Nitric oxide (NO) is an important molecule involved in a myriad of physiological functions. In pulmonary hypertensive diseases, NO production is decreased resulting in vasoconstriction and vascular remodeling. While in pulmonary inflammatory diseases, NO production is increased resulting in tissue damage. NO is generated from L-arginine (L-arg) by the NO synthases (NOS). The cellular bioavailability of L-arg to NOS is determined in large part by uptake of extracellular L-arg via the cationic amino acid transporters (CAT). Preliminary studies suggest that manipulation of L-arg uptake modifies clinically important parameters in highly vulnerable patient populations. Thus, the studies described in the present application are focused on elucidation of the functional and mechanistic aspects of endothelial cell uptake of L-arg by CAT and its role in regulation of NO production in the lung. The long-term goals of these studies are to develop therapies that increase NO production by facilitating CAT-mediated L-arg uptake in pulmonary hypertensive diseases, and that decrease NO production by inhibiting CAT-mediated L-arg uptake in inflammatory lung diseases. The working hypothesis is that NO production can be modulated by control of L-arg bioavailability to NOS through alterations in CAT-mediated L-arg transport. The studies will address the hypothesis in 3 specific aims: 1) to test the hypothesis that alterations in CAT activities regulate NO production by altering the bioavailability of L-arg to NOS;2) to test the hypothesis that Src-family tyrosine kinases and mitogen- activated protein kinases mediate inflammation-induced alterations in the expression of CAT and/or NOS; and 3) to test the hypothesis that gene transfer to regulate CAT expression in vivo will affect NO production in the lung, and thereby affect pulmonary vasomotor tone and lung injury.
Therapies aimed at manipulating NO-mediated effects in lung diseases have centered on pharmacological inhibition of NO production or inhalation of exogenous NO, however a majority of these critically ill patients do not respond to these therapies. L-arg uptake represents a rate-limiting step in lung NO production. The present proposal will provide translational data necessary for the design of rational clinical trials to determine safe and effective pharmacological and genetic manipulations of L-arg uptake rates, and thereby NO production, in severe pulmonary diseases, such as ARDS and pulmonary hypertension.
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