Beneficial effects of high dose of L-arginine on airway hyperresponsiveness and airway inflammation in a murine model of asthma Ulaganathan Mabalirajan,

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Beneficial effects of high dose of L-arginine on airway hyperresponsiveness and airway inflammation in a murine model of asthma Ulaganathan Mabalirajan, MBBS, Tanveer Ahmad, MSc, Geeta Devi Leishangthem, MVSc, Duraisamy Arul Joseph, MSc, Amit Kumar Dinda, MD, PhD, Anurag Agrawal, MD, PhD, Balaram Ghosh, PhD Journal of Allergy and Clinical Immunology Volume 125, Issue 3, Pages 626-635 (March 2010) DOI: 10.1016/j.jaci.2009.10.065 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Experimental protocol to induce allergic asthma in mice. Male BALB/c (8-10 weeks old) mice were grouped, sensitized, and challenged. Vehicle (water) or L-ARG had been given orally from days 19 to 32. Measurements of lung function were performed and mice were killed on day 33. Journal of Allergy and Clinical Immunology 2010 125, 626-635DOI: (10.1016/j.jaci.2009.10.065) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Effect of L-ARG on Penh and airway inflammation. Mice were randomly divided and named as per status of sensitization/challenge/treatment: SHAM/PBS/VEH, OVA/OVA/VEH, OVA/OVA/L-ARG 25, OVA/OVA/L-ARG 250, and OVA/OVA/L-ARG 500. ∗P < .05 vs SHAM/PBS/VEH; †P < .05 vs OVA/OVA/VEH. Data were means ± SEMs of 3 independent experiments. A, Penh. B, Representative photographs (×10 magnification) of hematoxylin and eosin staining. a, Alveolus; Br, bronchus; V, vessel. Black arrows indicate the eosinophils. C, Inflammation score. Hematoxylin and eosin–stained slides were evaluated by 2 different investigators blindly. Total inflammation score was calculated by addition of both peribronchial and perivascular inflammation scores. The sham group was given a value of 0.1 to make the graph. ∗P < .05 vs OVA/OVA/VEH. Journal of Allergy and Clinical Immunology 2010 125, 626-635DOI: (10.1016/j.jaci.2009.10.065) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Effect of L-ARG on airway resistance, sGAW, BAL fluid eosinophilia, goblet cell metaplasia, and subepithelial fibrosis. Data were means ± SEMs of 3 independent experiments. ∗P < .05 vs SHAM/PBS/VEH and †P < .05 vs OVA/OVA/VEH. A, Airway resistance. B, sGAW. C, Absolute cell types in BAL. Eosino, Eosinophils; Macro, macrophages; Mono, monocytes and lymphocytes; Neutro, neutrophils. Masson Trichrome (D) and periodic acid (E) stainings (i, ii, and iii) were performed and analyzed by quantitative morphometry (iv). All representative microphotographs were at ×10 magnification. Journal of Allergy and Clinical Immunology 2010 125, 626-635DOI: (10.1016/j.jaci.2009.10.065) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 L-ARG reduces arginase activity, expression in lung. Data were means ± SEMs of 3 independent experiments. †P < .05 vs OVA/OVA/VEH. A, Arginase activities in lung cytosols. B and C, Western blots for Arginase I and α-tubulin and spot densitometry signals. D, Immunohistochemistry for Arginase I expression. Brown indicates the positive expressions. In arginase activity and densitometry graphs, the sham group was given values of 1 and 0.01, respectively, to make the graphs. All representative photographs were at ×10 except insets of OVA/OVA/VEH (upper, ×40; and lower, ×100). CYTO, Cytosolic fraction. Journal of Allergy and Clinical Immunology 2010 125, 626-635DOI: (10.1016/j.jaci.2009.10.065) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 L-ARG enhances the levels of ENO and cGMP and reduces nitro-oxidative stress in the lung. Data were means ± SEMs of 3 independent experiments. ∗P < .05 vs SHAM/PBS/VEH; †P < .05 vs OVA/OVA/VEH. ENO levels (A), cGMP (B), 8-isoprostane (C), and nitrotyrosine, a marker of peroxynitrite (D), were determined. Journal of Allergy and Clinical Immunology 2010 125, 626-635DOI: (10.1016/j.jaci.2009.10.065) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 L-ARG enhances eNOS expression and reduces iNOS. Immunohistochemistry was determined to determine the expression of eNOS (A) and iNOS (B). Brown indicates the positive expressions. Representative photomicrographs from 3 independent experiments are shown. All photographs were at ×10 magnification except insets (×100). Journal of Allergy and Clinical Immunology 2010 125, 626-635DOI: (10.1016/j.jaci.2009.10.065) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Schematic diagram to illustrate the effects of L-ARG availability and exogenous administration of L-ARG on NO metabolism and asthma features. Arginine is a sole substrate for various arginine-metabolizing enzymes including NOS (constitutive NOS isoforms such as eNOS and neuronal NOS, and iNOS) and arginase. In normal airways, constitutive NOS isoforms consume endogenous arginine to produce NO to maintain the airway tone through cGMP activation. In allergic airways, proinflammatory cytokines induce the expressions of arginase and iNOS; the former leads to airway remodeling through the polyamines, and the latter releases NO, which has detrimental effects such as infiltration of inflammatory cells. Arginase activation also limits the availability of endogenous arginine as a substrate for iNOS, which leads to release both NO and superoxide anion (O2-) from iNOS to produce peroxynitrite, which has dangerous effects on the airway by causing airway inflammation and bronchoconstriction. Exogenous administration of L-ARG leads to displacement of ADMA, an L-ARG analog, to increase eNOS activity, and has also been shown to increase the expression of eNOS to enhance its beneficial effects through the NO-cGMP pathway and to reduce the inflammation on the one hand, and on the other hand eNOS also produces NG-hydroxy–L-ARG, which inhibits arginase. +, Positive modulation. Lines with buffers at the end indicate the inhibitory pathways. Journal of Allergy and Clinical Immunology 2010 125, 626-635DOI: (10.1016/j.jaci.2009.10.065) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions