The role of antioxidant enzymes in modulating lung airway and vascular diseases will be evaluated. One of the most important findings during the prior funding period of this grant was that the extracellular form of superoxide dismutase (EC-SOD) is a protein uniquely highly expressed in the lung. It was found to be primarily localized in the extracellular spaces surrounding smooth muscle cells in airways and in the pulmonary vasculature. The hypothesis to be tested is that EC-SOD plays a critical role in regulating the activity of nitric oxide (NO.) in the lung. The possible mechanism for EC-SOD regulation of NO. activity involves scavenging O2- and thereby preventing the reaction of O2- with NO.. The distributions and physical relationships of nitric oxide synthase (the enzymatic source of NO.) and EC-SOD in pulmonary airways and in the pulmonary vasculature will be determined. Both in vitro and in vivo animal models will be used to demonstrate the role of EC-SOD in regulating airway and vascular tone in the lung.
The Specific Aims are 1) Create tools for the study of EC-SOD in an animal model that will allow the biological function of EC-SOD to be explored, 2) Immunolocalize EC-SOD in airways and pulmonary vasculature, 3) Immunolocalize nitric oxide synthase in airways and pulmonary vasculature, 4) Study the mechanisms of airway bronchomotor tone regulation, and 5) Study the mechanisms of pulmonary vasculature tone regulation. These proposed studies are expected to demonstrate that EC-SOD plays a critical role in regulating both airway and vascular tone in the lung. By demonstrating the physiologic importance of this enzyme, we expect to identify new pharmacologic therapies for the treatment of diseases involving both airway hyperreactivity and pulmonary vascular hyperreactivity.
| Schwab, David E; Stamler, Jonathan S; Singel, David J (2010) EPR spectroscopy of nitrite complexes of methemoglobin. Inorg Chem 49:6330-7 |
| Sheng, Huaxin; Yang, Wei; Fukuda, Shiro et al. (2009) Long-term neuroprotection from a potent redox-modulating metalloporphyrin in the rat. Free Radic Biol Med 47:917-23 |
| Zhu, Jun; Li, Sheng; Marshall, Zermeena M et al. (2008) A cystine-cysteine shuttle mediated by xCT facilitates cellular responses to S-nitrosoalbumin. Am J Physiol Cell Physiol 294:C1012-20 |
| Buckley, Barbara J; Li, Sheng; Whorton, A Richard (2008) Keap1 modification and nuclear accumulation in response to S-nitrosocysteine. Free Radic Biol Med 44:692-8 |
| Diesen, Diana L; Hess, Douglas T; Stamler, Jonathan S (2008) Hypoxic vasodilation by red blood cells: evidence for an s-nitrosothiol-based signal. Circ Res 103:545-53 |
| Granillo, Olivia M; Brahmajothi, Mulugu V; Li, Sheng et al. (2008) Pulmonary alveolar epithelial uptake of S-nitrosothiols is regulated by L-type amino acid transporter. Am J Physiol Lung Cell Mol Physiol 295:L38-43 |
| Gutsaeva, Diana R; Carraway, Martha Sue; Suliman, Hagir B et al. (2008) Transient hypoxia stimulates mitochondrial biogenesis in brain subcortex by a neuronal nitric oxide synthase-dependent mechanism. J Neurosci 28:2015-24 |
| Reynolds, James D; Ahearn, Gregory S; Angelo, Michael et al. (2007) S-nitrosohemoglobin deficiency: a mechanism for loss of physiological activity in banked blood. Proc Natl Acad Sci U S A 104:17058-62 |
| Nozik-Grayck, Eva; Whalen, Erin J; Stamler, Jonathan S et al. (2006) S-nitrosoglutathione inhibits alpha1-adrenergic receptor-mediated vasoconstriction and ligand binding in pulmonary artery. Am J Physiol Lung Cell Mol Physiol 290:L136-43 |
| Leinenweber, Stephen B; Sheng, Huaxin; Lynch, John R et al. (2006) Effects of a manganese (III) porphyrin catalytic antioxidant in a mouse closed head injury model. Eur J Pharmacol 531:126-32 |
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