Signaling through beta/2-adrenergic receptors (ARs) is critically important for the normal regulatory of pulmonary smooth muscle in both airways and arteries. Activation of beta/2ARs in pulmonary smooth muscle leads to relaxation and dilatation. The role of beta/2/ARs in pulmonary disease processes are not well understood but betaAR signaling appears important in several types of lung cells. Such widespread involvement of beta/2ARs in basic pulmonary physiology does suggest a role for beta/2AR signaling in a multitude of disorders including reactive airway disease, obstructive pulmonary disease and pulmonary hypertension. The introduction of foreign DNA into somatic cells of intact organs in vivo has recently been shown to be feasible. The accessibility of airways and vasculature of the lungs likes this organ an important target for gene therapy where research may lead to specific genetic therapeutic strategies to alleviate pulmonary diseases which have components of increased resistance of airway and vascular smooth muscle. This proposal is formulated to learn whether increased betaAR signaling can occur in the adult lung and pulmonary vasculature after exogenous adenoviral transgene delivery of beta/2ARs and a peptide inhibitor of beta/2AR desensitization. These two transgenes have been shown to increase in vivo betaAR signaling. Increasing betaAR signaling properties in the lung through genetic manipulation represents a novel increase in vivo betaAR signaling. Increasing betaAR signaling properties in the ling through genetic manipulation represents a novel increase in vivo betaAR signaling. Increasing betaAR signaling properties in the lung through genetic manipulation represents a novel therapeutic approach for improving relaxation pulmonary smooth muscle. Thus, the Central Hypothesis of this proposal is that gene transfer of DNA's encoding specific betaAR signaling components to the lung will alter pulmonary function. We will use a rabbit model to perfect conditions for in vivo gene delivery of these beta/2AR adenoviral transgenes and test their specific effects on pulmonary function. We will use a rabbit model to perfect conditions for in vivo gene delivery of these beta/2AR adenoviral transgenes and test their specific effects on pulmonary biochemical signal transduction and the in vivo physiological consequences on both airway and vascular smooth muscle function.
