Exposure to Chlorine (C12) gas remains an ongoing health concern in both the industrial sector and its possibleuse in chemical warfare. C12 gas toxicity is complex comprising of an initial C12-derived injury to the lungswhich continues even after cessation of C12 exposure ultimately leading to pulmonary dysfunction, hypoxemiaand compromised oxygen delivery and vital organ perfusion and function. We forward the novel proposal thatan important element in C12 gas induced toxicity is loss of endothelial nitric oxide (NO) function leading tocompromised pulmonary and systemic vascular homeostasis. This thesis stems from data indicating that C12 gasstimulates an inflammatory response and that hypochlorous acid (HOC1), a reactive chlorinating species derivedfrom C12 gas, potently inactivates endothelial nitric oxide synthase dependent NO-formation. An importantfocus 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 repleteNO-bioactivity. We propose this can be achieved using nitrite, an inorganic anion that we and others haverecently shown to be hypoxia activated NO-donor. Supporting this concept are published data showing that lowdosenitrite 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 excitingpreliminary data showing that in a rat model nitrite administration post-C12 gas exposure significantly preventedpulmonary injury. Based on these and other preliminary studies we hypothesize that C12 gas exposure inducesboth pulmonary and systemic vascular injury, which will be inhibited by nitrite-dependent NO formation andwill test this via the following Specific Aims: 1. Test the hypothesis that inactivation of eNOS leads tocompromised pulmonary and systemic vascular function, 2. Establish protective effects of nitrite administrationto rats post-C12 gas exposure on cardio-pulmonary function and 3. Determine the mechanism by which nitritetherapy protects against C12 gas induced cardie-pulmonary toxicity. Proposed studies will utilize core facilitiesand importantly synergize with studies proposed in Projects 1 and 2 specifically with respect to evaluatingnitrite-therapy in conjunction with antioxidant therapy (Project 1) and evaluating nitrite-therapy in C12 gasexposure of populations with underlying pulmonary inflammation (due to viral infection or asthma).
| Song, Weifeng; Yu, Zhihong; Doran, Stephen F et al. (2015) Respiratory syncytial virus infection increases chlorine-induced airway hyperresponsiveness. Am J Physiol Lung Cell Mol Physiol 309:L205-10 |
| 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 |
| Gessner, Melissa A; Doran, Stephen F; Yu, Zhihong et al. (2013) Chlorine gas exposure increases susceptibility to invasive lung fungal infection. Am J Physiol Lung Cell Mol Physiol 304:L765-73 |
| Li, Changzhao; Weng, Zhiping; Doran, Stephen F et al. (2013) Chlorine induces the unfolded protein response in murine lungs and skin. Am J Respir Cell Mol Biol 49:197-203 |
| 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 |
| 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 |
| Bracher, Andreas; Doran, Stephen F; Squadrito, Giuseppe L et al. (2012) Targeted aerosolized delivery of ascorbate in the lungs of chlorine-exposed rats. J Aerosol Med Pulm Drug Deliv 25:333-41 |
| Fanucchi, Michelle V; Bracher, Andreas; Doran, Stephen F et al. (2012) Post-exposure antioxidant treatment in rats decreases airway hyperplasia and hyperreactivity due to chlorine inhalation. Am J Respir Cell Mol Biol 46:599-606 |
| Samal, Andrey A; Honavar, Jaideep; Brandon, Angela et al. (2012) Administration of nitrite after chlorine gas exposure prevents lung injury: effect of administration modality. Free Radic Biol Med 53:1431-9 |
| Filippidis, Aristotelis S; Zarogiannis, Sotirios G; Randich, Alan et al. (2012) Assessment of locomotion in chlorine exposed mice by computer vision and neural networks. J Appl Physiol 112:1064-72 |
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