Article thumbnail

Arginase and Arginine Dysregulation in Asthma

By Renée C. Benson, Karen A. Hardy and Claudia R. Morris


In recent years, evidence has accumulated indicating that the enzyme arginase, which converts L-arginine into L-ornithine and urea, plays a key role in the pathogenesis of pulmonary disorders such as asthma through dysregulation of L-arginine metabolism and modulation of nitric oxide (NO) homeostasis. Allergic asthma is characterized by airway hyperresponsiveness, inflammation, and remodeling. Through substrate competition, arginase decreases bioavailability of L-arginine for nitric oxide synthase (NOS), thereby limiting NO production with subsequent effects on airway tone and inflammation. By decreasing L-arginine bioavailability, arginase may also contribute to the uncoupling of NOS and the formation of the proinflammatory oxidant peroxynitrite in the airways. Finally, arginase may 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. Further research on modulation of arginase activity and L-arginine bioavailability may reveal promising novel therapeutic strategies for asthma

Topics: Review Article
Publisher: Hindawi Publishing Corporation
OAI identifier:
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles


  1. (2008). A .L a r a ,S .B .K h a t r i ,Z .W a n ge ta l . ,“ A l t e r a t i o n so f the arginine metabolome in asthma,”
  2. (2007). a k e m o t o ,K .O g i n o ,M .S h i b a m o r ie ta l . ,“ T r a n s i e n t l y , paralleled upregulation of arginase and nitric oxide synthase and the effect of both enzymes on the pathology of asthma,”
  3. (2006). a n g ,D .R a n g a s a m y ,K .I .M a t t h a e ie ta l . ,“ I n h i b i t i o n of arginase I activity by RNA interference attenuates IL-13-induced airways hyperresponsiveness,”
  4. (2006). Activation of alveolar macrophages via the alternative pathway in herpesvirus-induced lung fibrosis,”
  5. (2007). Airway hyperreactivity detected by methacholine challenge in children with sickle cell disease,” Pediatric Pulmonology,
  6. (1997). Airway hyperreactivity in children with sickle cell disease,”
  7. Allergeninduced increase in bronchial responsiveness to histamine: relationship to the late asthmatic response and change in airway caliber,”
  8. (2003). Alternative activation of macrophages,”
  9. (2009). Alternative activation of macrophages: an immunologic functional perspective,”
  10. (1999). AntiproliferativeeffectsofNOandANPincultured humanairwaysmooth muscle,”
  11. (2005). Arginase activity differs with allergen in the effector phase of ovalbumin- versus trimellitic anhydride-induced asthma,”
  12. (2008). Arginase and pulmonary diseases,”
  13. Arginase and respiratory viral infections,”
  14. (2005). Arginase attenuates inhibitory nonadrenergic noncholinergicnerve-induced nitric oxide generationandairwaysmooth muscle relaxation,” Respiratory Research,v o l .6 ,a r t i c l e2 3 ,
  15. (2005). Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity,”
  16. (2006). Arginase strongly impairs neuronal nitric oxidemediated airway smooth muscle relaxation in allergic asthma,”Respiratory
  17. (2009). Arginase: a key enzyme in the pathophysiology of allergic asthma opening novel therapeutic perspectives,”
  18. (2010). Arginasein asthma- recent developments in animal and human studies,”
  19. (1998). Arginine metabolism: nitric oxide and beyond,”
  20. (2004). Asthma and acute chest in sickle-cell disease,”
  21. (2009). Asthma and sickle cell disease: two distinct diseases or part of the same process?” Hematology. American Society of Hematology. Education Program,p p .
  22. (2005). Asthma in children with sickle cell disease and its association with acute chest syndrome,”
  23. (2005). Asthma in the pediatric sickle cell patient with acute chest syndrome,”
  24. Asthma is a risk factor for acute chest syndrome and cerebral vascular accidents in children with sickle cell disease,” Clinical and Molecular Allergy, vol.3, article 2,2005.
