Shyam Biswal, PhD
Our laboratory is focused on discovering novel mechanisms of host defense that determine immunobiology and pathobiology of environmental lung diseases to develop experimental therapeutics for their prevention and intervention in a susceptible population”. Exposure to environmental toxicants and stressors such as cigarette smoke, indoor/outdoor air pollutants, respiratory bacteria/viruses and allergens causes oxidative/nitrosative stress, inflammation, and cell injury and is associated with diverse pulmonary disease states. In response to environmental stressors, cells activate transcription factor Nrf2 in lungs that confers host defense by upregulating multitude of cytoprotective genes. Suboptimal or inappropriate host defense predisposes to inflammation, oxidative/nitrosative stress and cell injury and thus play a critical role in determining susceptibility to various diseases. Decline in the Nrf2 pathway is associated with the progression of COPD and other lung diseases. We are developing molecular understanding of the host defense factor Nrf2 that upregulates stress response transcriptional program and protects against a range of pathological processes (oxidative stress, inflammation, and apoptosis) in environmental diseases such as COPD. A novel approach for prevention and intervention of COPD and other environmental lung diseases by augmenting Nrf2 is underway.
- Harvey C, Thimmulappa R, Sethi S, Kong X, Yarmus L, Brown R, Feller-Kopman D, Wise R, and Biswal S. (2011) Targeting Nrf2 Signaling Improves Bacterial Clearance by Alveolar Macrophages in Patients with COPD and in a Mouse Model. Science Transl Med 3(78):78ra32.
- Malhotra D, Thimmulappa R, Mercado N, Ito K, Kombairaju P, Kumar S, Ma J, Feller-Kopman D, Wise R, Barnes P, and Biswal S. (2011) Denitrosylation of HDAC2 by Targeting Nrf2 Restores Glucocorticosteroid Sensitivity in Macrophages from COPD Patients. J Clin Invest. (in press)
- Kong X, Thimmulappa R, Craciun F, Harvey , Singh A, Kombairaju P, Reddy SP, Remick D, and Biswal S. (2011) Enhancing Nrf2 Pathway by Disruption of Keap1 in Myeloid Leukocytes Protects Against Sepsis. Am J Respir Crit Care Med. (in press)
- Sussan TE, Rangasamy T, Blake DJ, Malhotra D, El-Haddad H, Bedja D, Yates MS, Kombairaju P, Yamamoto M, Liby KT, Sporn MB, Gabrielson KL, Champion HC, Tuder RM, Kensler TW, and Biswal S. (2009) Targeting Nrf2 with the Triterpenoid CDDO-Imidazolide Attenuates Cigarette Smoke-Induced Emphysema and Cardiac Dysfunction in Mice. Proc. Natl. Acad. Sci. 106(1):250-5.
- Malhotra D, Thimmulappa RK, Navas-Acien A, Sandford A, Elliott M, Singh A, Chen L, Zhuang X, Hogg J, Pare P, Tuder RM, Biswal S. (2008) Decline in NRF2 regulated antioxidants in COPD lungs due to loss of its positive regulator DJ-1. Am J Respir Crit Care Med. 178(6):592-604.
- Singh A, Misra V, Thimmulappa RK, Lee H, Ames S, Hoque MO, Herman, JG, Baylin SB, Sidransky D, Gabrielson E, Brock MV, Biswal S. (2006) Dysfunctional KEAP1 Nrf2 Interaction in Non-Small-Cell Lung Cancer. PLoS Medicine3(10): e420