Cigarette Smoking Promotes Dendritic Cell Survival and Resistance to Apoptosis Through HEME-Oxygenase-1 Dependant Mechanisms
Robert Vassallo MD
Mayo Clinic – Rochester, Minnesota USA
Date of Award
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Pulmonary LCH is an unusual lung disease that occurs almost exclusively in cigarette smokers. Although the link between smoking and pulmonary LCH is strong, the mechanisms by which smoking may precipitate LCH in susceptible individuals are unknown. In this application, we propose that smoking inappropriately promotes the survival of dendritic cells in the lungs. We provide preliminary evidence that smoking does prolong the life-span of dendritic cells by switching on certain molecular pathways inside the dendritic cell, particularly the heme-oxygenase-1 (HO-1) protein. We also show in preliminary studies that smoking activates Bcl-xL, a cellular protein that confers resistance to cell death. These observations are important because a recent study showed that the pathologic cells in pulmonary LCH frequently expressed the Bcl-xL protein, suggesting that in the lungs of LCH patients, cells may be accumulating because they resist normal mechanisms that would otherwise cause their clearance.
This application will explore specific mechanisms by which smoking may confer enhanced survival of dendritic cells, the key cellular participant in the LCH lesion. We will also define which component in cigarette smoke (nicotine, carbon monoxide, or oxidative stress) is most likely to be causing this effect. We will also study the expression of HO-1 and Bcl-xL in lung biopsy specimens of patients with pulmonary LCH and determine if the intensity of expression is a marker of disease severity.
Through the studies proposed in this application we will have greater insight into the mechanisms that lead to pulmonary LCH. We will also identify new targets for the treatment of this disease. For example, the use of potent anti-oxidant strategies may be helpful to reverse the abnormalities in cell regulation induced by oxidative stress from cigarette smoke. Understanding mechanisms causing pulmonary LCH is absolutely critical in the quest for new treatment approaches for this frustrating disease.