title: L-arginine supplementation improves responses to injury and inflammation in dextran sulfate sodium colitis.
abstract: Inflammatory bowel disease (IBD), consisting of Crohn's disease and ulcerative colitis (UC), results in substantial morbidity and is difficult to treat. New strategies for adjunct therapies are needed. One candidate is the semi-essential amino acid, L-arginine (L-Arg), a complementary medicine purported to be an enhancer of immunity and vitality in the lay media. Using dextran sulfate sodium (DSS) as a murine colonic injury and repair model with similarities to human UC, we assessed the effect of L-Arg, as DSS induced increases in colonic expression of the y(+) cationic amino acid transporter 2 (CAT2) and L-Arg uptake. L-Arg supplementation improved the clinical parameters of survival, body weight loss, and colon weight, and reduced colonic permeability and the number of myeloperoxidase-positive neutrophils in DSS colitis. Luminex-based multi-analyte profiling demonstrated that there was a marked reduction in proinflammatory cytokine and chemokine expression with L-Arg treatment. Genomic analysis by microarray demonstrated that DSS-treated mice supplemented with L-Arg clustered more closely with mice not exposed to DSS than to those receiving DSS alone, and revealed that multiple genes that were upregulated or downregulated with DSS alone exhibited normalization of expression with L-Arg supplementation. Additionally, L-Arg treatment of mice with DSS colitis resulted in increased ex vivo migration of colonic epithelial cells, suggestive of increased capacity for wound repair. Because CAT2 induction was sustained during L-Arg treatment and inducible nitric oxide (NO) synthase (iNOS) requires uptake of L-Arg for generation of NO, we tested the effect of L-Arg in iNOS(-/-) mice and found that its benefits in DSS colitis were eliminated. These preclinical studies indicate that L-Arg supplementation could be a potential therapy for IBD, and that one mechanism of action may be functional enhancement of iNOS activity.
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Coburn
authors.forename: Xue
authors.initials: X
authors.lastname: Gong
authors.forename: Kshipra
authors.initials: K
authors.lastname: Singh
authors.forename: Mohammad
authors.initials: M
authors.lastname: Asim
authors.forename: Brooks P
authors.initials: BP
authors.lastname: Scull
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Allaman
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Williams
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rosen
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Barry
authors.forename: M Blanca
authors.initials: MB
authors.lastname: Piazuelo
authors.forename: Robert A
authors.initials: RA
authors.lastname: Casero
authors.forename: Rupesh
authors.initials: R
authors.lastname: Chaturvedi
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhao
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
mesh_terms: D000596:Amino Acids / Q000097:blood / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D027202:Cationic Amino Acid Transporter 2 / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D016264:Dextran Sulfate / Q000633:toxicity*; D019587:Dietary Supplements; D004847:Epithelial Cells / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D009504:Neutrophils / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D009929:Organ Size / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000596:Amino Acids; D027202:Cationic Amino Acid Transporter 2; D018925:Chemokines; D016207:Cytokines; D017931:DNA Primers; D016264:Dextran Sulfate; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse