The Importance of Immunonutrition
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Our daily food intake not only provides the calories and the macro- and micronutrients necessary for survival - nutrients also have a tremendous potential to modulate the actions of the immune system, a fact which has a significant impact on public health and clinical practice.



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Date de parution 16 septembre 2013
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EAN13 9783318024470
Langue English
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The Importance of Immunonutrition
Nestlé Nutrition Institute Workshop Series
Vol. 77
The Importance of Immunonutrition
Maria Makrides North Adelaide, Australia
Juan B. Ochoa Florham Park, NJ, USA
Hania Szajewska Warsaw, Poland
Nestec Ltd., 55 Avenue Nestlé, CH-1800 Vevey (Switzerland)
S. Karger AG, P.O. Box, CH-4009 Basel (Switzerland)
Library of Congress Cataloging-in-Publication Data
Nestlé Nutrition Workshop (77th: 2012: Panama, Panama), author.
The importance of immunonutrition / editors, Maria Makrides, Juan B. Ochoa, Hania Szajewska.
p.; cm. –– (Nestlé Nutrition Institute workshop series, ISSN 1664-2147; vol. 77)
Includes bibliographical references and index.
ISBN 978-3-318-02446-3 (hard cover: alk. paper) –– ISBN 978-3-318-02447-0 (e-ISBN)
I. Makrides, Maria, editor of compilation. II. Ochoa, Juan B., editor of compilation. III. Szajewska, Hania, editor of compilation. IV. Nestlé Nutrition Institute, issuing body. V. Title. VI. Series: Nestlé Nutrition Institute workshop series; v. 77. 1664-2147
[DNLM: 1. Child Nutritional Physiological Phenomena––immunology––Congresses. 2. Lipids––physiology––Congresses. 3. Metagenome––immunology––Congresses. 4. Nutritional Status––immunology––Congresses. W1 NE228D v.77 2013 / WS 130]
The material contained in this volume was submitted as previously unpublished material, except in the instances in which credit has been given to the source from which some of the illustrative material was derived.
Great care has been taken to maintain the accuracy of the information contained in the volume. However, neither Nestec Ltd. nor S. Karger AG can be held responsible for errors or for any consequences arising from the use of the information contained herein.
© 2013 Nestec Ltd., Vevey (Switzerland) and S. Karger AG, Basel (Switzerland). All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or recording, or otherwise, without the written permission of the publisher.
Printed on acid-free and non-aging paper (ISO 9706)
ISBN 978-3-318-02446-3
e-ISBN 978-3-318-02447-0
ISSN 1664-2147
e-ISSN 1664-2155
Modulation of Immune Responses and Nutrition
Arginine and Asthma
Morris, C.R. (USA)
Changes in Arginine Metabolism during Sepsis and Critical Illness in Children
de Betue, C.T.I. (The Netherlands); Deutz, N.E.P. (USA)
Arginine Deficiency Caused by Myeloid Cells: Importance, Identification and Treatment
Ochoa, J.B. (USA)
Glutamine Supplementation in Neonates: Is There a Future?
Neu, J. (USA)
Insulin in Human Milk and the Use of Hormones in Infant Formulas
Shamir, R.; Shehadeh, N. (Israel)
Microbiota and Pro-/Prebiotics
Diet, Gut Enterotypes and Health: Is There a Link?
Bushman, F.D.; Lewis, J.D.; Wu, G.D. (USA)
Understanding Immunomodulatory Effects of Probiotics
Pot, B.; Foligné, B.; Daniel, C.; Grangette, C. (France)
Transforming Growth Factor and Intestinal Inflammation: The Role of Nutrition
Ruemmele, F.M.; Garnier-Lengliné, H. (France)
Microbiota Modulation: Can Probiotics Prevent/Treat Disease in Pediatrics?
Szajewska, H. (Poland)
Membrane Composition and Cellular Responses to Fatty Acid Intakes and Factors Explaining the Variation in Response
Agostoni, C.; Risé, P.; Marangoni, F. (Italy)
Docosahexaenoic Acid and Its Derivative Neuroprotectin D1 Display Neuroprotective Properties in the Retina, Brain and Central Nervous System
Bazan, N.G.; Calandria, J.M.; Gordon, W.C. (USA)
Branched-Chain Fatty Acids in the Neonatal Gut and Estimated Dietary Intake in Infancy and Adulthood
Ran-Ressler, R.R.; Glahn, R.P.; Bae, S.; Brenna, J.T. (USA)
Clinical Overview of Effects of Dietary Long-Chain Polyunsaturated Fatty Acids during the Perinatal Period
Scholtz, S.A.; Colombo, J.; Carlson, S.E. (USA)
Dietary n-3 LC-PUFA during the Perinatal Period as a Strategy to Minimize Childhood Allergic Disease
Makrides, M.; Gunaratne, A.W.; Collins, C.T. (Australia)
Concluding Remarks
Subject Index
For more information on related publications, please consult the NNI website:
A healthy immune system is essential for normal existence and recovery from illness. Innate immunity, activated during illness, prepares us for successfully combating infection and healing wounds. Adaptive immune responses allow for long-term monitoring protecting us from neoplasia, fungi and mycobacterial infections among others. Successful immune responses require a careful orchestration of complex checks and balances avoiding excessive inflammation while preventing anergy. Uncontrolled inflammation can lead to self-injury as is observed in autoimmune diseases such as rheumatoid arthritis. On the other hand, dysfunctional T lymphocyte responses lead to uncontrolled opportunistic infections and tumor growth.
Nutrients in our diet form the necessary building blocks and substrate for all cellular function. We are indeed ‘what we eat’, literally. In just one generation, humanity has gone from struggling at finding ways to feed all to an epidemic of obesity that grips the entire world. Modern dietary habits are a causative factor for abnormal immune responses and illness. Type 2 diabetes, hypertension, atherosclerosis, and a growing list of cancers are linked to inflammation caused by the same dietary habits that cause obesity. The types of lipids and carbohydrates (and the amount) that we eat make us sick. Obesity is associated with uncontrolled inflammation and with an increased incidence of certain tumors.
Just as certain nutrients make us sick, others could potentially be beneficial in the prevention or management of illness. These nutrients appear to work by modifying immune responses (hence the name immunonutrition) when given during illness. Progressively, and sometimes painstakingly, we have accrued knowledge as to their mechanisms of action. This book summarizes the work performed by scientists at the forefront of studying immunonutrients in health and disease and provides the compilation of the data presented at 77th Nestlé Nutrition Institute Workshop on Immunonutrition. This book will discuss several different topics on immunonutrition: (1) arginine and glutamine; (2) lipids, including fish oil and branched-chain fatty acids, and (3) probiotics. In addition, this book will also discuss the presence of insulin, TGF-β and other bioactive peptides in milk.
Arginine and glutamine are two closely related amino acids described as being ‘conditionally’ essential, meaning that deficiencies in these amino acids develop during illnesses and may require dietary replacement to maintain or restore normal biological functions. Deficiencies in arginine are now being recognized in a number of illnesses and conditions such as asthma and sickle cell disease and after trauma. Arginine deficiency may also be important in the pathophysiology of sepsis. Glutamine may be highly important for maintaining mucosal trophism.
Milk contains more than just a combination of macro- and micronutrients with bioactive peptides such as insulin, TGF-β and others. The roles of peptides are progressively being understood. Insulin for example may play important roles in mucosal trophism for the GI tract, while it has been suggested that TGF-β may help regulate inflammation in inflammatory bowel disease.
Lipids may modify immune responses through several mechanisms. The type of lipid in the diet may determine the type of prostaglandin generated by cyclooxygenases. Eicosapentaenoic acid may play biological roles in T cells as agonists for peroxisome proliferator-activated receptors. Docosahexaenoic acid (DHA) is an essential fatty acid in the growth of the brain. Neuroprotectin 1 produced from DHA may regulate inflammation in the brain.
Humans have ten times more microbial cells than human cells, with the highest concentration of microorganisms located within the digestive tract. Around 1,000 different species have been identified with current microbiological techniques. Microbiota mediates many key functions, including metabolic, trophic, and protective (barrier) functions. Many of the microbes maintain health, while others are potential pathogens and can cause illness. Though the concept is not new, surprisingly little is known about the exact role and mechanisms by which these microorganisms contribute to human health or disease. Significant progress at identifying the gut microbiome has led to a better understanding of the interactions between them and our organs and tissues. Probiotics, while not considered a nutrient, are certainly part of our diet. The roles that resident or ingested organisms may play in disease are now potential targets of treatment.
It is our hope that you find this book useful in your practices, be it in the research lab or at the bedside.
Maria Makrides Juan B. Ochoa Hania Szajewska
Nutrients have a tremendous potential to modulate the actions of the immune system, a fact which has a significant impact on public health and clinical practice.
The concept of pharmaconutrition – a central element of intensive care management – implies a bridge between drugs and nutrition. During the last decade, the role of nutrition, beyond providing the calories and the macro- and micronutrients for survival, has been well established and clinically proven. At the 77th Nestlé Nutrition Institute Workshop held from October 28th to November 1st 2012, world experts gathered in Panama City to present their latest findings on how nutrient status can modulate immunity and improve health conditions in pediatric patients. The 3 sessions of this workshop covered major aspects of the interplay between nutrients and the regulation of immunity and inflammatory processes.
The first session explored the pharmaceutical value of specific amino acids (arginine and glutamine) and hormones for addressing immune disorders and infant development. It is now understood that some amino acids have the ability to speed up the recovery of children admitted to intensive care. We took a closer look at the relationship between arginine metabolism and asthma, the role of this amino acid in T-lymphocyte function, and investigated the rationale for glutamine supplementation to improve outcomes in premature infants.
Many immune disorders and diseases are associated with dysregulation of the gut microbial homeostasis. The second session revolved around gut function and immunity, and the right balance of probiotics. The right microbiome can modulate the immune system and help protect from infectious disease, obesity and allergy. Getting the right mix of probiotics is key to unlocking their full benefits. The overview of the MetaHIT project presented during this session showed that individuals can be clustered based on their microbial metagenome profile, thus laying the framework for profiling health and disease.
The third session explored the role of lipid mediators and how their types and proportions can tip the balance in favor of health or disease. Given in the right time and conditions, lipids can prevent allergy, modulate the inflammatory process in the gut and play a protective role when cell homeostasis is threatened by neurodegeneration. It was discussed that early LC-PUFA supplementation not only supports cognitive function but also may program brain development in later life stages.
We wish to thank the three chairpersons – Prof. M. Makrides, Prof. J. Ochoa and Prof. H. Szajewska for establishing an excellent scientific workshop program. We are also indebted to the renowned speakers who have further debated and increased our understanding of this important topic through their presentations and participation. We thank the many experts who came from across the globe to review and discuss the importance of immunonutrition.
