Elevated Asymmetric Dimethylarginine Alters Lung Function and Induces Collagen Deposition in Mice

摘要

The role of L-arginine metabolism in the pathology of airway diseases such as asthma has not been resolved. Increasing evidence suggests that lung mechanics and structure are maintained in part by an intimate balance between the L-arginine-metabolizing enzymes nitric oxide synthase (NOS) and arginase. Asymmetric dimethylarginine (ADMA) is a competitive endogenous inhibitor of NOS. The role of ADMA in the regulation of NOS and arginase in the airways has not yet been explored. To investigate the in vivo role of ADMA in lung physiology, a murine model of continuous subcutaneous infusion via osmotic minipump was used. Two weeks after minipump placement, animals were anesthetized, mechanically ventilated, and lung mechanical responses were evaluated. Lungs were assessed for collagen content, arginase activity, and arginase protein levels. Lung lavage fluid was assessed for cellularity, nitrite, urea, and cytokine concentrations. ADMA infusion resulted in significantly enhanced lung resistance and decreased dynamic compliance in response to methacholine. These physiologic changes were associated with significantly increased lung collagen content in the absence of inflammation. These findings provide the first evidence that elevated endogenous ADMA may contribute to lung functional and structural changes and suggest that this molecule can play a role in airway diseases, including asthma and pulmonary fibrosis. Furthermore, regulation of ADMA metabolism could present a novel therapeutic modality in treating lung fibrosis.