  25. (2006). Asthma is associated with acute chest syndrome and pain in children with sickle cell anemia,”
  26. (2007). Asthma is associated with increased mortality in individuals with sickle cell anemia,” Haematologica,v o l .9 2 ,n o .8 ,p p .
  27. (2000). Asthma: from bronchoconstriction to airways inflammation and remodeling,”
  28. (2009). B r a t t ,L .M .F r a n z i ,A .L .L i n d e r h o l m ,M .S .L a s t
  29. (2009). Bone marrow cell derived arginaseIisthe majorsourceofallergen-induced lung arginasebut is notrequired forairwayhyperresponsiveness, remodeling and lung inflammatory responses in mice,”
  30. (1995). C o r r a l i z a ,G .S o l e r ,K .E i c h m a n n ,a n dM .M o d o l e l l , “Arginase induction by suppressors of nitric oxide synthesis (IL-4, IL-10 and PGE) in murine bone-marrow-derived macrophages,”BiochemicalandBiophysicalResearchCommunications,
  31. (2006). C.R.Morris,“New strategies forthetreatment ofpulmonary hypertension in sickle cell disease: the rationale for arginine therapy,” Treatments
  32. (2003). C.R.Morris,S.M.Morris,W.Hagaretal.,“Argininetherapy: a new treatment for pulmonary hypertension in sickle cell disease?”
  33. (1999). Cationic proteins inhibit L-arginine uptake in rat alveolar macrophages and tracheal epithelial cells: implications for nitric oxide synthesis,”
  34. (2008). Clinical differences between children and adults with pulmonary hypertension and sickle cell disease,”
  35. (1996). Coers et al., “Deficiency of nitric oxide in allergen-induced airway hyperreactivity to contractile agonists after the early asthmatic reaction: an ex vivo study,”
  36. (1994). Constitutive and inducible nitric oxide synthase gene expression, regulation, andactivity in humanlung epithelial cells,”
  37. (1999). Constitutive expressions of type I NOS in human airway smooth muscle cells: evidence for an antiproliferative role,”
  38. (1998). Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with mild asthma,”Thorax,
  39. (2004). Decreased arginine bioavailability and increased serum arginase activity in asthma,”
  40. (2005). Decreased arginine bioavailability contributes to the pathogenesis of pulmonary artery hypertension,”
  41. (1999). Deficiency of nitric oxide in polycation-induced airway hyperreactivity,”
  42. (1997). Direct measurement of nitric oxide generation from nitric oxide synthase,”
  43. (2008). Disease-specific gene expression profilingin multiplemodels oflungdisease,”
  44. (2003). Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis,”
  45. (1995). e c k e r ,H .N e m a t o l l a h i ,C .H e y ,R .B u s s e ,a n dK . Racke, “Inhibition of arginase by N(G)-hydroxy-L-arginine in alveolar macrophages: implications for the utilization of L-arginine for nitric oxide synthesis,”
  46. e n z e la n dS .T .H o l g a t e ,“ T h em o u s et r a p :i ts t i l ly i e l d s few answers in asthma,”
  47. (2001). e s s e ,M .M o d o l e l l ,A .C .L aF l a m m ee ta l . ,“ D i fferential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism,”
  48. (1998). e sandC .A .R .Bo y d ,“T ransp ort e r sf orc at ionicamino acids in animal cells: discovery, structure, and function,”
  49. (2000). e, “In rat alveolar macrophages lipopolysaccharides exert divergent effects on the transport of the cationic amino acids
  50. (2001). e, “Inhibition of nitric oxide synthase abrogates lipopolysaccharides-induced up-regulation of L-arginine uptake in rat alveolar macrophages,”
  51. eB o e r ,M .D u y v e n d a k ,F .E .S c h u u r m a n ,F .M . H .P o u w ,J . Zaagsma,andH.Meurs,“RoleofL-arginineinthe deficiency of nitric oxide and airway hyperreactivity after the allergeninduced early asthmatic reaction in guinea-pigs,”
  52. (1998). Effect of inhaled L-arginine on exhaled nitric oxide in normal and asthmatic subjects,” Thorax,v o l .