Finally, we wish to thank and congratulate Luis Carlos Delgado and his team from Nestlé Nutrition LATAM for their excellent logistical support and hospitality that allowed us to not only enjoy the scientific program but also experience the historical spirit of Panama City.
Ferdinand Haschke , MD, PhD Chairman Nestlé Nutrition Institute Vevey, Switzerland
Natalia Wagemans , MD, PhD Global Medical Advisor Nestlé Nutrition Institute Vevey, Switzerland

77th Nestlé Nutrition Institute Workshop Panama, October 28th-November 1st 2012
Chairpersons & Speakers
Prof. Carlo Agostoni
Department of Maternal and Pediatric Sciences
University of Milan
Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico
Via della Commenda 9
IT-20122 Milano
Prof. Nicolas G. Bazan
LSU Health New Orleans
School of Medicine Neuroscience Center of Excellence and
Department of Ophthalmology
2020 Gravier Street, Suite D
New Orleans, LA 70112
Prof. James Thomas Brenna
Cornell University
Division of Nutritional Sciences
Savage Hall
244 Garden Ave
Ithaca, NY 14853
Prof. Susan E. Carlson
University of Kansas Medical Center
Department of Dietetics and Nutrition
MS 4013, 3901 Rainbow Boulevard
Kansas City, KS 66160
Dr. Carlijn T.I. de Betue
Erasmus MC – Sophia Children's Hospital
Department of Pediatric Surgery
Dr. Molewaterplein 60
NL-3015 GJ Rotterdam
The Netherlands
Prof. Maria Makrides
Women's & Children's Health Research Institute
University of Adelaide
72 King William Road
North Adelaide SA 5006
Dr. Claudia R. Morris
Emory University School of Medicine
Department of Pediatrics
1645 Tullie Circle
Atlanta, CA 30322
Prof. Josef Neu
University of Florida
1600 SW Archer Road
Gainesville, FL 32610-0296
Dr. Juan B. Ochoa
Nestlé Nutrition
12 Vreeland Road, 2nd floor
Florham Park, NJ 07932
Prof. Bruno Pot
Institut Pasteur de Lille
1, Rue du Prof Calmette
FR-59000 Lille Cedex
Prof. Frank M. Ruemmele
Hospital Necker-Enfants Malades
149 Rue de Sevres
FR-75015 Paris
Prof. Raanan Shamir
Institute of Gastroenterology, Nutrition and Liver Diseases
Schneider Children's Medical Center of Israel
14 Kaplan Street, Petach-Tikva
IL-49202 Israel
Prof. Hania Szajewska
The Medical University of Warsaw
Department of Pediatrics
Działdowska 1
PL-01-184 Warsaw
Prof. Gary D. Wu
University of Pennsylvania
Perelman School of Medicine
Suite 600 CRB
415 Curie Blvd
Philadelphia, PA 19104
Carlos Lifschitz/Argentina
Jennifer Campbell/Barbados
Jose Enrique Samos/Belize
Christiane Leite/Brazil
Virginia Weffort/Brazil
Sara Bernal/Colombia
Andres Chacon Jorge/Colombia
Silvana Dadan/Colombia
Wilson Daza/Colombia
Luis Carlos Delgado/Colombia
Monica Escobar/Colombia
David Espinal/Colombia
Patrick Levieil/Colombia
Enilda Puello Mendoza/Colombia
Norberto Salamanca/Colombia
Arturo Abdelnour/Costa Rica
Javier Alvarez/Costa Rica
Ommar Parra/Costa Rica
Carlos Quiros/Costa Rica
Isaura Cornelio/Dominican Republic
Patricia Fernandez/Dominican Republic
Wendy Hamilton/Dominican Republic
Yun Zyon Kim/Dominican Republic
Sara Tolentino/Dominican Republic
Xavier Abril/Ecuador
Hugo Bardellini/Ecuador
Marina Bran/Ecuador
Indira Castillo/Ecuador
Joffre Egas/Ecuador
Rosario Jijon/Ecuador
Alejandro Xavier Lara Borja/Ecuador
Angel Luna/Ecuador
Jean Mero/Ecuador
Carlos Moncayo/Ecuador
Carlos Mosquera/Ecuador
Roberto Nunez/Ecuador
Amapola Ortiz/Ecuador
Nidia Ortola/Ecuador
Natasha Robalino/Ecuador
Ivan Serpa/Ecuador
Ivan Williams/Ecuador
Jose Oliva/El Salvador
Juan Carlos Reyes Cisneros/El Salvador
Lorena Zeceña/El Salvador
Jean Pierre Chouraqui/France
Dominique Darmaun/France
Victor Alfonso/Guatemala
Jorge Palacios/Guatemala
Carlos Manuel Perez Valdez/Guatemala
Flor Ramirez/Guatemala
Norma Gonzalez/Honduras
Karla Fernandez/Honduras
Martha Matamoros/Honduras
Giovanni Corsello/Italy
Garfield Badal/Jamaica
Andrea Garbutt/Jamaica
Tracia James Powell/Jamaica
Lyer Ramos/Jamaica
Osmond Tomlinson/Jamaica
Aristóteles Alvarez Cardona/Mexico
Martin Mauricio Breton La Loza/Mexico
Ana Paola Campos/Mexico
Arturo Castro Cue/Mexico
Alejandra Consuelo/Mexico
Manuel Diaz Gómez/Mexico
Jesus Gonzalez Frias/Mexico
Manuel Guajardo/Mexico
José Antonio Hurtado/Mexico
Fernando Infante/Mexico
Victor Javier Lara Diaz/Mexico
Victoria Lima/Mexico
Jesus Magana/Mexico
Luis Gustavo Orozco/Mexico
Sergio Romero Tapia/Mexico
Edgar Vazquez/Mexico
Osvaldo Zarco Del Cid/Mexico
Benjamin Barbosa/Nicaragua
Ariadne Espinosa/Nicaragua
César López/Nicaragua
Alberto Bissot/Panama
María Iované/Panama
Argelia Loo/Panama
Roberto Murgas Torraza/Panama
Katia Rueda/Panama
Jose Luis Gonzales Benavides/Peru
Casilda Maribel Diaz Toledo/Puerto Rico
Etienne Nel/South Africa
Christina West/Sweden
Ferdinand Haschke/Switzerland
