Arginase: a key enzyme in the pathophysiology of allergic asthma opening novel therapeutic perspectives.
Allergic asthma is a chronic inflammatory airways' disease, characterized by allergen-induced early and late bronchial obstructive reactions, airway hyperresponsiveness (AHR), airway inflammation and airway remodelling. Recent ex vivo and in vivo studies in animal models and asthmatic patients have indicated that arginase may play a central role in all these features. Thus, increased arginase activity in the airways induces reduced bioavailability of L-arginine to constitutive (cNOS) and inducible (iNOS) nitric oxide synthases, causing a deficiency of bronchodilating and anti-inflammatory NO, as well as increased formation of peroxynitrite, which may be involved in allergen-induced airways obstruction, AHR and inflammation. In addition, both via reduced NO production and enhanced synthesis of L-ornithine, increased arginase activity may be involved in airway remodelling by promoting cell proliferation and collagen deposition in the airway wall. Therefore, arginase inhibitors may have therapeutic potential in the treatment of acute and chronic asthma. This review focuses on the pathophysiological role of arginase in allergic asthma and the emerging effectiveness of arginase inhibitors in the treatment of this disease.
Maarsingh
Harm
H
Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands. h.maarsingh@rug.nl
Zaagsma
Johan
J
Meurs
Herman
H
D056151:Airway Remodeling; D000818:Animals; D018926:Anti-Allergic Agents / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001119:Arginase / Q000037:antagonists & inhibitors / Q000502:physiology*; D001249:Asthma / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000201:enzymology / Q000503:physiopathology; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000503:physiopathology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000502:physiology; D012143:Respiratory Physiological Phenomena
D018926:Anti-Allergic Agents; D000893:Anti-Inflammatory Agents; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D001119:Arginase
Am J Respir Crit Care Med. 1999 Aug;160(2):663-71
10430744
Lancet. 1993 Dec 18-25;342(8886-8887):1510-3
7504773
FEBS Lett. 1995 Feb 13;359(2-3):251-4
7532597
Am J Respir Crit Care Med. 2002 Aug 1;166(3):392-6
12153977
J Exp Med. 1999 May 17;189(10):1621-30
10330441
Am Rev Respir Dis. 1992 Dec;146(6):1543-7
1456572
J Allergy Clin Immunol. 2007 Feb;119(2):391-7
17291856
Biochemistry. 2001 Mar 6;40(9):2689-701
11258880
Eur J Pharmacol. 1992 Jan 14;210(2):221-2
1350993
J Allergy Clin Immunol. 2006 Sep;118(3):551-9; quiz 560-1
16950269
FEBS Lett. 2001 Oct 5;506(2):91-6
11591378
J Immunol. 2001 Feb 15;166(4):2173-7
11160269
Am J Physiol Lung Cell Mol Physiol. 2003 Aug;285(2):L313-21
12679322
Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):10089-93
7524082
Inflamm Res. 2002 Jan;51(1):33-7
11852910
Am J Respir Crit Care Med. 2000 May;161(5):1720-45
10806180
Lancet. 1994 Jan 15;343(8890):133-5