  53. (1999). Effect of inhaled steroids on airway hyperresponsiveness, sputum eosinophils, and exhaled nitric oxide levels in patients with asthma,”Thorax,
  54. (1992). Effect of lipopolysaccharide on transport and metabolism of arginine in mouse peritoneal macrophages,”
  55. (1999). Effect ofdifferingdosesofinhaledbudesonideonmarkersofairway inflammationin patients with mild asthma,”Thorax,
  56. (2001). Effects of endothelin-1 and nitric oxide on proliferation of cultured guinea pig bronchial smooth muscle cells,”
  57. (2006). Effects of inducible nitric oxide synthase inhibitors on asthma depending on administration schedule,”
  58. (2006). Effects ofnitricoxide synthasesin chronicallergic airwayinflammation and remodeling,”
  59. (1998). Exhaled nitric oxide correlates with airway hyperresponsiveness in steroid-naive patients with mild asthma,”
  60. (2004). Expression of nitric oxide synthase-2 in the lungs decreases airway resistance and responsiveness,”
  61. (2009). Functionally important role for arginase 1 in the airway hyperresponsiveness of asthma,”
  62. (2003). Global gene expression profiles during acute pathogen-induced pulmonaryinflammationrevealdivergent roles for Th1 and Th2 responses in tissue repair,”
  63. (2008). H.Maarsingh,A.B.Zuidhof,I.S.T.Bosetal.,“Arginaseinhibition protects against allergen-induced airway obstruction, hyperresponsiveness, and inflammation,”
  64. (1995). harit ono v
  65. (2007). Hemolysis-associated pulmonary hypertension in sickle cell disease: global disruption of the argininenitric oxide pathway,”
  66. Hemolysisassociated pulmonary hypertension in thalassemia,”
  67. (2008). Identification oftransforminggrowthfactorβ1-driven genetic programsof acute lung fibrosis,”
  68. (1997). Impairment of bronchoprotection by nitric oxide in severe asthma,”
  69. (2007). Increased arginase activity underlies airway hyperresponsiveness in a guinea pig model of chronic allergic asthma,”
  70. (2002). Increased arginase activity underlies allergen-induced deficiency of cNos-derived nitric oxide and airway hyperresponsiveness,”
  71. (2004). Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension,”
  72. (1998). Increased formation of the potent oxidant peroxynitrite in the airwaysof asthmaticpatients is associatedwith induction of nitric oxide synthase: effect of inhaled glucocorticoid,”
  73. (2000). Increased nitrotyrosine in exhaled breath condensate of patients with asthma,”
  74. (1998). Inducible nitric-oxide synthase generates superoxide from the reductase domain,” J o u r n a lo fB i o l o g i c a lC h e m i s t r y ,v o l .