Natalia Wagemans/Switzerland
Brenda Babulal/Trinidad and Tobago
Jatinder Bhatia/USA
Andrea Papamandjaris/USA
Abraham Abraham Greege/Venezuela
Jorge Bonini/Venezuela
Maria Jose Castro/Venezuela
Jose Diaz/Venezuela
Claudio Gutierrez/Venezuela
Marianella Herrera/Venezuela
Keira Leon/Venezuela
Cisneros Liz/Venezuela
Ana Nucette/Venezuela
Maria Eugenia Reymundez/Venezuela
Luciano Saglimbeni/Venezuela
Carmen Salazar/Venezuela
Anadina Salvatierra/Venezuela
Rafael Santiago/Venezuela
Rosa Maria Soto Rodriguez/Venezuela
Modulation of Immune Responses and Nutrition
Makrides M, Ochoa JB, Szajewska H (eds): The Importance of Immunonutrition. Nestlé Nutr Inst Workshop Ser, vol 77, pp 1-15, (DOI: 10.1159/000351365) Nestec Ltd., Vevey/S. Karger AG., Basel, © 2013
Arginine and Asthma
Claudia R. Morris
Division of Emergency Medicine, Department of Pediatrics, Emory-Children's Center for Developmental Lung Biology, Emory University School of Medicine, Atlanta, GA, USA
Recent studies suggest that alterations of the arginine metabolome and a dysregulation of nitric oxide (NO) homeostasis play a role in the pathogenesis of asthma. L -Arginine, a semi-essential amino acid, is a common substrate for both the arginases and NO synthase (NOS) enzyme families. NO is an important vasodilator of the bronchial circulation, with both bronchodilatory and anti-inflammatory properties, and is synthesized from oxidation of its obligate substrate L -arginine, which is catalyzed by a family of NOS enzymes. Arginase is an essential enzyme in the urea cycle, responsible for the conversion of arginine to ornithine and urea. The NOS and arginase enzymes can be expressed simultaneously under a wide variety of inflammatory conditions, resulting in competition for their common substrate. Although much attention has been directed towards measurements of exhaled NO in asthma, accumulating data show that low bioavailability of L -arginine also contributes to inflammation, hyperresponsiveness and remodeling of the asthmatic airway. Aberrant arginine catabolism represents a novel asthma paradigm that involves excess arginase activity, elevated levels of asymmetric dimethyl arginine, altered intracellular arginine transport, and NOS dysfunction. Addressing the alterations in arginine metabolism may result in new strategies for treatment of asthma.
Copyright © 2013 Nestec Ltd., Vevey/S. Karger AG, Basel
Asthma is a common pulmonary condition that involves heightened bronchial hyperresponsiveness and reversible bronchoconstriction together with acute-on-chronic inflammation that leads to airway remodeling [ 1 ]. Over 22 million people in the United States have asthma including more than 6.5 million chil-dren, and as many as 250 million worldwide are affected. Mechanisms that contributed to asthma are complex and multi-factorial, influenced by genetic polymorphisms as well as environmental and infectious triggers. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli [ 2 ].
‘Asthma’ is a clinical diagnosis based on a constellation of symptoms described above, yet asthma is not one disease. Different patients have biochemically distinct phenotypes despite a similar clinical manifestation [ 3 ]. Examples include decreased activity of superoxide dismutases, increased activity of eosinophil peroxidase, S-nitrosoglutathione reductase, decreased airway pH, and finally alterations of the arginine metabolome. Low plasma arginine concentration together with increased activity of the arginase enzymes, elevated levels of asymmetric dimethylarginine (ADMA), altered intracellular arginine transport, and nitric oxide synthase (NOS) dysfunction, including endogenous NOS inhibitors and uncoupled NOS can contribute to arginine dysregulation in asthma and is the focus of this discussion.
Asthma: Global Disruption of the Arginine-Nitric Oxide Pathway
Altered Nitric Oxide Homeostasis
Nitric oxide (NO) has been well described in the literature as an important signaling molecule involved in the regulation of many mammalian physiologic and pathophysiologic processes, particularly in the lung [ 4 ]. NO plays a role in regulation of both pulmonary vascular tone as well as airway bronchomotor tone through effects on relaxation of smooth muscle. In addition, NO participates in inflammation and host defense against infection via alterations in vascular permeability, changes in epithelial barrier function and repair, cytotoxicity, upregulation of ciliary motility, altered mucus secretion, and inflammatory cell infiltration [ 5 ]. These multiple functions of NO have been implicated in the pathogenesis of chronic inflammatory airway diseases such as asthma.
