Altered Asymmetric Dimethyl Arginine Metabolism in Allergically Inflamed Mouse Lungs

Abstract

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), causes uncoupling of NOS leading to generation of reactive nitrogen species, such as peroxynitrite. The lung generates a significant amount of ADMA, potentially contributing to plasma ADMA levels that have been related to endothelial dysfunction. ADMA infusion causes increased collagen deposition in lungs, suggesting that it could influence the development of chronic lung diseases such as fibrosis, chronic obstructive pulmonary disease, and asthma. To explore the link between endogenous ADMA and asthma, we determined the levels of ADMA, enzymes implicated in its metabolism, and peroxynitrite in murine models of allergic airway inflammation (AAI) resembling asthma. ADMA levels and nitrosative stress were found to be positively correlated in cytosol and mitochondria during AAI. This was associated with increased expression of protein-arginine methyltransferase-2, an ADMA-synthesizing enzyme, and reduced expression of dimethylarginine dimethylaminohydrolase-2, an ADMA-degrading enzyme, in bronchial epithelia. Increased nitrotyrosine similarly localized to the bronchial epithelium, as well as in infiltrated inflammatory cells. Administration of L-arginine, which was expected to compete with ADMA and reverse the uncoupling/inhibition of NOS, restored normal ADMA metabolism, along with the expected reduction of nitrosative stress in lung. Because dimethylarginine dimethylaminohydrolase-2 function is known to be negatively related to oxidative stress, this may represent a feed-forward loop effect. We conclude that a delicate balance between ADMA-metabolizing enzymes is disturbed in bronchial epithelium during AAI, potentially causing increased nitrosative stress in a self-propagating cycle. This represents a potential therapeutic target in asthma.

Asymmetric dimethyl-arginine metabolism in a murine model of cigarette smoke-mediated lung inflammation

“…Our laboratory and others have demonstrated that ADMA is not only elevated in allergic inflammation (Ahmad et al, 2010;Scott et al, 2011;, but that elevated ADMA also potentiates inflammation in allergic inflammation models (Klein et al, 2010). However, the association between ADMA levels and the pathophysiology of other chronic respiratory diseases such as COPD remain unclear.…”

“…Lung ADMA levels have been associated with airway inflammation in both allergic asthma models (Ahmad et al, 2010;Klein et al, 2010) and in asthmatics (Scott et al, 2011). Further, circulating ADMA levels are altered in smokers (Sobczak et al, 2009;Wang et al, 2006;Zhang et al, 2006); however, the contribution of ADMA to the pathophysiology of chronic lung inflammation is unknown.…”

“…Both isoforms are expressed in the lung (Bulau et al, 2007). Decreased DDAH pulmonary expression has been associated with elevated ADMA levels in a mouse model of allergic asthma (Ahmad et al, 2010). However, whether DDAH expression in the lung is altered following CS exposure has not yet been explored.…”

L-Arginine Metabolism in the Lung: Reciprocal Regulation of the NOS and Arginase Pathways

“…Ahmad et al demonstrated increased expression of PRMT2 and increased ADMA in the lungs of allergically inflamed mice [77]. Additionally, exogenous administration of ADMA to lung epithelial cells in vitro has been demonstrated to lead to uncoupling of NOS, resulting in the formation of superoxide [72].…”

“…Endogenous ADMA production has recently been shown to be upregulated in a murine model of allergic airways inflammation [77]. Ahmad et al demonstrated increased expression of PRMT2 and increased ADMA in the lungs of allergically inflamed mice [77].…”