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Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229
3To whom correspondence should be addressed. E-mail: zimmn0{at}cchmc.org.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • arginine • arginase • asthma • allergy • lung
Asthma is a disease characterized by eosinophil-rich inflammatory cell infiltrates, increased mucus production, airway hyperreactivity, and reversible airway obstruction (1–3). Analysis of lung tissue biopsies from patients with asthma has revealed that chronic airway inflammation is associated with lung remodeling. These chronic changes include epithelial shedding and hypertrophy, hyperplasia and metaplasia of submucosal mucus glands and smooth muscle cells, and fibrosis (4–6). Experimentation in the asthma field has largely focused on analysis of the cellular and molecular events induced by allergen exposure in sensitized animals (primarily mice) and humans (7–9). Although no animal model adequately mimics human disease, experimentation in animals has provided an experimental framework to dissect key cells and molecules involved in the pathogenesis of allergic lung disease. In these studies, mice are typically sensitized with antigen [e.g., ovalbumin (OVA)4 ]in the presence of an adjuvant (e.g., alum) by intraperitoneal injection (10). Subsequently, mice are challenged by exposure to a respiratory allergen (via intratracheal, intranasal, or nebulized routes) and pathological responses are monitored. In other murine asthma models, unsensitized mice are repeatedly exposed to mucosal allergens (e.g., extracts of Aspergillus fumigatus) and the development of experimental asthma is monitored (11). In patient studies, naturally sensitized individuals are similarly challenged by exposure to allergen in the respiratory tract (e.g., segmental antigen challenge) (12). Collectively, these studies have provided important insight into the complexity of allergic lung disease by revealing the involvement of diverse cells including infiltrating leukocytes and residential cells including endothelial, epithelial, and smooth muscle cells (4,8,13). In addition, these studies have elucidated that Th2 cells induce asthma through the secretion of an array of cytokines (IL-4, -5, -9, -10, -13) that activate inflammatory and residential effector pathways both directly and indirectly (14,15). In particular, IL-4 and IL-13 are produced at elevated levels in the asthmatic lung and are thought to be central regulators of many of the hallmark features of this disease (8). Collectively, these studies have provided the rationale for the development of multiple therapeutic agents that interfere with specific inflammatory pathways (13,16). Despite this active ongoing research and the availability of an increasing number of medications to treat patients with asthma, there is currently an epidemic of this disease in the western world and the incidence continues to rise (17,18). This highlights the importance of taking new approaches in the scientific analysis of the asthma problem.
We hypothesized that DNA microarray analysis of lung tissue from mice undergoing induction of experimental antigen-induced asthma would provide novel and empiric insight into the pathogenesis of experimental asthma. After identifying a subset of the mouse genome involved in experimental asthma, we were struck by the upregulation of specific genes involved in L-arginine metabolism (19,20). In particular, the genes for the L-arginine transporter [cationic amino acid transporter (CAT)2], arginase I, and arginase II were strongly induced. Involvement of L-arginine metabolism via nitric oxide synthase (NOS) in asthma pathogenesis has been extensively studied (21–23). However, the role of the arginase pathway is largely unexplored. Arginase may be a regulator of diverse pathways including production of nitric oxide, polyamines, and proline; these molecules regulate critical processes associated with asthma including airway tone, cell hyperplasia, and collagen deposition, respectively. Thus, in this review we will mainly focus on the role of arginase and L-arginine transport in asthma pathogenesis.
L-arginine metabolism by NOS
L-arginine metabolism via NOS results in the production of nitric oxide (NO), a free radical molecule involved in a wide range of biological processes (24). Three isoforms of NOS have been described (24). NOS1 and NOS3 are constitutively expressed and their activity is calcium dependent. NOS1 is expressed in neurons and is thought to have a role in neurotransmission, whereas NOS3, or endothelial NOS, has a role in smooth muscle relaxation and bronchodilation. NOS2, inducible NOS (iNOS), is calcium-independent, and is upregulated in response to pro-inflammatory mediators leading to the increased production of NO (25). All 3 NOS isoforms have been found in the respiratory tract and are involved in the regulation of multiple pulmonary functions. The role of NO depends on milieu and local concentration. For instance, NOS2 is markedly upregulated in asthmatic lungs and elevated levels of exhaled NO in asthma patients correlate with asthma severity (22,26). High concentrations of NO may be detrimental by promoting inflammation and by causing mucosal swelling and epithelial damage, therefore contributing to airway hyperreactivity (AHR) (21). However, in recent years it became clear that endogenous NO is involved in regulation of airway reactivity to bronchoconstrictor stimuli, including muscarinic receptor agonists, histamine, and bradykinin (21). A number of studies have shown that endogenous NO deficiency may potentiate AHR in response to various stimuli (27–30). NO deficiency in asthmatic airways may be a result of reduced availability of NOS substrate, L-arginine, via decreased cellular uptake or increased utilization via other metabolic pathways, as discussed below.