NO is produced by a family of NOS enzymes that metabolize L -arginine through the intermediate N-hydroxy- L -arginine (NOHA) to form NO and L -citrulline using oxygen and NADPH as cosubstrates. Three NOS mammalian isoenzymes have been identified with varying distributions and production of NO. Neuronal (nNOS or NOS I) and endothelial (eNOS or NOS III) NOS are constitutively expressed (cNOS) in airway epithelium, inhibitory nonadrenergic noncholinergic (iNANC) neurons, and airway vasculature endothelial cells. Their activity is regulated by intracellular calcium, with rapid onset of activity and production of small amounts of NO on the order of picomolar concentrations. Inducible NOS (iNOS or NOS II) is transcriptionally regulated by proinflammatory stimuli, with the ability to produce large amounts (nanomolar concentrations) of NO over hours [ 5 ].
iNOS is known to be upregulated in asthmatic lungs, and increased levels of exhaled NO are well described in asthma patients. In both human and experimental animal models of asthma, increased NO production occurs in the airways related to upregulation of NOS II (iNOS) by proinflammatory cytokines after allergen challenge and during the late asthmatic reaction [ 4 ]. This upregulation of NOS II in airway epithelial cells and inflammatory cells is associated with airway eosinophilia, airway hyperresponsiveness (AHR), and increased NO in exhaled air [ 6 ]. Although initially assumed to contribute to asthma, the increased production of NO itself may not be responsible for AHR as NO also seems to have a protective effect on bronchial muscle tone. It is believed that the AHR after the late asthmatic reaction is caused by increased formation of peroxynitrite [ 7 ] that occurs due to reduced availability of L -arginine for NOS II, which potentially causes uncoupling of this enzyme [ 8 ]. Increased activity of the arginase enzyme, which competes with NOS for the substrate L -arginine seems to be, at least in part, responsible for this process [ 9 ].
Mechanisms of Arginine Dysregulation
As the obligate substrate for NOS, L -arginine bioavailability plays a key role in determining NO production, and is dependent on pathways of biosynthesis, cellular uptake, and catabolism by several distinct enzymes ( fig. 1 ), including those from the NOS and arginase enzyme families. Biosynthesis of the semi-essential amino acid occurs in a stepwise fashion in what is called the ‘intestinal-renal axis’. L -Glutamine and L -proline are absorbed from the small intestine and converted to L -ornithine. L -Citrulline is then synthesized from L -ornithine by ornithine carbamoyltransferase and carbamoylphosphate synthetase 1 in hepatocytes as part of the urea cycle, as well as in the intestine. L -Arginine is produced from L -citrulline by cytosolic enzymes argininosuccinate synthetase 1 and argininosuccinate lyase. When L -arginine is subsequently metabolized to NO via NOS, L -citrulline is again produced and can be used for recycling back to L -ar-ginine, which may be an important source of L -arginine during prolonged NO synthesis by iNOS [ 10 ]. Low arginine bioavailability develops abruptly during acute asthma exacerbations and normalizes with clinical recovery [ 11 ]. In severe asthma, however, low arginine bioavailability at baseline is strongly associated with airflow abnormalities [ 12 ]. Overlapping mechanism that contribute to arginine depletion in asthma are summarized below.

Fig. 1. Sources and metabolic fates of L -arginine. Arginine is produced through de novo synthesis from citrulline primarily in the proximal tubules of the kidney, through protein turnover or via uptake from the diet. Four enzymes use arginine as their substrate: the NOS, arginases, arginine decarboxylase (ADC) and arginine:glycine amidinotransferase (AGAT). The action of these 4 sets of enzymes ultimately results in production of the 7 products depicted in the figure. Putrescine, spermine and spermidine are the polyamines produced as downsteam byproducts of arginase activity. Turnover of proteins containing methylated arginine residues releases ADMA, SDMA and N-methylarginine (NMMA) which are potent inhibitors of NOS. Reproduced with permission from Morris [ 10 ].
Increased Arginase Concentration and Activity
Arginase is an essential enzyme in the urea cycle, responsible for the conversion of arginine to ornithine and urea. The NOS and arginase enzymes can be expressed simultaneously under a wide variety of inflammatory conditions, resulting in competition for their common substrate [ 9 ]. Two forms of arginase have been identified, type 1, a cytosolic enzyme highly expressed in the liver, and type 2, a mitochondrial enzyme found predominantly in the kidney, prostate, testis, and small intestine [ 13 ]. Both forms are expressed in human airways. Arginase-1 is also present in human red blood cells, which has significant implications for hemolytic disorders. Of particular interest is the high prevalence of asthma in sickle cell disease [ 14 ], a hemolytic anemia also associated with an altered arginine metabolome ( fig. 2 ) [ 15 , 16 ].

