Our laboratory is focused on discovering novel mechanisms of host defense against environmental toxicants that determine immunobiological and pathobiological susceptibility to lung diseases, in order to develop experimental therapeutics for their prevention and intervention among susceptible populations.
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 the transcription factor Nrf2 in lungs, which activates the host defense response via upregulation of a multitude of cytoprotective genes. A suboptimal or inappropriate host defense predisposes to inflammation, oxidative/nitrosative stress and cell injury and thus plays a critical role in determining susceptibility to various diseases. Decline in Nrf2 activity is associated with the progression of COPD and other lung diseases. We are developing a molecular understanding of the host defense factor Nrf2, which upregulates the stress response transcriptional program and protects against a range of pathological processes (oxidative stress, inflammation, and apoptosis) in environmental diseases, such as COPD. Augmenting Nrf2 is a novel approach to prevent or treat COPD and other environmental lung diseases, and these studies are currently underway. We have also discovered that there is gain of Nrf2 function, via Keap1 mutation and other mechanisms, in cancers of the lung and other organs. In collaboration with NCATS, the first in class Nrf2 inhibitors are being developed as anti-cancer agents to ameliorate therapeutic resistance of lung and other incurable cancers.
Keywords: COPD, Nrf2, Keap1, oxidative stress, lung cancer