L-arginine metabolism by arginase
Besides the NO pathway, L-arginine is also metabolized by arginase as part of the urea cycle (31,32). The bulk of the urea cycle occurs in the liver, the main organ containing the full enzymatic machinery necessary for the urea cycle. The enzyme arginase is the only urea cycle enzyme that exists in 2 isoforms (60% amino acid homology), which are encoded by different genes on distinct chromosomes, designated type I and type II. Arginase I is a cytoplasmic protein that is primarily expressed in the liver, whereas arginase II is a mitochondrial protein expressed in a variety of tissues, especially the kidney and prostate (33). The downstream enzymes L-ornithine decarboxylase (ODC) and L-ornithine amino transferase (OAT) are specifically expressed in the cytoplasm and mitochondria, respectively (32), suggesting coordinated biochemical links for the 2 isoenzymes. Arginase I deficiency in humans results in hyperargininemia and a progressive neurological deterioration that is usually fatal (33). Whereas arginase I gene targeted mice die within 10–14 d after birth, arginase II-deficient mice are grossly normal (34,35). One of the most exciting developments in the past several years concerning L-arginine metabolism was the finding that arginase can be expressed in many tissues and cell types following exposure to a variety of cytokines and agents (32).
Arginase in asthma
In our effort to identify important allergen-induced genes that were not previously associated with asthma, we used microarray analysis of transcripts that were induced in 2 different murine asthma models. We were struck by the high level of arginase messenger RNA (mRNA) transcripts in allergen-treated lungs compared with saline-treated lungs (Fig. 1). Both arginase I and arginase II were strongly induced during experimental asthma. In addition, the CAT2 gene expression was significantly increased following allergen challenges (Fig. 1). These findings were confirmed by Northern blot analysis (19). In situ hybridization and immunohistochemistry indicated that arginase I was produced in the active inflammatory sites around airways and blood vessels during induction of allergic airway inflammation (Fig. 2). A subpopulation of mononuclear cells, most consistent with macrophages, appeared to be the major cellular source (19). The upregulation of arginase mRNA during induction of experimental asthma was associated with functional changes in arginase activity in the lung. Consistent with the absence of arginase mRNA in the lung of control mice, the level of arginase activity in control lung was close to background. Following induction of experimental asthma by the OVA/alum protocol, there was a marked increase in lung arginase activity (Fig. 3). Finally, immunocytochemistry and in situ hybridization analysis of samples from patients with asthma demonstrated that this pathway is also operational in human asthma (19).
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3-fold increase in the level of putrescine compared with saline challenged mice (19). Increased production of putrescine in the lung can have several important ramifications on pulmonary responses (41). Based on their basic charge and small size, polyamines interact with macromolecules including RNA and DNA, thereby regulating diverse cellular responses including cell growth, division, and differentiation. The inhibitor of ODC and polyamine synthesis, difluoromethylornithine (DFMO), has been shown to block cell growth and differentiation, and is an effective anti-cancer therapeutic (37,42,43). With regard to asthma, DFMO inhibits smooth muscle cell proliferation in vitro (44), a process that is associated with the chronic airway remodeling in the asthmatic lung (4). Polyamines can be secreted from cells and indeed elevated levels of these molecules are found in the serum of patients with asthma (45). This may be particularly important in the lung because respiratory epithelial cells have a potent polyamine uptake system (41). Interestingly, with regard to allergic responses, polyamines have also been shown to directly interact with allergens and modulate signaling in mast cells (41,46–48). In addition, L-ornithine (whose production is regulated by arginase) is a precursor of proline (following metabolism by OAT). Work from several laboratories led to the notion that macrophage-derived arginase has a role in the recovery of host tissues from inflammation and infection. This effect is not only mediated by removing L-arginine as a substrate for NOS, but also by generating L-ornithine for synthesis of proline, which is required for collagen synthesis (31). This may be particularly important in inflammatory sites characterized by tissue remodeling/repair (such as the asthmatic airway) because proline often becomes a rate limiting substrate for collagen synthesis (49,50). Under these conditions, it is believed that extracellular L-ornithine and proline, secreted from arginase expressing cells (e.g., macrophages), are transported into fibroblasts, where they subsequently become incorporated into collagen (49,50).
