The Biswal Laboratory
Experimental Therapeutics for COPD
COPD is a major public health problem for both the developed and the developing world. Characterized by chronic bronchitis and emphysema, COPD is the third leading cause of death in the US. COPD affects 24 million Americans and 210 million worldwide. Bacterial and viral acute respiratory infections cause exacerbations leading to a severe decline in lung function in patients with COPD. Current treatments are largely symptomatic and supportive, but do not reverse the underlying biological defect in the lung. Our lab is interested in experimental therapeutics in COPD by understanding the immunomodulation of bacterial and viral exacerbation in COPD.
Our studies have shown that Nrf2 is an important modifier gene that determines susceptibility to COPD. Nrf2 plays a central role in preserving the extracellular matrix and alveolar structures by maintaining the balance between pulmonary antioxidants and oxidants and between antiproteinases and proteinases during cigarette smoke (CS) exposure. Disruption of Nrf2 response results in these imbalances that lead to early onset and more severe emphysema after exposure to chronic CS (). Our studies have also shown that Nrf2 is a modifier for allergic asthma (J Exp Med. 2005, J Immunol. 2008, JI) and acute lung injury (J Clin Invest. 2006) indicating that this pathway plays a critical role in major pulmonary diseases that impact public health.
There is a dramatic decline in Nrf2 pathway in the lungs of patients with advanced COPD due to increased proteasomal degradation of Nrf2 (). Decline in Nrf2 pathway is also associated with increased oxidative stress and ER stress in the lungs of COPD patients (Am J Respir Crit Care Med. 2009).
Macrophages from COPD patients are defective in phagocytosis. This leads to colonization of bacteria that causes exacerbations and lung function decline. Enhancing Nrf2 pathway in macrophages of COPD patients increases bacterial uptake (Sci Transl Med. 2011).
Sulforaphane treatment of alveolar macrophages from COPD patients increases bacterial phagocytosis.
Alveolar macrophages represent the body’s first line of defense against respiratory pathogens; however, alveolar macrophages from COPD patients have a defect in their ability to phagocytose bacteria. Patients with COPD have colonization of bacteria in lungs leading to bacterial exacerbations. Using FITC-labeled Pseudomonas aeruginosa, we assessed bacterial uptake in alveolar macrophages from COPD patients after 16 hours of treatment with sulforaphane. Increased phagocytosis of FITC-PA was confirmed by immunofluorescence microscopy. FITC fluorescence (green) confirmed presence of labeled bacteria in intracellular phagosomes. Image was obtained at 40x magnification.
- Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients. (J Clin Invest. 2011)
- Targeting Nrf2 Signaling Improves Bacterial Clearance by Alveolar Macrophages in Patients with COPD and in a Mouse Model. (Sci Transl Med. 2011)
- (Am J Respir Crit Care Med. 2009)
- (Am J Respir Crit Care Med. 2008)
- (J Immunol. 2008)
- Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. (J Clin Invest. 2006)
- Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. (J Exp Med. 2005)
- (J Clin Invest. 2004)