Elevated asymmetric dimethylarginine alters lung function and induces collagen deposition in mice

SM Wells, MC Buford, CT Migliaccio… - American journal of …, 2009 - atsjournals.org
SM Wells, MC Buford, CT Migliaccio, A Holian
American journal of respiratory cell and molecular biology, 2009atsjournals.org
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. Our objective was to investigate the role of ADMA in lung physiology.
A murine model of continuous subcutaneous ADMA infusion via osmotic minipump was …
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. Our objective was to investigate the role of ADMA in lung physiology. A murine model of continuous subcutaneous ADMA infusion via osmotic minipump was used for assessment of elevated ADMA in vivo, and primary lung fibroblasts were used for in vitro assessments. Two weeks after minipump placement, animals were anesthetized and mechanically ventilated, and lung mechanical responses were evaluated. Lungs were assessed histologically and biochemically 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. Significant decreases in lung fluid nitrite were accompanied by elevated lung fluid urea and arginase activity in lung homogenates. These changes were reversed in mice 4 weeks after completion of ADMA administration. In addition, treatment of primary mouse lung fibroblasts with ADMA stimulated arginase activity and collagen formation in vitro. These data support the idea that ADMA may play a role in airway diseases, including asthma and pulmonary fibrosis, through NOS inhibition and enhancement of arginase activity.
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