The overall goal of our research is to elucidate the role of macrophages and inflammatory mediators in acute and chronic pulmonary injury induced by vesicants with the long-term objective of identifying targets for therapeutic intervention. We hypothesize that macrophages play a dual role in the pulmonary toxicity of vesicants. Whereas initially classically activated M1 macrophages contribute to acute tissue injury by releasing excessive quantities of proinflammatory/cytotoxic mediators, subsequent release of mitogenic and fibrogenic mediators by overactive M2 macrophages leads to chronic injury including pulmonary fibrosis. Using sulfur mustard and nitrogen mustard as model vesicants, plans are to determine if M1 and M2 macrophage subpopulations differentially contribute to the acute and long-term consequences of vesicant intoxication, and if pharmacologically modifying their activity or mediators they release mitigates toxicity. Working with the Medicinal Chemistry and Pharmaceutics Core, we also plan to engineer and evaluate an injectable lung delivery system consisting of poly(ethylene glycol) hydrogel particles (

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
7U54AR055073-08
Application #
8545531
Study Section
Special Emphasis Panel (ZRG1-MDCN-J)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
8
Fiscal Year
2013
Total Cost
$596,214
Indirect Cost
$44,839
Name
Rbhs-Robert Wood Johnson Medical School
Department
Type
DUNS #
078795875
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Malaviya, Rama; Laskin, Jeffrey D; Laskin, Debra L (2014) Oxidative stress-induced autophagy: role in pulmonary toxicity. Toxicol Appl Pharmacol 275:145-51
Joseph, Laurie B; Heck, Diane E; Cervelli, Jessica A et al. (2014) Structural changes in hair follicles and sebaceous glands of hairless mice following exposure to sulfur mustard. Exp Mol Pathol 96:316-27
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
Mishin, Vladimir; Heck, Diane E; Laskin, Debra L et al. (2014) Human recombinant cytochrome P450 enzymes display distinct hydrogen peroxide generating activities during substrate independent NADPH oxidase reactions. Toxicol Sci 141:344-52
Zheng, Ruijin; Heck, Diane E; Black, Adrienne T et al. (2014) Regulation of keratinocyte expression of stress proteins and antioxidants by the electrophilic nitrofatty acids 9- and 10-nitrooleic acid. Free Radic Biol Med 67:1-9
Pinkerton, Nathalie M; Zhang, Stacey W; Youngblood, Richard L et al. (2014) Gelation chemistries for the encapsulation of nanoparticles in composite gel microparticles for lung imaging and drug delivery. Biomacromolecules 15:252-61
Jan, Yi-Hua; Heck, Diane E; Dragomir, Ana-Cristina et al. (2014) Acetaminophen reactive intermediates target hepatic thioredoxin reductase. Chem Res Toxicol 27:882-94
Page, Eric J; Gray, Joshua P (2014) Agents of Bioterrorism: Curriculum and Pedagogy in an Online Masters Course. J Toxicol Educ 1:31-53
Chang, Yoke-Chen; Wang, James D; Hahn, Rita A et al. (2014) Therapeutic potential of a non-steroidal bifunctional anti-inflammatory and anti-cholinergic agent against skin injury induced by sulfur mustard. Toxicol Appl Pharmacol 280:236-44
Chen, Peiming; Zhang, Xiaoping; Jia, Lee et al. (2014) Optimal structural design of mannosylated nanocarriers for macrophage targeting. J Control Release 194:341-9

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