Regulation of arginase expression in lungs
Although both arginase isoforms are inducible by various stimuli in vitro, arginase I appears to be more strongly induced by Th2 cytokines such as IL-4 and IL-13 (38,51–53). However, this has not been extensively studied in cell types other than macrophages. In our studies we observed that Th2 cytokines have a major role in regulation of lung arginase expression. For example, mice that overexpress the IL-4 transgene in pulmonary epithelium (under the control of the Clara cell 10 promoter) and exhibit several features of asthma including eosinophil-rich inflammatory cell infiltrates, mucus production, and changes in baseline airway hyperreactivity (54) also had a marked increase in the level of arginase I (Fig. 4). Interestingly, arginase II was also inducible in the IL-4 lung transgenic mice (Fig. 4). Another Th2 cytokine, IL-13, has been shown to be critically involved in the development of several features of experimental asthma (55). IL-13 has been shown to induce arginase expression in vitro and IL-13-deficient mice have impaired induction of arginase during experimental Th2-associated granuloma/fibrosis formation (56–58). Pharmacological delivery of IL-13 to the lung of mice induced marked levels of arginase I compared with saline treated control mice (Fig. 4). Consistent with the finding that IL-4 transgenic mice had elevated levels of arginase II mRNA, IL-13 also increased arginase II mRNA levels (Fig. 4).
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chain and the induction of janus kinase 1 and signal transducer and activation of transcription (STAT6). A subset of their responses has been shown to be STAT6-dependent (59–61). To test the role of STAT6 in the induction of arginase I in vivo, we examined IL-4 lung transgenic mice that contained wild type or gene targeted STAT6. We have previously described these mice (62). As shown in Figure 4, whereas IL-4 lung transgenic mice contained abundant arginase I mRNA, in the absence of STAT6 there was a complete loss of the IL-4 induced arginase I mRNA. This is in agreement with the report that arginase expression (induced by IL-4 and IL-13) is associated with inhibition of NO production in macrophages by a STAT6-dependent pathway (57). Interestingly, the IL-4 transgene-induced arginase II mRNA signal was not attenuated in STAT6-deficient mice, indicating that arginase II, in contrast to arginase I, was STAT6-independent. These findings are consistent with in vitro studies that demonstrated shared and distinct signaling requirements for these 2 isoenzymes (32,36). The finding that both arginase isoforms are highly upregulated in asthmatic lung challenges the conventional view that L-arginine is primarily metabolized by NOS in asthmatic responses. It also suggests that L-arginine is an important molecule in asthma pathogenesis and modulation of L-arginine levels may affect L-arginine metabolism by both NOS and arginase pathways.
L-arginine transport
Extracellular L-arginine is required for sustained NO and L-ornithine generation from L-arginine (63), implicating an important role for L-arginine transport through the plasma membrane. Among the several transport systems that mediate L-arginine uptake, system y+ is widely expressed and considered to be the major L-arginine transporter in most cells and tissues (64). Encoded by cationic amino acid transporters CAT1, CAT2, and CAT3, system y+ is an Na+-independent high affinity cationic amino acid transport system. With the exception of the liver, CAT1 is expressed virtually ubiquitously and is required for viability, whereas CAT2 is expressed in a more restricted number of tissues (64); CAT3 is primarily expressed in the brain (65). Due to differential splicing of 2 exons, the CAT2 mRNA exists in 2 isoforms: CAT2A, a low affinity transporter that is expressed primarily in the liver, and the high affinity CAT2 (CAT2B) (66). Interestingly, CAT2 was originally cloned from lymphoma cell line cDNA and was named Tea (T cell early activation factor), because it is induced early in the response of normal T cells to mitogens (66). The first indication that CAT2 may be involved in critically regulating substrate availability for iNOS or arginase was the finding that pro-inflammatory molecules [e.g., lipopolysaccharide (LPS)]) regulate CAT2 expression. In contrast, cat-1 is a "housekeeping" gene that is not induced under conditions that induce CAT2 (67). A further interesting relationship has been established by the findings that eosinophil cationic proteins inhibit L-arginine uptake by macrophages and affect both NOS and arginase activity, albeit to a different degree (68). Recent analysis of CAT2-deficient mice has revealed that sustained NO production in macrophages requires CAT2 (69). The 95% decrease in L-arginine uptake by CAT2-deficient macrophages indicates that CAT2 is the major L-arginine transporter in macrophages. Upregulation of CAT2 expression mainly was studied in the context of iNOS induction after treatment with LPS or IFN
(69). We have observed induction of CAT2 mRNA in lungs in a murine experimental asthma model that is associated with marked increase in arginase activity (Fig. 1). Induction of CAT2 expression may be required for maintenance of intracellular L-arginine supply. Depletion of extracellular L-arginine is common in inflammatory conditions (70,71). Delivery of L-arginine in vivo resulted in increased mucosal antibody production following sensitization with antigen (72). In an asthma model, delivery of dietary L-arginine increased airway eosinophilia and levels of IL-5 production (73). Notably, aerosolized delivery of L-arginine in individuals with asthma induces bronchoconstriction (74). However, one report in guinea pigs infected with parainfluenza virus demonstrated that delivery of aerosolized L-arginine prevented airway hyperresponsiveness (75). Taken together, these studies provided evidence that modulation of L-arginine availability can have profound effects on a variety of inflammatory parameters in the lung.
