delivery devices. The optimal vector should be safe, targetspecific, regulatable, and result in a suitable temporal pattern of therapeutic transgene expression. Currently available vectors meet a number of criteria for specific interventions such as improving endothelial function and treating hypertension, but significant advances are still required. The identification of the biological properties of NO is one of the scientific discoveries of the century, and its fate in clinical medicine is yet to be fully realized.

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Oxidative Stress: Clinical and Biomedical Implications

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Chapter in Oxidative Stress: Clinical and Biomedical Implications, Matata & Elahi (eds.) Pages 291-306.

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