Fig. 2. Altered arginine metabolism in hemolysis. A path to pulmonary dysfunction. Dietary glutamine serves as a precursor for the de novo production of arginine through the citrulline-arginine pathway. Arginine is synthesized endogenously from citrulline primarily via the intestinal-renal axis. Arginase and NOS compete for arginine, their common substrate. In sickle cell disease (SCD) and thalassemia, bioavailability of arginine and NO are decreased by several mechanisms linked to hemolysis. The release of erythrocyte arginase during hemolysis increases plasma arginase levels and shifts arginine metabolism towards ornithine production, limiting the amount of substrate available for NO production. The bioavailability of arginine is further diminished by increased ornithine levels because ornithine and arginine compete for the same transporter system for cellular uptake. Despite an increase in NOS, NO bioavailability is low due to low substrate availability, NO scavenging by cell-free hemoglobin released during hemolysis, and through reactions with free radicals such as superoxide and other reactive NO species. Superoxide is elevated in SCD due to low superoxide dismutase activity, high xanthine oxidase activity and potentially as a result of uncoupled NOS in an environment of low arginine and/or tetrahydrobiopterin concentration or insufficient NADPH. Endothelial dysfunction resulting from NO depletion and increased levels of the downstream products of ornithine metabolism (polyamines and proline) likely contribute to the pathogenesis of lung injury, pulmonary hypertension and asthma in SCD. This model has implications for all hemolytic processes as well as pulmonary diseases associated with excess arginase production. This novel disease paradigm is now recognized as an important mechanism in the pathophysiology of SCD and thalassemia. Abnormal arginase activity emerges as a recurrent theme in the pathogenesis of a growing number of diverse pulmonary disorders. Regardless of the initiating trigger, excess arginase activity represents a common pathway in the pathogenesis of asthma and pulmonary hypertension. Reproduced with permission from the American Society of Hematology [ 16 ].
While the affinity (Km) of L -arginine for arginase is in the low micromolar range compared to the low millimolar range for NOS, substrate competition does occur between arginase and NOS because the V max of arginase is 1,000-fold higher [ 13 ]. As arginase plays a role in regulating bioavailability of L -arginine for NOS by competitive consumption of the substrate, increased arginase activity may be responsible in part, for the AHR in asthma. In allergen-challenged mice, arginase activity is increased in the airways at the same time as L -arginine and L -citrulline levels are decreased [ 17 ]. Specific arginase inhibitor N-hydroxynor- L -arginine (nor-NOHA) has been shown to attenuate methacholine-induced constriction of guinea pig trachea and to increase iNANC-mediated relaxation of tracheal smooth muscle preparations, which is consistent with increased NO production through NOS under conditions of arginase inhibition [ 18 , 19 ]. This effect was prevented by coincubation with NOS inhibitor N G -nitro- L -arginine methyl ester (L-NAME), indicating that arginase leads to AHR by decreasing cNOS-derived NO production [ 20 ]. iNANC nerve-mediated NO production and smooth muscle relaxation are also restored after the EAR by treatment with nor-NOHA to a similar level also seen with L -arginine supplementation [ 21 ]. Another specific arginase inhibitor [2(S)-amino-6-boronohex-anoic acid or ABH] not only reverses AHR after both the early and late asthmatic reaction following histamine challenge in a guinea pig model of acute allergic asthma, but also prevents AHR when delivered 30 min prior to the histamine challenge, most likely related to increased NO production [ 22 ]. Similarly, intraperitoneal treatment with nor-NOHA prior to repeated allergen challenge reduced AHR to methacholine in mice [ 23 ]. In contrast, another study found that in mice sensitized to ovalbumin, arginase inhibitor S-(2-boronoethyl)-L-cysteine increased peribronchiolar and perivascular inflammation associated with increased S-nitrosothiols and 3-nitrotyrosine, but did not change allergen-induced increases in differential cell counts or cytokine levels in bronchoalveolar lavage (BAL) samples [ 24 ]. Unfortunately, the role of low arginine bioavailability and NOS uncoupling as a plausible contributing factor to excess superoxide production in this model is unknown. Finally, in chimeric mice with arginase I -/- bone marrow, no change was seen in basal or allergen-induced inflammatory cell infiltration or BAL differential cell counts, indicating that at least bone-marrow derived arginase I is not required for development of lung inflammation in this mouse model [ 25 ].
It is evident that the arginine metabolome involves a complex system of checks and balances to maintain homeostasis. NOS itself can inhibit arginase activity through accumulation of NOHA, the intermediate in NO synthesis [ 26 ]. The arginase product L -ornithine may also play a role in regulating availability of L -arginine to NOS through competitive inhibition of arginase [ 27 ] as well as inhibition of L -arginine intracellular transport. L -Ornithine also serves as a substrate for ornithine decarboxylase, which synthesizes polyamines involved in promotion of cell growth and repair, and for ornithine aminotransferase, leading to formation L -proline which is required for collagen synthesis.
The balance of iNOS versus arginase activity and level of NO production in the airway may be related to the balance of T H 1/T H 2 cytokines during the inflammatory cascade. Experimental models of asthma have demonstrated that iNOS is induced by proinflammatory T H 1 cytokines released from mast cells immediately after allergen challenge and during the late asthma reaction, an intense IgE-mediated inflammatory response that begins several hours after an allergen challenge [ 4 , 28 , 29 ]. Arginase activity is induced (and iNOS suppressed) by T H 2 cytokines IL-4 and IL-10 in murine macrophages, although IL-4 does not induce arginase in human macrophages unless combined with agents that increase cAMP [ 30 ]. Arginase activity increases following challenge with allergens in guinea pig tracheal preparations, and in mouse and rat models of allergic asthma [ 9 , 31 - 34 ]. Inducing loss of function of arginase 1 specifically in the lung of an allergic asthma mouse model using RNA interference abolished the development of T H 2 cytokine IL-13-induced AHR [ 35 ]. Gene expression studies have also shown induction of arginase 1 more than arginase 2 gene expression in mouse models of allergen-challenged lungs and T H 2 cytokine-mediated lung inflammation [ 35 - 38 ]. However, pollutant particles were recently shown to induce arginase 2 in human bronchial epithelial cells [ 39 ]. Interestingly, DNA methylation of arginase 2 and to a lesser extent, arginase 1 is significantly associated with FeNO in both asthmatic and nonasthmatic children, whereas DNA methylation of NOS genes is surprisingly not associated with FeNO [ 40 ]. These findings highlight the complexity of interactions between arginase and NOS on NO production.