The interplay between arginase and NOS
It is important to understand the inter-relationships between arginase and NOS, since both enzymes utilize the same substrate and both are implicated in asthma pathogenesis. There are several levels at which arginase and NOS affect each other. While the Km for L-arginine is in the 2–20 mmol/L range for arginase compared with the 2–20 µmol/L range for various NOS isoenzymes, the Vmax of arginase is 1000-fold higher than for NOS (32,33). Thus, arginase and NOS effectively compete for L-arginine, and thereby negatively coregulate the function of each other. Indeed, induction of arginase by IL-4 and IL-13 induces substrate depletion for nitric oxide production by macrophages (57). Furthermore, the NOS product hydroxyarginine is an inhibitor of arginase (36). Conversely, polyamines inhibit the NOS enzymes (76). These biochemical properties are likely to have functional significance since arginase activity in macrophages limits NO production (38,53,77,78). In summary, because there is an intimate balance between NOS and arginase, any biochemical or genetic perturbation in the NOS pathway that affects the pathogenesis of asthma/atopy may be mediated, at least in part, by effects on arginase. Thus, fully elucidating the functional importance of NOS in asthma is also dependent upon understanding the role of arginase in asthma. A number of studies have demonstrated that functional interactions between the 2 enzymes indeed exist and may affect the outcome of allergic responses (79,80). In these experiments, inhibition of arginase with the specific arginase inhibitor (N
-hydoxy-nor-L-arginine) attenuates methacholine induced airway constriction in perfused guinea pig tracheal explants, presumably by increasing endogenous NO production (79,80). These results are consistent with the ability of arginase to "functionally" inhibit NOS by depleting L-arginine availability.
Summary
We have described pathways involved in L-arginine metabolism and transport in allergic airway inflammation. Data presented here suggest that in addition to being metabolized by NOS, significant metabolism occurs by arginase, and that this process has important ramifications on the manifestations of disease. As such, this pathway may represent an important therapeutic intervention strategy for the treatment of allergic disease.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 This work was supported in part by the American Heart Association Scientist Development (N.Z.) and Post-doctorate fellowship (N.K.) grants, NIH grants R01 AI42242 (M.E.R.), AI45898 (M.E.R.), AI53479 (M.E.R.), the Human Frontier Science Program (M.E.R.), International Life Sciences Institute (M.E.R.) and Burroughs Wellcome Fund (M.E.R.).
4 Abbreviations used: AHR, airway hyperresponsiveness; CAT, cationic amino acid transporter; DFMO, difluoromethylornithine; iNOS, inducible NOS; LPS, lipopolysaccharide; mRNA, messenger RNA; NO, nitric oxide; NOS, nitric oxide synthase; ODC, L-ornithine decarboxylase; OAT, L-ornithine amino transferase; OVA, ovalbumin; STAT6, signal transducer and activator of transcription.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