  75. (1995). Induction of nitric oxide synthase in a model of allergic occupational asthma,”
  76. (2008). Induction of nitric oxide synthases in primary human cultured mast cells by IgE and proinflammatory cytokines,”
  77. (1987). Induction of ornithine decarboxylase activity and putrescine synthesis in arterial smooth muscle cells stimulated with platelet-derived growth factor,”
  78. (2008). Inhibition of arginase activity enhances inflammation in mice with allergic airway disease, in association with increases in protein Snitrosylation and tyrosine nitration,”
  79. (2006). Inhibition of phosphodiesterase4amplifiescytokine-dependent induction of arginase in macrophages,”
  80. (1998). Intestinal mucosal amino acid catabolism,”
  81. (2000). J.Barnes,“Clinicalaspects ofexhaled nitric oxide,”
  82. (2011). J.J.Fieldetal.,“Airwayhyper-responsiveness inchildren with sickle cell anemia,”
  83. (2008). K e n y o n ,J .M .B r a t t ,A .L .L i n d e r h o l m ,M .S .L a s t ,a n dJ
  84. (1994). K h a r i t o n o v ,D .Y a t e s ,R .A .R o b b i n s ,R .L o g a n - S i n c l a i r , E.A.Shinebourne, andP.J.Barnes,“Increased nitric oxidein exhaled air of asthmatic patients,”
  85. (1995). K h a r i t o n o v ,G .L u b e c ,B .L u b e c ,M .H j e l m ,a n dP .J . Barnes, “L-Arginine increases exhaled nitric oxide in normal human subjects,”
  86. (2009). L-Arginine deficiency causes airwayhyperresponsiveness afterthelateasthmaticreaction,”
  87. (1992). L-Arginine transport is increased in macrophages generating nitric oxide,”
  88. (2007). L-ornithine causes NO deficiency and airway hyperresponsiveness in perfused guinea pig tracheal preparations in vitro,”
  89. (2006). Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease,”
  90. (2003). M a n n e r ,B .N i c h o l s o n ,a n dC .L .M a c L e o d
  91. (1993). M.G.PerssonandL.E.Gustafsson,“Allergen-induced airway obstructioninguinea-pigsisassociatedwithchangesinnitric oxide levels in exhaled air,”
  92. (2006). Mechanism of interleukin-25 (IL-17E)-induced pulmonary inflammation and airways hyper-reactivity,”
  93. (2001). Mechanisms mediating the antiproliferative effects of nitric oxide in cultured human airwaysmoothmusclecells,”
  94. (2006). Mechanisms of airway hyperresponsiveness,”
  95. (2008). Mechanisms of vasculopathy in sickle cell disease and thalassemia,” Hematology.
  96. Mechanistic and metabolic inferences from the binding of substrate analogues and products to arginase,” Biochemistry,v o l .4 0 ,n o .9 ,p p . 2689–2701,
  97. (2010). Metabolic fate of oral glutamine supplementation within plasma and erythrocytes of patients with sickle cell disease: preliminary pharmacokinetics results,”
  98. (1987). Modulation of arterial smooth muscle cells from contractile to synthetic phenotype requires induction of ornithine decarboxylase activity and polyamine synthesis,”
  99. (2000). Modulation of cholinergic airway reactivity and nitric oxide production by endogenous arginase activity,”
  100. (2006). Modulation of nitric oxide pathways: therapeutic potential in asthma and chronic obstructive pulmonary disease,”
  101. (1998). Molecular basis of allergic diseases,”
  102. (2009). Morris,“Asthmamanagement:reinventingthewheel in sickle cell disease,”
  103. (2003). n d o ,S .O y a d o m a r i ,Y .T e r a s a k ie ta l . ,“ I n d u c t i o no f arginase I and II in bleomycin-induced fibrosis of mouse lung,”
  104. (2008). n g e l i ,C .M .P r a d o ,D .G .X i s t oe ta l . ,“ E ffects of chronic L-NAME treatment lung tissue mechanics, eosinophilic and extracellular matrix responses induced by chronic pulmonary inflammation,”
  105. (2002). Neutrophil elastase induces MUC5AC geneexpression in airwayepithelium via a pathwayinvolving reactive oxygen species,”
  106. (2008). Nitric oxide and arginine dysregulation: a novel pathway to pulmonary hypertension in hemolytic disorders,”
  107. (1995). Nitric oxide synthases: properties and catalytic mechanism,”
  108. (2000). Nuclear factor-κB mediates simultaneous induction of inducible nitric-oxide synthase and up-regulation of the cationic amino acid transporter CAT-2B in rat alveolar macrophages,”
  109. (2001). o l k e r t s ,J .K l o e k ,R .B .R .M u i j s e r s ,a n dF .P .N i j k a m p , “Reactive nitrogen and oxygen species in airway inflammation,”
  110. (1991). o n c a d a ,R .M .J .P a l m e r ,a n dE .A .H i g g s ,“ N i t r i co x i d e : physiology,pathophysiology,andpharmacology,”Pharmacological Reviews,
  111. (2001). Oral citrulline as arginine precursor may be beneficial in sickle cell disease: early phase two results,”
  112. Oyake et al., “Role of peroxynitrite in airway microvascular hyperpermeability during late allergicphasein guinea pigs,”American Journal of Respiratory and Critical Care Medicine,vol.160,no.2,pp.663–671,1999.