Studies in human asthma confirm the importance of arginase in the pathogenesis of experimental asthma. While increased arginase activity in the sputum of asthmatic patients was documented as early as 1980 [ 41 ], its role in the pathophysiology of asthma was not further elucidated until decades later. Increased arginase I activity, mRNA and protein expression have been demonstrated in inflammatory cells and airway epithelium from bronchial biopsies as well as BAL samples from asthmatic patients [ 31 , 42 ]. Single nucleotide polymorphisms (SNPs) in both arginase I and arginase II have been associated with atopy, while SNPs in arginase II were associated with increased risk of childhood asthma [ 43 ]. Increased arginase activity has also been demonstrated in the serum of asthmatic children experiencing an exacerbation, while plasma L -arginine levels and the arginine/ornithine ratio (a biomarker that inversely correlates with arginase activity) [ 11 , 15 , 44 ] were simultaneously reduced [ 11 ]. Clinical improve-ment in asthma symptoms corresponded temporally with reduction of arginase activity and increase in plasma L -arginine levels and the arginine/ornithine ratio [ 11 ]. The lung function of severe asthmatics correlates directly with L -arginine bioavailability, and inversely with serum arginase activity [ 12 ]. Arginase may also play a role in the development of chronic airway remodeling through formation of L -ornithine with downstream production of polyamines and L -proline, which are involved in processes of cellular proliferation and collagen deposition [ 45 ].
Intracellular Arginine Transport: Role of Cationic Amino Acid Transporter
The primary source of L -arginine for most cells is cellular uptake via the Naindependent cationic amino acid transporter (CAT) proteins of the y + -system. In particular, upregulation of CAT-2B has been associated with increased L -arginine uptake under conditions of iNOS induction stimulated by proinflammatory mediators [ 46 - 48 ]. This suggests that, at least in some cells, increased uptake may offset reductions in circulating arginine levels. Ablation of the CAT-2 gene is associated with impaired iNOS-mediated NO synthesis in macrophages and astrocytes, which implies an important role of CAT-2 in uptake of L -arginine substrate for iNOS [ 49 , 50 ].
L -Arginine uptake via the y + -system can be inhibited by other amino acids such as L -ornithine and L -lysine, as well as by polycations such as eosinophil-derived major basic protein (MBP) and poly- L -arginine [ 46 , 51 ]. MBP inhibition of L -arginine uptake was associated with decreased NO synthesis in rat alveolar macrophages and tracheal epithelial cells, most likely related to reduced L -arginine availability [ 48 ]. In addition, AHR to methacholine has been shown to increase in rats and guinea pigs after treatment with poly- L -arginine, related to attenuation of epithelial NO production. Treatment with combined poly- L -arginine and the antagonist polyanion heparin restored L -arginine uptake and NO production, and reversed AHR [ 52 , 53 ].
Uncoupled Nitric Oxide Synthase
Airway inflammation in asthma may not be the result of increased NO production itself, but rather due to the formation of the proinflammatory oxidant peroxynitrite from reaction of NO with superoxide anions in the airway. Peroxynitrite activates eosinophils, increases microvascular permeability, induces airway epithelial damage, and augments airway smooth muscle contraction [ 54 , 55 ]. Airway epithelial cells and inflammatory cells from bronchial biopsies of asthmatics as well as allergen-challenged guinea pigs demonstrate increased nitrotyrosine immunostaining (a marker for peroxynitrite nitration of protein tyrosine), which is also correlated with increased exhaled NO, iNOS expression, AHR, and eosinophilic inflammation [ 56 ]. The AHR observed after allergen challenge and the late asthmatic reaction may be the result of increased peroxynitrite formation [ 54 , 57 ]. Further evidence for this relationship comes from the lungs of allergen-challenged mice which demonstrate increased nitrotyrosine staining and concomitant increased expression of arginase and iNOS [ 34 ].
In contrast to the increased NO production seen during the late asthmatic reaction, the increased AHR seen after the early asthmatic reaction may paradoxically involve NO deficiency within the airways related to reduced bioavailability of L -arginine to both cNOS and iNOS. Low L -arginine conditions may also lead to increased production of peroxynitrite by uncoupling iNOS, allowing it to produce superoxide anions via its reductase domain, which react with NO to form peroxynitrite [ 58 ]. Increasing L -arginine availability increases NO production and decreases superoxide and peroxynitrite production in macrophages. This model helps to explain the paradox of reduced NO bioavailability in the face of increased expression of iNOS in asthma.