|---|
1. Busse, W. W. & Lemanske, R. F., Jr (2001) Asthma. N. Engl. J. Med. 344:350-362.
2. Hamelmann, E. & Gelfand, E. W. (2001) IL-5-induced airway eosiniphilia—the key to asthma?. Immunol. Rev. 179:182-191.[Medline]
3. Lee, N. A., Gelfand, E. W. & Lee, J. J. (2001) Pulmonary T cells and eosinophils: coconspirators or independent triggers of allergic respiratory pathology?. J. Allergy Clin. Immunol. 107:945-957.[Medline]
4. Bochner, B. S., Undem, B. J. & Lichtenstein, L. M. (1994) Immunological aspects of allergic asthma. Annu. Rev. Immunol. 12:295-335.[Medline]
5. Wilson, J. W. & Li, X. (1997) The measurement of reticular basement membrane and submucosal collagen in the asthmatic airway. Clin. Exp. Allergy. 27:363-371.[Medline]
6. Muro, S., Minshall, E. M. & Hamid, Q. A. (2000) The pathology of chronic asthma. Clin. Chest Med. 21:225-244.[Medline]
7. Leong, K. P. & Huston, D. P. (2001) Understanding the pathogenesis of allergic asthma using mouse models. Ann. Allergy Asthma Immunol. 87:96-109.[Medline]
8. Wills-Karp, M. (1999) Immunologic basis of antigen-induced airway hyperresponsiveness. Annu. Rev. Immunol. 17:255-281.[Medline]
9. O’Byrne, P. M., Inman, M. D. & Parameswaran, K. (2001) The trials and tribulations of IL-5, eosinophils, and allergic asthma. J. Allergy Clin. Immunol. 108:503-508.[Medline]
10. Lloyd, C. M., Gonzalo, J. A., Coyle, A. J. & Gutierrez-Ramos, J. C. (2001) Mouse models of allergic airway disease. Adv. Immunol. 77:263-295.[Medline]
11. Kurup, V. P., Mauze, S., Choi, H., Seymour, B. W. & Coffman, R. L. (1992) A murine model of allergic bronchopulmonary aspergillosis with elevated eosinophils and IgE. J. Immunol. 148:3783-3788.[Abstract]
12. Makker, H. K., Montefort, S. & Holgate, S. (1993) Investigative use of fibreoptic bronchoscopy for local airway challenge in asthma. Eur. Respir. J. 6:1402-1408.[Abstract]
13. Barnes, P. J. (2000) New directions in allergic diseases: mechanism-based anti-inflammatory therapies. J. Allergy Clin. Immunol. 106:5-16.[Medline]
14. Drazen, J. M., Arm, J. P. & Austen, K. F. (1996) Sorting out the cytokines of asthma. J. Exp. Med. 183:1-5.
15. Ray, A. & Cohn, L. (1999) Th2 cells and GATA-3 in asthma: new insights into the regulation of airway inflammation. J. Clin. Invest. 104:985-993.[Medline]
16. Boushey, H. A., Jr (2001) Experiences with monoclonal antibody therapy for allergic asthma. J. Allergy Clin. Immunol. 108:S77-S83.[Medline]
17. ISAAC (1998) Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet 351:1225-1232.[Medline]
18. Holgate, S. T. (1999) The epidemic of allergy and asthma. Nature 402:B2-B4.[Medline]
19. Zimmermann, N., King, N. E., Laporte, J., Yang, M., Mishra, A., Pope, S. M., Muntel, E. E., Witte, D. P., Pegg, A. E., Foster, P. S., Hamid, Q. & Rothenberg, M. E. (2003) Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis. J. Clin. Invest. 111:1863-1874.[Medline]
20. Zimmermann, N., Mishra, A., King, N. E., Fulkerson, P. C., Doepker, M. P., Nikolaidis, N. M., Kindinger, L. E., Moulton, E. A., Aronow, B. J. & Rothenberg, M. E. (2004) Transcript signatures in experimental asthma: identification of STAT6-dependent and -independent pathways. J. Immunol. 172:1815-1824.
21. Meurs, H., Maarsingh, H. & Zaagsma, J. (2003) Arginase and asthma: novel insights into nitric oxide homeostasis and airway hyperresponsiveness. Trends Pharmacol. Sci. 24:450-455.[Medline]
22. Folkerts, G., Kloek, J., Muijsers, R. B. & Nijkamp, F. P. (2001) Reactive nitrogen and oxygen species in airway inflammation. Eur. J. Pharmacol. 429:251-262.[Medline]
23. Fischer, A., Folkerts, G., Geppetti, P. & Groneberg, D. A. (2002) Mediators of asthma: nitric oxide. Pulm. Pharmacol. Ther. 15:73-81.[Medline]
24. Bogdan, C. (2001) Nitric oxide and the immune response. Nat. Immunol. 2:907-916.[Medline]
25. Fang, F. C. (1997) Perspectives series: host/pathogen interactions. Mechanisms of nitric oxide-related antimicrobial activity. J. Clin. Invest. 99:2818-2825.[Medline]
26. Hamid, Q., Springall, D. R., Riveros-Moreno, V., Chanez, P., Howarth, P., Redington, A., Bousquet, J., Godard, P., Holgate, S. & Polak, J. M. (1993) Induction of nitric oxide synthase in asthma. Lancet 342:1510-1513.[Medline]
27. De Boer, J., Meurs, H., Coers, W., Koopal, M., Bottone, A. E., Visser, A. C., Timens, W. & Zaagsma, J. (1996) Deficiency of nitric oxide in allergen-induced airway hyperreactivity to contractile agonists after the early asthmatic reaction: an ex vivo study. Br. J. Pharmacol. 119:1109-1116.[Medline]
28. De Boer, J., Meurs, H., Flendrig, L., Koopal, M. & Zaagsma, J. (2001) Role of nitric oxide and superoxide in allergen-induced airway hyperreactivity after the late asthmatic reaction in guinea-pigs. Br. J. Pharmacol. 133:1235-1242.[Medline]
29. Nijkamp, F. P., van der Linde, H. J. & Folkerts, G. (1993) Nitric oxide synthesis inhibitors induce airway hyperresponsiveness in the guinea pig in vivo and in vitro. Role of the epithelium. Am. Rev. Respir. Dis. 148:727-734.[Medline]
30. Schuiling, M., Meurs, H., Zuidhof, A. B., Venema, N. & Zaagsma, J. (1998) Dual action of iNOS-derived nitric oxide in allergen-induced airway hyperreactivity in conscious, unrestrained guinea pigs. Am. J. Respir. Crit. Care Med. 158:1442-1449.
