This mentored career development plan will help the P.I. re-enter the field of biomedical research after a 3- year hiatus, and will prepare her to conduct independent research focusing on pulmonary disease pathogenesis and treatment. The plan includes training in pulmonary toxicity, inflammation, and drug delivery through mentored research and educational activities. This experience will enable the P.I. to achieve her overall goal of becoming an independent investigator. The overall goal of the research is to elucidate inflammatory mechanisms mediating lung disease with a particular emphasis on the role of reactive nitrogen species (RONS) in disease pathogenesis. Although RONS have been shown to play a key role in acute lung injury and disease, their role in pneumonitis and consequent fibrosis is unknown and represents the focus of the research. To induce pneumonitis, a mouse model of radiation-induced lung injury will be used. The research plan will test the hypothesis that inhibiting production of RONS immediately following radiation exposure, while not reducing acute injury during the early latent phase of radiation induced injury, will significantly mitigate pneumonitis and consequent fibrosis. For these studies 1400W, a highly specific inhibitor of inducible nitric oxide synthase (iNOS), which has previously been shown to be effective in ameliorating acute lung injury in rodent models will be used.
In aim 1, the efficacy of 1400W administered by Alzet micro-osmotic pumps in mitigating radiation induced iNOS activation and RONS generation will be assessed. Measurements will be made of markers of acute lung injury and oxidative/nitrosative stress.
Aim 2 will be focused on assessing the effectiveness of 1400W in reducing consequent pneumonitis and fibrosis.
In Aim 3, we will optimize a novel nanogel microparticle system to selectively deliver 1400W to the pulmonary vascular compartment of mice after radiation exposure. The results of these studies will provide important mechanistic information on the role of RONS in radiation induced lung injury and may provide clues on a novel efficacious treatment protocol for mitigating lung pneumonitis and fibrosis.
Pneumonitis and fibrosis consequent to acute lung injury are of major health concern. The identification of mechanisms leading to these pathologies and effective treatment protocols is key to minimizing chronic lung injury.
|Malaviya, Rama; Sunil, Vasanthi R; Venosa, Alessandro et al. (2016) Inflammatory mechanisms of pulmonary injury induced by mustards. Toxicol Lett 244:2-7|
|Malaviya, Rama; Sunil, Vasanthi R; Venosa, Alessandro et al. (2015) Attenuation of Nitrogen Mustard-Induced Pulmonary Injury and Fibrosis by Anti-Tumor Necrosis Factor-Î± Antibody. Toxicol Sci 148:71-88|
|Malaviya, Rama; Gow, Andrew J; Francis, Mary et al. (2015) Radiation-induced lung injury and inflammation in mice: role of inducible nitric oxide synthase and surfactant protein D. Toxicol Sci 144:27-38|
|Malaviya, Rama; Laskin, Jeffrey D; Laskin, Debra L (2014) Oxidative stress-induced autophagy: role in pulmonary toxicity. Toxicol Appl Pharmacol 275:145-51|
|Malaviya, Rama; Venosa, Alessandro; Hall, Leroy et al. (2012) Attenuation of acute nitrogen mustard-induced lung injury, inflammation and fibrogenesis by a nitric oxide synthase inhibitor. Toxicol Appl Pharmacol 265:279-91|
|Malaviya, Rama; Laskin, Debra L; Malaviya, Ravi (2010) Janus kinase-3 dependent inflammatory responses in allergic asthma. Int Immunopharmacol 10:829-36|
|Malaviya, Rama; Sunil, Vasanthi R; Cervelli, Jessica et al. (2010) Inflammatory effects of inhaled sulfur mustard in rat lung. Toxicol Appl Pharmacol 248:89-99|