The central role that Nitric Oxide (NO) plays within pulmonary physiology is highlighted by the number of functions in which it plays a role including the maintenace of ariway tone, blood vessel tone, inflammation, and even lung growth and development. In addition to these important physiological roles, NO has also been implicated in a number of pulmonary diseases including ARDS, Asthma, and cystic fibrosis. As yet the molecular mechanisms by which this simple diatomic molecule can produce such a wide range of signals is unclear, furthermore, it is unclear how disruption of NO metabolism may play a role in pathology. In inflammation, the most important source of NO is the inducible form of the enzyme iNOS. A key downstream effect of iNOS-derived NO is S-nitrosylation of thiol residues to form S-nitrosothiol (SNO). We hypothesize that, by SNO modification of different target proteins, iNOS-derived NO can regulate both the pro-inflammatory and the resolution responses to injury. We have constructed a model in which NO produced early in the inflammatory response within resident macrophages serves to S-nitrosylate extracellular targets, such as Surfactant Protein-D (SP-D);while later in the response, with increasing fluxes of NO and the generation of other oxidants, intracellular S-nitrosylation of targets, such as NF-?B, promotes resolution and repair. We plan to investigate how the presence of iNOS and the SNO-degrading enzyme, GSNOR, in resident and recruited macrophages alters the outcome of bleomycin-mediated lung injury. We have chosen this injury model as it has both an inflammatory and a resolution/repair phase and is therefore ideal for examining our hypothesis. In the first aim differential expression of these enzymes that balance the S-nitrosylation response will be achieved with the use of adoptive transfer. We will determine the effects of loss of iNOS and GSNOR within resident and recruited macrophages at the molecular, cellular, and organ function level. In the second aim, we will examine how we can use knowledge of the signaling mechanisms of a particular SNO target protein, SP-D, to either accentuate or exacerbate bleomycin-mediated lung injury. These studies use state of the art techniques to determine how NO can signal through S-nitrosylation of different target proteins and may provide novel avenues for therapeutic design.
This proposal seeks to understand the molecular mechanisms by which nitric oxide controls pulmonary inflammation and resolution in response to injury. Although it as well understood that nitric oxide plays a role in these processes pharmacological approaches utilizing nitric oxide have been unsuccessful. With a better understanding of how NO signals in the lung one may be able to design targeted therapeutics.
|Gandhi, Sampada K; Rich, David Q; Ohman-Strickland, Pamela A et al. (2014) Plasma nitrite is an indicator of acute changes in ambient air pollutant concentrations. Inhal Toxicol 26:426-34|
|Massa, Christopher B; Scott, Pamela; Abramova, Elena et al. (2014) Acute chlorine gas exposure produces transient inflammation and a progressive alteration in surfactant composition with accompanying mechanical dysfunction. Toxicol Appl Pharmacol 278:53-64|
|Knudsen, Lars; Atochina-Vasserman, Elena N; Guo, Chang-Jiang et al. (2014) NOS2 is critical to the development of emphysema in Sftpd deficient mice but does not affect surfactant homeostasis. PLoS One 9:e85722|
|Helbo, Signe; Gow, Andrew J; Jamil, Amna et al. (2014) Oxygen-linked S-nitrosation in fish myoglobins: a cysteine-specific tertiary allosteric effect. PLoS One 9:e97012|
|Sunil, Vasanthi R; Vayas, Kinal N; Cervelli, Jessica A et al. (2014) Pentoxifylline attenuates nitrogen mustard-induced acute lung injury, oxidative stress and inflammation. Exp Mol Pathol 97:89-98|
|Atochina-Vasserman, Elena N; Biktasova, Asel; Abramova, Elena et al. (2013) Aquaporin 11 insufficiency modulates kidney susceptibility to oxidative stress. Am J Physiol Renal Physiol 304:F1295-307|
|Shi, Jin Dong; Golden, Thea; Guo, Chang-Jiang et al. (2013) Tocopherol supplementation reduces NO production and pulmonary inflammatory response to bleomycin. Nitric Oxide 34:27-36|
|Groves, Angela M; Gow, Andrew J; Massa, Christopher B et al. (2013) Age-related increases in ozone-induced injury and altered pulmonary mechanics in mice with progressive lung inflammation. Am J Physiol Lung Cell Mol Physiol 305:L555-68|
|Sunil, Vasanthi R; Vayas, Kinal N; Massa, Christopher B et al. (2013) Ozone-induced injury and oxidative stress in bronchiolar epithelium are associated with altered pulmonary mechanics. Toxicol Sci 133:309-19|
|Atochina-Vasserman, Elena N; Winkler, Carla; Abramova, Helen et al. (2011) Segmental allergen challenge alters multimeric structure and function of surfactant protein D in humans. Am J Respir Crit Care Med 183:856-64|
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