31. Wu, G. & Morris, S. M., Jr (1998) Arginine metabolism: nitric oxide and beyond. Biochem. J. 336:1-17.
32. Morris, S. M., Jr (2002) Regulation of enzymes of the urea cycle and arginine metabolism. Annu. Rev. Nutr. 22:87-105.[Medline]
33. Iyer, R., Jenkinson, C. P., Vockley, J. G., Kern, R. M., Grody, W. W. & Cederbaum, S. (1998) The human arginases and arginase deficiency. J. Inherit. Metab. Dis. 21:86-100.[Medline]
34. Shi, O., Morris, S. M., Jr, Zoghbi, H., Porter, C. W. & O’Brien, W. E. (2001) Generation of a mouse model for arginase II deficiency by targeted disruption of the arginase II gene. Mol. Cell. Biol. 21:811-813.
35. Iyer, R. K., Yoo, P. K., Kern, R. M., Rozengurt, N., Tsoa, R., O’Brien, W. E., Yu, H., Grody, W. W. & Cederbaum, S. D. (2002) Mouse model for human arginase deficiency. Mol. Cell. Biol. 22:4491-4498.
36. Morris, S. M., Jr (2000) Regulation of arginine availability and its impact on NO synthesis. Ignarro, L. J. eds. Nitric Oxide. Biology and Pathobiology 2000:187-197 Academic Press San Diego, CA. .
37. Pegg, A. E. & McCann, P. P. (1982) Polyamine metabolism and function. Am. J. Physiol. 243:C212-C221.
38. Kepka-Lenhart, D., Mistry, S. K., Wu, G. & Morris, S. M., Jr (2000) Arginase I: a limiting factor for nitric oxide and polyamine synthesis by activated macrophages?. Am. J. Physiol. Regul. Integr. Comp. Physiol. 279:R2237-R2242.
39. Wei, L. H., Wu, G., Morris, S. M., Jr & Ignarro, L. J. (2001) Elevated arginase I expression in rat aortic smooth muscle cells increases cell proliferation. Proc. Natl. Acad. Sci. U.S.A. 98:9260-9264.
40. Li, H., Meininger, C. J., Kelly, K. A., Hawker, J. R., Jr, Morris, S. M., Jr & Wu, G. (2002) Activities of arginase I and II are limiting for endothelial cell proliferation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 282:R64-R69.
41. Hoet, P. H. & Nemery, B. (2000) Polyamines in the lung: polyamine uptake and polyamine-linked pathological or toxicological conditions. Am. J. Physiol. Lung Cell. Mol. Physiol. 278:L417-L433.
42. Bacchi, C. J., Garofalo, J., Mockenhaupt, D., McCann, P. P., Diekema, K. A., Pegg, A. E., Nathan, H. C., Mullaney, E. A., Chunosoff, L., Sjoerdsma, A. & Hutner, S. H. (1983) In vivo effects of alpha-DL-difluoromethylornithine on the metabolism and morphology of Trypanosoma brucei. Mol. Biochem. Parasitol. 7:209-225.[Medline]
43. Van Voorhis, W. C. (1990) Therapy and prophylaxis of systemic protozoan infections. Drugs 40:176-202.[Medline]
44. Ignarro, L. J., Buga, G. M., Wei, L. H., Bauer, P. M., Wu, G. & del Soldato, P. (2001) Role of the arginine-nitric oxide pathway in the regulation of vascular smooth muscle cell proliferation. Proc. Natl. Acad. Sci. U.S.A. 98:4202-4208.
