Exposure to Chlorine (C12) gas remains an ongoing health concern in both the industrial sector and its possible use in chemical warfare. C12 gas toxicity is complex comprising of an initial C12-derived injury to the lungs which continues even after cessation of C12 exposure ultimately leading to pulmonary dysfunction, hypoxemia and compromised oxygen delivery and vital organ perfusion and function. We forward the novel proposal that an important element in C12 gas induced toxicity is loss of endothelial nitric oxide (NO) function leading to compromised pulmonary and systemic vascular homeostasis. This thesis stems from data indicating that C12 gas stimulates an inflammatory response and that hypochlorous acid (HOC1), a reactive chlorinating species derived from C12 gas, potently inactivates endothelial nitric oxide synthase dependent NO-formation. An important focus of this proposal and Center application is to develop therapeutic strategies that can be administered post- C12 gas exposure to limit C12 gas toxicity. In this context, we propose that a major goal should be to replete NO-bioactivity. We propose this can be achieved using nitrite, an inorganic anion that we and others have recently shown to be hypoxia activated NO-donor. Supporting this concept are published data showing that lowdose nitrite is cytoprotective and anti-inflammatory in pathologic settings associated with hypoxia, inflammation and NO-deficiency, which are also features of C12 gas toxicity. Moreover, we provide exciting preliminary data showing that in a rat model nitrite administration post-C12 gas exposure significantly prevented pulmonary injury. Based on these and other preliminary studies we hypothesize that C12 gas exposure induces both pulmonary and systemic vascular injury, which will be inhibited by nitrite-dependent NO formation and will test this via the following Specific Aims: 1. Test the hypothesis that inactivation of eNOS leads to compromised pulmonary and systemic vascular function, 2. Establish protective effects of nitrite administration to rats post-C12 gas exposure on cardio-pulmonary function and 3. Determine the mechanism by which nitrite therapy protects against C12 gas induced cardie-pulmonary toxicity. Proposed studies will utilize core facilities and importantly synergize with studies proposed in Projects 1 and 2 specifically with respect to evaluating nitrite-therapy in conjunction with antioxidant therapy (Project 1) and evaluating nitrite-therapy in C12 gas exposure of populations with underlying pulmonary inflammation (due to viral infection or asthma).
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| Balakrishna, Shrilatha; Song, Weifeng; Achanta, Satyanarayana et al. (2014) TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 307:L158-72 |
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| Ambalavanan, Namasivayam; Stanishevsky, Andrei; Bulger, Arlene et al. (2013) Titanium oxide nanoparticle instillation induces inflammation and inhibits lung development in mice. Am J Physiol Lung Cell Mol Physiol 304:L152-61 |
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| Zarogiannis, Sotirios G; Noah, James W; Jurkuvenaite, Asta et al. (2012) Comparison of ribavirin and oseltamivir in reducing mortality and lung injury in mice infected with mouse adapted A/California/04/2009 (H1N1). Life Sci 90:440-5 |
| Lazrak, Ahmed; Chen, Lan; Jurkuvenaite, Asta et al. (2012) Regulation of alveolar epithelial Na+ channels by ERK1/2 in chlorine-breathing mice. Am J Respir Cell Mol Biol 46:342-54 |
| Zhao, Run-Zhen; Nie, Hong-Guang; Su, Xue-Feng et al. (2012) Characterization of a novel splice variant of ? ENaC subunit in human lungs. Am J Physiol Lung Cell Mol Physiol 302:L1262-72 |
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