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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL086621-05
Application #
8581605
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Lin, Sara
Project Start
2006-09-01
Project End
2017-05-30
Budget Start
2013-07-01
Budget End
2014-05-30
Support Year
5
Fiscal Year
2013
Total Cost
$326,879
Indirect Cost
$112,679
Name
Rutgers University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Guo, Changjiang; Atochina-Vasserman, Elena; Abramova, Helen et al. (2016) Role of NOS2 in pulmonary injury and repair in response to bleomycin. Free Radic Biol Med 91:293-301
Venosa, Alessandro; Malaviya, Rama; Choi, Hyejeong et al. (2016) Characterization of Distinct Macrophage Subpopulations during Nitrogen Mustard-Induced Lung Injury and Fibrosis. Am J Respir Cell Mol Biol 54:436-46
Wei, Yongjie; Zhang, Junfeng Jim; Li, Zhigang et al. (2016) Chronic exposure to air pollution particles increases the risk of obesity and metabolic syndrome: findings from a natural experiment in Beijing. FASEB J 30:2115-22
Knudsen, Lars; Atochina-Vasserman, Elena N; Massa, Christopher B et al. (2015) The role of inducible nitric oxide synthase for interstitial remodeling of alveolar septa in surfactant protein D-deficient mice. Am J Physiol Lung Cell Mol Physiol 309:L959-69
Venosa, Alessandro; Malaviya, Rama; Gow, Andrew J et al. (2015) Protective role of spleen-derived macrophages in lung inflammation, injury, and fibrosis induced by nitrogen mustard. Am J Physiol Lung Cell Mol Physiol 309:L1487-98
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
Atochina-Vasserman, Elena N; Guo, Chang-Jiang; Abramova, Elena et al. (2015) Surfactant dysfunction and lung inflammation in the female mouse model of lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 53:96-104
Pettit, Ashley P; Kipen, Howard; Laumbach, Robert et al. (2015) Disrupted Nitric Oxide Metabolism from Type II Diabetes and Acute Exposure to Particulate Air Pollution. PLoS One 10:e0144250
Atochina-Vasserman, Elena N; Abramova, Elena; James, Melane L et al. (2015) Pharmacological targeting of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth in the mouse model of lymphangioleiomyomatosis. Am J Physiol Lung Cell Mol Physiol 309:L1447-54
Rusu, Mirabela; Golden, Thea; Wang, Haibo et al. (2015) Framework for 3D histologic reconstruction and fusion with in vivo MRI: Preliminary results of characterizing pulmonary inflammation in a mouse model. Med Phys 42:4822-32

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