45. Kurosawa, M., Shimizu, Y., Tsukagoshi, H. & Ueki, M. (1992) Elevated levels of peripheral-blood, naturally occurring aliphatic polyamines in bronchial asthmatic patients with active symptoms. Allergy 47:638-643.[Medline]
46. Kurosawa, M., Uno, D., Hanawa, K. & Kobayashi, S. (1990) Polyamines stimulate the phosphorylation of phosphatidylinositol in rat mast cell granules. Allergy 45:262-267.[Medline]
47. Kurosawa, M., Uno, D. & Kobayashi, S. (1991) Naturally occurring aliphatic polyamines-induced histamine release from rat peritoneal mast cells. Allergy 46:349-354.[Medline]
48. Mousli, M., Hugli, T. E., Landry, Y. & Bronner, C. (1994) Peptidergic pathway in human skin and rat peritoneal mast cell activation. Immunopharmacology 27:1-11.[Medline]
49. Albina, J. E., Abate, J. A. & Mastrofrancesco, B. (1993) Role of ornithine as a proline precursor in healing wounds. J. Surg. Res. 55:97-102.[Medline]
50. Kershenobich, D., Fierro, F. J. & Rojkind, M. (1970) The relationship between the free pool of proline and collagen content in human liver cirrhosis. J. Clin. Invest. 49:2246-2249.
51. Louis, C. A., Mody, V., Henry, W. L., Jr, Reichner, J. S. & Albina, J. E. (1999) Regulation of arginase isoforms I and II by IL-4 in cultured murine peritoneal macrophages. Am. J. Physiol. 276:R237-R242.
52. Mistry, S. K., Zheng, M., Rouse, B. T. & Morris, S. M., Jr (2001) Induction of arginases I and II in cornea during herpes simplex virus infection. Virus Res. 73:177-182.[Medline]
53. Modolell, M., Corraliza, I. M., Link, F., Soler, G. & Eichmann, K. (1995) Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow-derived macrophages by TH1 and TH2 cytokines. Eur. J. Immunol. 25:1101-1104.[Medline]
54. Rankin, J. A., Picarella, D. E., Geba, G. P., Temann, U.-A., Prasad, B., DiCosmo, B., Tarallo, A., Stripp, B., Whitsett, J. & Flavell, R. A. (1996) Phenotypic and physiologic characterization of transgenic mice expressing interleukin 4 in the lung: lymphocytic and eosinophilic inflammation without airway hyperreactivity. Proc. Natl. Acad. Sci. U.S.A. 93:7821-7825.
55. Wills-Karp, M. (2001) IL-12/IL-13 axis in allergic asthma. J. Allergy Clin. Immunol. 107:9-18.[Medline]
56. Wei, L. H., Jacobs, A. T., Morris, S. M., Jr & Ignarro, L. J. (2000) IL-4 and IL-13 upregulate arginase I expression by cAMP and JAK/STAT6 pathways in vascular smooth muscle cells. Am. J. Physiol. Cell. Physiol. 279:C248-C256.
57. Rutschman, R., Lang, R., Hesse, M., Ihle, J. N., Wynn, T. A. & Murray, P. J. (2001) Cutting edge: Stat6-dependent substrate depletion regulates nitric oxide production. J. Immunol. 166:2173-2177.
58. Hesse, M., Modolell, M., La Flamme, A. C., Schito, M., Fuentes, J. M., Cheever, A. W., Pearce, E. J. & Wynn, T. A. (2001) Differential 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. J. Immunol. 167:6533-6544.
59. Takeda, K., Tanaka, T., Shi, W., Matsumoto, M., Minami, M., Kashiwamura, S., Nakanishi, K., Yoshida, N., Kishimoto, T. & Akira, S. (1996) Essential role of Stat6 in IL-4 signalling. Nature 380:627-630.[Medline]
60. Shimoda, K., van Deursen, J., Sangster, M. Y., Sarawar, S. R., Carson, R. T., Tripp, R. A., Chu, C., Quelle, F. W., Nosaka, T., Vignali, D. A., Doherty, P. C., Grosveld, G., Paul, W. E. & Ihle, J. N. (1996) Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 380:630-633.[Medline]
61. Ihle, J. N. (2001) The Stat family in cytokine signaling. Curr. Op. Cell Biol. 13:211-217.[Medline]
62. Zimmermann, N., Hogan, S. P., Mishra, A., Brandt, E. B., Bodette, T. R., Pope, S. M., Finkelman, F. D. & Rothenberg, M. E. (2000) Murine eotaxin-2: A constitutive eosinophil chemokine induced by allergen challenge and IL-4 overexpression. J. Immunol. 165:5839-5846.
63. Closs, E. I., Scheld, J. S., Sharafi, M. & Forstermann, U. (2000) Substrate supply for nitric-oxide synthase in macrophages and endothelial cells: role of cationic amino acid transporters. Mol. Pharmacol. 57:68-74.
