The overall goal of this application is to understand the role of oxidative stress as a potential target in the pathogenesis of chronic beryllium disease (CBD). CBD is an inflammatory hypersensitivity lung disease that occurs in over 800,000 beryllium-exposed workers in the US characterized by pulmonary granulomas. The molecular mechanisms by which beryllium regulates the chronic production of lung inflammation and granuloma formation are unknown. We hypothesize that beryllium induces oxidative stress by altering thiol homeostasis which enhances beryllium specific T cells to produce excessive Th1 cytokines and proliferate, two key features of CBD pathophysiology.
Three specific aims are proposed to address the hypothesis.
Specific aim 1 will examine the mechanisms by which beryllium stimulates oxidative stress in beryllium specific CD4+ T cells by altering thiol redox status.
Specific aim 2 will determine whether beryllium-mediated oxidative stress alters the balance between histone acetyltransferase (HAT) and histone deacetyltransferase (HDAC) activities that modulates inflammation and steroid sensitivity in CBD.
This aim will test whether beryllium exposure creates oxidative stress that impairs HDAC activity as a mechanism that amplifies inflammation in CBD.
Specific aim 3 will examine the potential therapeutic effect of a 5 aminosalicylic acid in CBD subjects. This last aim will assess a novel new therapy in CBD patients that targets beryllium-mediated oxidative stress and inflammation. The proposed experiments elucidate novel mechanisms that explain the excessive cytokine response to beryllium and pinpoint the role of antioxidant imbalance in CBD and mechanistic approaches to treat CBD.

Public Health Relevance

CBD is a granulomatous lung disease that occurs in a large population of US workers exposed to beryllium. The proposed study focuses on novel findings that beryllium is both an antigen and initiator of oxidative stress that results in alterations in cellular thiol status. The studies will mechanistically target these changes with a novel therapeutic approach using 5 aminosalicylic acid in CBD subjects.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-RES-B (03))
Program Officer
Nadadur, Srikanth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Jewish Health
United States
Zip Code
Day, Brian J; Huang, Jie; Barkes, Briana Q et al. (2018) A Pilot Study Assessing the Ability of 5-Aminosalicylic Acid to Modulate the Immune Response in Chronic Beryllium Disease. Ann Am Thorac Soc 15:S133
Day, Brian J (2014) Antioxidant therapeutics: Pandora's box. Free Radic Biol Med 66:58-64
Shalaby, Karim H; Allard-Coutu, Alexandra; O'Sullivan, Michael J et al. (2013) Inhaled birch pollen extract induces airway hyperresponsiveness via oxidative stress but independently of pollen-intrinsic NADPH oxidase activity, or the TLR4-TRIF pathway. J Immunol 191:922-33
Brechbuhl, Heather M; Kachadourian, Remy; Min, Elysia et al. (2012) Chrysin enhances doxorubicin-induced cytotoxicity in human lung epithelial cancer cell lines: the role of glutathione. Toxicol Appl Pharmacol 258:1-9
Valdameri, Glaucio; Gauthier, Charlotte; Terreux, Raphaƫl et al. (2012) Investigation of chalcones as selective inhibitors of the breast cancer resistance protein: critical role of methoxylation in both inhibition potency and cytotoxicity. J Med Chem 55:3193-200
Gould, Neal S; Min, Elysia; Martin, Richard J et al. (2012) CFTR is the primary known apical glutathione transporter involved in cigarette smoke-induced adaptive responses in the lung. Free Radic Biol Med 52:1201-6
Kachadourian, Remy; Day, Brian J; Pugazhenti, Subbiah et al. (2012) A synthetic chalcone as a potent inducer of glutathione biosynthesis. J Med Chem 55:1382-8
Gould, Neal S; Day, Brian J (2011) Targeting maladaptive glutathione responses in lung disease. Biochem Pharmacol 81:187-93
Kachadourian, Remy; Pugazhenthi, Subbiah; Velmurugan, Kalpana et al. (2011) 2',5'-Dihydroxychalcone-induced glutathione is mediated by oxidative stress and kinase signaling pathways. Free Radic Biol Med 51:1146-54
Dobis, Dave R; Sawyer, Richard T; Gillespie, May M et al. (2010) Sulfasalazine and mesalamine modulate beryllium-specific lymphocyte proliferation and inflammatory cytokine production. Am J Respir Cell Mol Biol 43:458-64

Showing the most recent 10 out of 13 publications