7904001
Exp Mol Med. 2004 Aug 31;36(4):311-24
15365250
Am J Respir Crit Care Med. 1996 May;153(5):1697-701
8630623
Int Immunopharmacol. 2006 Jul;6(7):1040-52
16714207
Br J Pharmacol. 2001 Aug;133(8):1235-42
11498508
Br J Pharmacol. 1999 Nov;128(5):1114-20
10556950
Br J Pharmacol. 1998 Apr;123(7):1450-6
9579742
J Biol Chem. 1998 Aug 28;273(35):22635-9
9712892
Pneumonol Pol. 1980 May;48(5):329-32
7413457
J Cell Biochem. 2000 Apr;77(3):345-60
10760944
Br J Pharmacol. 1990 Aug;100(4):663-4
2207492
Am J Physiol Lung Cell Mol Physiol. 2007 Dec;293(6):L1419-26
17890324
Biochem Biophys Res Commun. 1994 Sep 30;203(3):1614-21
7945311
Biochem J. 1998 Nov 15;336 ( Pt 1):1-17
9806879
Am J Respir Crit Care Med. 1996 Oct;154(4 Pt 2):S202-6
8876543
J Immunol. 2003 Oct 1;171(7):3655-67
14500663
J Allergy Clin Immunol. 2006 Jan;117(1):119-26
16387594
Am J Physiol Cell Physiol. 2000 Jul;279(1):C248-56
10898736
Am J Physiol Lung Cell Mol Physiol. 2008 Jan;294(1):L34-45
17934065
Br J Pharmacol. 2001 Mar;132(6):1349-57
11250887
Thorax. 1998 Mar;53(3):172-5
9659350
Am J Physiol Lung Cell Mol Physiol. 2000 Mar;278(3):L417-33
10710513
Biochem Biophys Res Commun. 1999 Aug 27;262(2):355-8
10462479
Curr Med Chem. 2007;14(20):2204-13
17691958
J Immunol. 2008 Sep 15;181(6):4255-64
18768883
Am J Respir Cell Mol Biol. 2009 Feb;40(2):179-88
18703795
Am J Physiol. 1997 Feb;272(2 Pt 1):E181-90
9124321
Physiol Rev. 1998 Apr;78(2):487-545
9562037
Am Rev Respir Dis. 1993 Sep;148(3):727-34
8368646
Biochemistry. 2001 Feb 13;40(6):1688-93
11327828
Trends Pharmacol Sci. 2003 Sep;24(9):450-5
12967769
Free Radic Biol Med. 2006 Mar 15;40(6):1083-95
16540403
Nitric Oxide. 1999 Dec;3(6):427-38
10637120
Am J Respir Cell Mol Biol. 1997 Sep;17(3):279-83
9308913
Allergy. 1992 Dec;47(6):638-43
1285570
Exp Cell Res. 1987 May;170(1):160-9
3106075
Cell Mol Life Sci. 1999 Jul;55(8-9):1015-28
10484661
Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6954-8
9192673
Naunyn Schmiedebergs Arch Pharmacol. 2003 Dec;368(6):546-50
14618299
Am J Respir Crit Care Med. 2008 Feb 15;177(4):376-87
18029791
J Immunol. 2006 Oct 15;177(8):5595-603
17015747
Eur Respir J. 2002 Sep;20(3):609-16
12358336
Circ Res. 1998 Jul 27;83(2):217-23
9686762
Amino Acids. 2004 Jul;26(4):321-9
15290337
Allergy. 1995 Sep;50(9):760-4
8546274
Am J Respir Crit Care Med. 2008 Oct 1;178(7):673-81
18635886
Am J Respir Crit Care Med. 1998 Nov;158(5 Pt 1):1442-9
9817691
Naunyn Schmiedebergs Arch Pharmacol. 2008 Aug;378(2):171-84
18437360
Br J Pharmacol. 1999 Feb;126(3):559-62
10188962
Eur Respir J. 2003 May;21(5):770-3
12765418
Toxicol Appl Pharmacol. 2009 Feb 1;234(3):273-80
19027033
Clin Exp Allergy. 2006 Dec;36(12):1575-83
17177681
Am J Respir Crit Care Med. 2001 Jul 1;164(1):149-54
11435253
Biochem Biophys Res Commun. 1997 Apr 17;233(2):487-91
9144563
Respir Res. 2006 Jan 12;7:6
16409620
Eur J Pharmacol. 2008 May 13;585(2-3):375-84
18410920
Br J Pharmacol. 2002 Jun;136(3):391-8
12023942
Am J Hum Genet. 1986 Aug;39(2):186-93