  113. (1996). Peroxynitrite induces airway hyperresponsiveness in guinea pigs in vitro andin vivo,”American
  114. (2005). Pirfenidone inhibits lung allograft fibrosis through L-arginine-arginase pathway,”
  115. (2005). Poljakovic et al., “Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease,”
  116. (2001). Prevalence and reversibility of lower airway obstruction in children with sickle cell disease,”
  117. (2009). Pulmonary function and airway hyperresponsiveness in adults with sickle cell disease,”
  118. (2010). Pulmonary hypertension in thalassemia,”
  119. (2007). Pulmonary hypertension in thalassemia: association with hemolysis, arginine metabolism dysregulation and a hypercoaguable state,”
  120. (2010). Pulmonaryhypertension in hemolytic disorders: pulmonary vascular disease: the global perspective,”
  121. (1994). R e c z k o w s k ia n dD .E .A s h ,“ R a tl i v e ra r g i n a s e :K i n e t i c mechanism, alternate substrates, and inhibitors,”
  122. (2004). R i c c i a r d o l o ,P .J .S t e r k ,B .G a s t o n ,a n dG .F o l k e r t s , “Nitric oxide in health anddisease ofthe respiratory system,”
  123. (1995). Reciprocal regulation of the nitric oxide synthase-arginase balance in mouse bone marrow-derived macrophages by TH1 and TH2 cytokines,”
  124. (2001). Remodeling in asthma and chronic obstructive lung disease,” American journal of respiratory and critical care medicine,
  125. (2006). Remodeling in asthma and chronic obstructive pulmonary disease,”
  126. (1993). Riveros-Moreno et al., “Induction of nitric oxide synthase in asthma,”
  127. (2010). Role of arginase in sickle cell lung disease and hemolytic anemias,”
  128. (2001). Role of nitric oxide and superoxide in allergen-induced airway hyperreactivity after the late asthmatic reaction in guinea-pigs,”
  129. (1998). Role of nitric oxide in the development and partial reversal of allergen-induced airway hyperreactivity in conscious, unrestrained guineapigs,”
  130. (1998). S c h a p i r a ,J .H .W i e s s n e r ,J .F .M o r r i s e y ,U .A .A l m a g r o
  131. (1980). Sputum arginase activity in bronchial asthma,”
  132. (2003). Susceptibility to ovalbumin-induced airway inflammation and fibrosis in induciblenitric oxidesynthetase-deficientmice:mechanisms and consequences,” T o x i c o l o g ya n dA p p l i e dP h a r m a c o l o g y ,
  133. (2001). Sustained nitric oxide production in macrophages requires the arginine transporter CAT2,” J o u r n a lo fB i o l o g i c a lC h e m -istry,
  134. (2002). T.Yahata,Y.Nishimura,H.Maeda,andM.Yokoyama,“Modulation of airway responsiveness by anionic and cationic polyelectrolyte substances,”
  135. (2007). Temporal relationship of asthma to acute chest syndrome in sickle cell disease,” Pediatric Pulmonology,
  136. (2008). TGF-β, eosinophils and IL13 in allergic airway remodeling: a critical appraisal with therapeutic considerations,”
  137. (1993). The effect of human eosinophil granule major basic protein on airway responsiveness in the rat in vivo: a comparison with polycations,” American Review of Respiratory Disease,v o l .
  138. (1998). Thrombin stimulates vascular smooth muscle cell polyamine synthesis by inducing cationic amino acid transporter and ornithine decarboxylase gene expression,”
  139. (2001). Transforming growth factor-β stimulates Larginine transport and metabolism in vascular smooth muscle cells: role in polyamine and collagen synthesis,”
  140. (2010). Warnken,“L-arginine metabolic pathways,”
  141. (2006). Wheezing in Older Children: Asthma,”