Arginine Therapy for Lung Diseases

Abstract

Nitric oxide (NO) is produced by a family of isoenzymes, nitric oxide synthases (NOSs), which all utilize L-arginine as substrate. The production of NO in the lung and airways can play a number of roles during lung development, regulates airway and vascular smooth muscle tone, and is involved in inflammatory processes and host defense. Altered L-arginine/NO homeostasis, due to the accumulation of endogenous NOS inhibitors and competition for substrate with the arginase enzymes, has been found to play a role in various conditions affecting the lung and in pulmonary diseases, such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pulmonary hypertension, and bronchopulmonary dysplasia. Different therapeutic strategies to increase L-arginine levels or bioavailability are currently being explored in pre-clinical and clinical studies. These include supplementation of L-arginine or L-citrulline and inhibition of arginase.

Keywords: Pulmonary hypertension; airway hyperresponsiveness; asthma; asymmetric dimethyl arginine; chronic obstructive pulmonary desease; cystic fibrosis; remodeling.

FIGURE 1

Changes in l-Arginine metabolism in disease and potential interventions. (A) Under normal physiologic conditions, cationic amino acid transporters (CAT) transport l-arginine into the cell where it can be metabolized by nitric oxide synthase (NOS) to NO and l-citrulline in a two-step process with Nω-hydroxy-l-arginine (NOHA) as intermediate. Under pathophysiologic conditions, excess induction of the arginase isozymes can lead to increased competition for substrate, thus limiting the l -arginine available for the NOS isozymes, and leading to NOS uncoupling and the production of peroxynitrite. (B) As potential sites of intervention, local or systemic administration of arginase inhibitors can increase the cellular bioavailability of l-arginine for the NOS isozymes and improve the production of NO. Supplemental l-citrulline can be recycled to l-arginine by argininosuccinate synthase (ASS) and argininosuccinate lyase (ASL), with argininosuccinate as an intermediate; thus, also improving intracellular bioavailability of l-arginine to improve NO production.