Mechanisms of Asthma Pathogenesis
Chronic lung diseases such as asthma and COPD are among the leading causes of death in the US and the mechanisms for the progressive remodeling of lung tissue that occurs in these diseases are incompletely understood. Adenosine levels are elevated in the lungs of these subjects where it engages four subtypes of receptors, which results in the release of the pro-fibrotic cytokine IL-6, leading to augmented bronchoconstriction to stimuli, airway inflammation, and remodeling. In animal models, decreasing the accumulation of adenosine is known to alter the course of lung inflammation and increase survival. The bronchospastic response in subjects with asthma and COPD to adenosine is not seen in normal subjects, indicating that the underlying mechanisms of increased bronchospasm, airway inflammation, and remodeling are augmented in these diseases. Adenosine is generated by dephosphorylation of ATP at sites ofinflammation and remodeling as well as generated intracellularly and transported through the nucleoside transporters.
The goal of this project is to generate evidence that CD38, a cell surface protein expressed in airway smooth muscle, is a significant source of adenosine from NAD+ by the enzymatic cascade CD38/CD203a/CD73. The enzymatic activity that converts NAD+ to AMP involves CD38, whose expression in airway smooth muscle is augmented by inflammatory and Th2 cytokines and to a greater extent in cells derived from asthmatics. This pathway of adenosine and IL-6 production is sufficient to cause airway hyperresponsiveness, airway inflammation, and airway remodeling independent of the roles of CD38 inintracellular calcium signaling and innate immunity. Thus the researchers postulate that inhibiting CD38 expression in airway smooth muscle will limit the progression of chronic lung diseases by decreasing adenosine and IL-6.
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