3752085
J Allergy Clin Immunol. 2001 Aug;108(2):198-204
11496234
Biochem Biophys Res Commun. 1995 May 25;210(3):1009-16
7539253
Toxicol Appl Pharmacol. 2008 Aug 1;230(3):269-75
18439639
Biochem Pharmacol. 1989 Jun 1;38(11):1709-15
2567594
J Clin Invest. 2003 Jun;111(12):1863-74
12813022
Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9260-4
11470919
Am J Respir Crit Care Med. 2001 Oct 1;164(7):1119-26
11673196
Am J Respir Crit Care Med. 2004 Jul 15;170(2):148-53
15070820
Eur Respir J. 1998 Jan;11(1):126-32
9543281
Br J Pharmacol. 1991 Jan;102(1):91-4
2043935
Br J Pharmacol. 1997 Jun;121(3):395-400
9179379
J Appl Physiol (1985). 2004 Jul;97(1):249-59
15020581
Gene. 2005 Jun 20;353(1):98-106
15922518
Physiol Rev. 2004 Jul;84(3):731-65
15269335
Respir Res. 2005 Mar 04;6:23
15748286
FASEB J. 1998 Aug;12(11):929-37
9707165
Br J Pharmacol. 2000 Aug;130(8):1793-8
10952667
Trends Pharmacol Sci. 2003 Feb;24(2):91-5
12559774
Arch Biochem Biophys. 1994 Jul;312(1):31-7
8031143
Am J Respir Crit Care Med. 2008 Oct 1;178(7):688-94
18617639
Clin Exp Allergy. 1998 Dec;28(12):1464-73
10024216
Am J Physiol. 1997 Sep;273(3 Pt 1):L656-62
9316502
Am J Respir Crit Care Med. 2008 Sep 15;178(6):565-73
18583571
Br J Pharmacol. 1996 Nov;119(6):1109-16
8937712
Exp Cell Res. 1987 May;170(1):153-9
3106074
Eur Respir J. 2009 Jul;34(1):191-9
19251784
Am J Physiol Lung Cell Mol Physiol. 2001 Jul;281(1):L258-67
11404269
Respir Res. 2006 Apr 05;7:58
16597326
Expert Opin Investig Drugs. 2005 Oct;14(10):1221-31
16185164
Eur J Pharmacol. 1991 Jun 6;198(2-3):219-21
1650703
Annu Rev Physiol. 1995;57:707-36
7539994
Biochem Biophys Res Commun. 1994 Jul 15;202(1):174-80
8037711
Am J Physiol. 1998 Jul;275(1):L96-102
9688940
Am J Respir Cell Mol Biol. 2005 Oct;33(4):394-401
15994432
Eur J Immunol. 1995 Apr;25(4):1101-4
7537672
Eur J Pharmacol. 1992 Oct 20;221(2-3):385-8
1426015
Thorax. 1999 Nov;54(11):1033-5
10525564
Naunyn Schmiedebergs Arch Pharmacol. 2000 Jun;361(6):621-8
10882037
Am J Respir Cell Mol Biol. 1999 Aug;21(2):155-62
10423396
Comp Biochem Physiol B Biochem Mol Biol. 1996 May;114(1):107-32
8759304
Br J Pharmacol. 2009 Jan;156(1):84-93
19133993
Curr Drug Targets. 2006 May;7(5):547-65
16719766
Br J Pharmacol. 2004 Aug;142(8):1293-9
15265801
Eur Respir J. 2008 Aug;32(2):487-502
18669789
Lancet. 1997 Nov 1;350(9087):1297-8
9357414
Biochem Biophys Res Commun. 1995 Jan 17;206(2):667-73
7530004
Am J Physiol Lung Cell Mol Physiol. 2006 Mar;290(3):L534-9
16257997
Toxicol Sci. 2005 Dec;88(2):420-33
16141432
Am J Respir Cell Mol Biol. 2007 Jun;36(6):645-53
17218616
Am J Respir Cell Mol Biol. 2002 Apr;26(4):447-52
11919081
Br J Pharmacol. 2001 Sep;134(2):434-40
11564663
Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7821-5
8755560
J Immunol. 1999 Jan 1;162(1):445-52
9886418
Clin Sci (Lond). 1995 Feb;88(2):135-9
7720336
Circulation. 2001 Feb 27;103(8):1121-7
11222476
Am J Respir Cell Mol Biol. 1998 Aug;19(2):308-15
9698604
Am J Respir Crit Care Med. 2004 Sep 1;170(5):477-84
15151919