64. MacLeod, C. L. (1996) Regulation of cationic amino acid transporter (CAT) gene expression. Biochem. Soc. Trans. 24:846-852.[Medline]
65. Hosokawa, H., Sawamura, T., Kobayashi, S., Ninomiya, H., Miwa, S. & Masaki, T. (1997) Cloning and characterization of a brain-specific cationic amino acid transporter. J. Biol. Chem. 272:8717-8722.
66. MacLeod, C. L., Finley, K., Kakuda, D., Kozak, C. A. & Wilkinson, M. F. (1990) Activated T cells express a novel gene on chromosome 8 that is closely related to the murine ecotropic retroviral receptor. Mol. Cell. Biol. 10:3663-3674.
67. MacLeod, C. L., Finley, K. D. & Kakuda, D. K. (1994) y(+)-type cationic amino acid transport: expression and regulation of the mCAT genes. J. Exp. Biol. 196:109-121.
68. Hammermann, R., Hirschmann, J., Hey, C., Mossner, J., Folkerts, G., Nijkamp, F. P., Wessler, I. & Racke, K. (1999) Cationic proteins inhibit L-arginine uptake in rat alveolar macrophages and tracheal epithelial cells. Implications for nitric oxide synthesis. Am. J. Respir. Cell Mol. Biol. 21:155-162.
69. Nicholson, B., Manner, C. K., Kleeman, J. & MacLeod, C. L. (2001) Sustained nitric oxide production in macrophages requires the arginine transporter CAT2. J. Biol. Chem. 276:15881-15885.
70. Currie, G. A., Gyure, L. & Cifuentes, L. (1979) Microenvironmental arginine depletion by macrophages in vivo. Br. J. Cancer 39:613-620.[Medline]
71. Albina, J. E., Mills, C. D., Barbul, A., Thirkill, C. E., Henry, W. L., Jr, Mastrofrancesco, B. & Caldwell, M. D. (1988) Arginine metabolism in wounds. Am. J. Physiol. 254:E459-E467.
72. Kobayashi, T., Yamamoto, M., Hiroi, T., McGhee, J., Takeshita, Y. & Kiyono, H. (1998) Arginine enhances induction of T helper 1 and T helper 2 cytokine synthesis by Peyer’s patch alpha beta T cells and antigen-specific mucosal immune response. Biosci. Biotechnol. Biochem. 62:2334-2340.[Medline]
73. Takano, H., Lim, H. B., Miyabara, Y., Ichinose, T., Yoshikawa, T. & Sagai, M. (1998) Oral administration of L-arginine potentiates allergen-induced airway inflammation and expression of interleukin-5 in mice. J. Pharmacol. Exp. Ther. 286:767-771.
74. Sapienza, M. A., Kharitonov, S. A., Horvath, I., Chung, K. F. & Barnes, P. J. (1998) Effect of inhaled L-arginine on exhaled nitric oxide in normal and asthmatic subjects. Thorax 53:172-175.
75. Folkerts, G., van der Linde, H. J. & Nijkamp, F. P. (1995) Virus-induced airway hyperresponsiveness in guinea pigs is related to a deficiency in nitric oxide. J. Clin. Invest. 95:26-30.
76. Szabo, C., Southan, G. J., Wood, E., Thiemermann, C. & Vane, J. R. (1994) Inhibition by spermine of the induction of nitric oxide synthase in J774.2 macrophages: requirement of a serum factor. Br. J. Pharmacol. 112:355-356.[Medline]
77. Li, L., Rao, J. N., Guo, X., Liu, L., Santora, R., Bass, B. L. & Wang, J. Y. (2001) Polyamine depletion stabilizes p53 resulting in inhibition of normal intestinal epithelial cell proliferation. Am. J. Physiol. Cell. Physiol. 281:C941-C953.
78. Morris, S. M., Jr, Kepka-Lenhart, D. & Chen, L. C. (1998) Differential regulation of arginases and inducible nitric oxide synthase in murine macrophage cells. Am. J. Physiol. 275:E740-E747.
79. Meurs, H., Hamer, M. A., Pethe, S., Vadon-Le Goff, S., Boucher, J. L. & Zaagsma, J. (2000) Modulation of cholinergic airway reactivity and nitric oxide production by endogenous arginase activity. Br. J. Pharmacol. 130:1793-1798.[Medline]
80. Meurs, H., McKay, S., Maarsingh, H., Hamer, M. A., Macic, L., Molendijk, N. & Zaagsma, J. (2002) Increased arginase activity underlies allergen-induced deficiency of cNOS-derived nitric oxide and airway hyperresponsiveness. Br. J. Pharmacol. 136:391-398.[Medline]
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