Endogenous Nitric Oxide Synthase Inhibitors
ADMA is an endogenous NOS inhibitor that competes with L -arginine for binding to NOS. Well established as a biomarker of cardiovascular disease and endothelial dysfunction [ 16 ], it may also contribute to inflammation, collagen deposition, nitrosative stress and abnormal lung function in asthma. High levels of ADMA together with symmetric dimethylarginine (SDMA) were found in a mouse model of allergic asthma as well as in human lung and sputum samples. Endogenous administration of nebulized inhaled ADMA to naive control mice at doses consistent with levels observed in the allergic inflamed lungs of the mouse model resulted in augmentation of AHR in response to metacholine [ 59 ]. In contrast, Riccioni et al. [ 60 ] recently reported low levels of ADMA and SDMA together with low L -arginine in the plasma of children with a history of mild allergic asthma compared to healthy subjects. Although this may appear incongruent, these studies are evaluating concentrations compartmentalized in the lung and sputum versus plasma. Extracellular plasma levels may not necessarily reflect intracellular concentrations in different cell types, organs, compartments and species. Arginine metabolism in asthma is also quite different at baseline compared to an acute exacerbation when inflammatory mediators are upregulated [ 11 ]. In addition, inflammatory mechanisms contributing to asthma symptoms may vary not only from animal model to human, but also from patient to patient, particularly in those with mild versus severe asthma. Patients with ‘asthma’ are often studied in trials as if asthma was just one homogeneous disease, potentially explaining discrepant observations in these and other asthma models.
The Arginine Metabolome: A Novel Therapeutic Target for Asthma
Increased understanding of the role of arginase in the pathogenesis of asthma naturally leads to consideration of novel therapeutic targets for treatment. As noted above, animal models of specific arginase inhibition have demonstrated prevention or reversal of AHR associated with allergen challenge. Further development and study of inhaled arginase inhibitors may be a promising area of research.
Restoration of L -arginine bioavailability to NOS through exogenous supplementation of L -arginine is another potential therapeutic target, although a great deal of orally administered L -arginine is metabolized to urea in the liver. Supplemental oral or inhaled L -arginine increases exhaled NO in both normal and asthmatic subjects, indicating that the bioavailability of L -arginine for NOS determines NO production within the airways [ 61 ]. In guinea pig tracheal preparations, L -arginine has been shown to inhibit AHR to methacholine and to increase iNANC nerve-mediated airway smooth muscle relaxation via increased production of NOS-derived NO [ 18 , 62 ]. Conversely, inhibition of NOS-derived NO by L -NAME amplifies bronchoconstriction in guinea pigs [ 63 ]. L -Arginine administration also reduces peroxynitrite formation, AHR, airway injury and mitochondrial dysfunction in murine allergic airway inflammation [ 64 , 65 ].
A single inhalation of nebulized L -arginine results in a significant increase of airway NO formation and improved pulmonary function in patients with cystic fibrosis [ 66 ], promising results that have not been documented in human asthma to date. Chambers and Ayres [ 67 ] found that nebulized L -arginine paradoxically induced bronchospasm in asthmatic adults; however, a similar effect was found with the use of 2% saline in the control arm. Other studies using murine asthma models found that arginine supplementation amplified the asthmatic inflammatory response [ 68 , 69 ] while a small study of 14 patients with asthma found that pretreatment with oral L -arginine (50 mg/kg) had no significant influence on AHR to histamine [ 70 ]. The same dose given twice a day for 3 months to 15 patients completing a randomized placebo-controlled trial had no impact on number of exacerbations, exhaled NO levels or lung function compared to placebo in patients studied with moderate to severe persistent asthma [ 71 ].
The few human studies that evaluate arginine therapy for asthma are all limited by small sample size and preliminary results are disappointing. The utility of arginine therapy in human asthma may be limited by excess arginase found in plasma [ 11 ], skewing metabolism away from NO towards ornithine and its downstream metabolites, proline and polyamines. Combination therapy utilizing L -arginine with an arginase inhibitor may circumvent this issue. Alternatively, L -citrulline or L -glutamine (converted to citrulline by the enterocytes) could be administered as a prodrug for L -arginine, as citrulline is converted in the kidney to arginine through the ‘intestinal-renal axis’ [ 10 ], thus bypassing liver metabolism by arginase. Interestingly, citrulline supplementation in a pilot phase II clinical trial in sickle cell patients resulted in an increase in plasma L -arginine levels [ 72 ]. Preliminary results of pharmacokinetic studies using oral L -glutamine have also demonstrated improvement in global arginine bioavailability in patients with sickle cell disease and pulmonary hypertension risk [ 73 ].
Contradictory studies of arginase inhibition also exist, reporting enhancement, attenuation, and no effect on inflammation in animal models [ 22 - 25 ]. This may reflect issues specific to animal models of asthma in general that often limit our understanding and treatment of asthma [ 74 ]. Since chronic asthma is a disease unique to humans, the fact that mice do not have asthma may contribute to the conflicting reports that make the mechanistic translation to human disease more of a challenge. Further studies are needed to clarify these effects and their implications in man. Understanding the biochemistry behind mechanistic variants of asthma may help identify unique subpopulations of patients with asthma and lead to novel therapies that target these pathways. The arginine metabolome represents one such pathway in asthma that holds promise for future drug development.
Dr. Morris's research is supported in part by the FDA grant R01 FD003531-04.
Disclosure Statement
Claudia R. Morris, MD, declares no conflicts of interest, but discloses that she is the inventor or coinventor of several patents or pending patents owned by Children's Hospital & Research Center Oakland, some which involve therapies and biomarkers of cardiovascular disease that target global arginine bioavailability, has served on scientific advisory committees for Merck and Icagen, received an educational stipend from INO Therapeutics, and has been a consultant for Biomarin, Gilead Sciences Inc., and the Clinical Advisors Independent Consulting Group.
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