title: Nitric oxide deficiency in pulmonary hypertension: Pathobiology and implications for therapy.
abstract: Nitric oxide (NO) is a diffusible gas with diverse roles in human physiology and disease. Significant progress in the understanding of its biological effects has taken place in recent years. This has led to a better understanding of the pathobiology of pulmonary hypertension (PH) and the development of new therapies. This article provides an overview of the NO physiology and its role in the pathobiology of lung diseases, particularly PH. We also discuss current and emerging specific treatments that target NO signaling pathways in PH.
authors: Department of Pulmonary, Allergy and Critical Care Medicine, Respiratory Institute, Cleveland, Ohio, USA.
authors: Adriano R
authors: AR
authors: Tonelli
authors: Sarah
authors: S
authors: Haserodt
authors: Metin
authors: M
authors: Aytekin
authors: Raed A
authors: RA
authors: Dweik
keywords: nitric oxide; physiopathology and therapeutics; pulmonary hypertension
references: Am J Respir Crit Care Med. 1998 Sep;158(3):917-23
references: 9731026
references: J Clin Invest. 1996 Jul 15;98(2):317-24
references: 8755640
references: Am J Respir Crit Care Med. 2007 Dec 1;176(11):1154-60
references: 17872491
references: Circ Res. 1992 Nov;71(5):1268-76
references: 1394884
references: Methods Enzymol. 1996;268:281-93
references: 8782594
references: Am J Respir Cell Mol Biol. 1993 Oct;9(4):371-7
references: 7691109
references: FASEB J. 1992 Sep;6(12):3051-64
references: 1381691
references: Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7809-13
references: 7544004
references: Atheroscler Suppl. 2003 Dec;4(4):33-40
references: 14664901
references: Cleve Clin J Med. 2001 Jun;68(6):486, 488, 490, 493
references: 11405609
references: Circulation. 2003 Sep 23;108(12):1493-8
references: 12952847
references: J Appl Physiol (1985). 2003 Jul;95(1):436-40; discussion 435
references: 12576414
references: J Clin Invest. 1989 May;83(5):1774-7
references: 2540223
references: J Biol Chem. 1989 Jun 15;264(17):10205-9
references: 2722865
references: Am J Physiol Lung Cell Mol Physiol. 2008 Dec;295(6):L976-8
references: 18931050
references: J Appl Physiol (1985). 2007 Jan;102(1):417-25
references: 16888048
references: Thorax. 1993 Oct;48(10):1034-43
references: 7903007
references: Circ Res. 1995 Feb;76(2):305-9
references: 7834842
references: J Clin Invest. 2005 May;115(5):1232-40
references: 15841216
references: Nat Rev Drug Discov. 2008 Feb;7(2):156-67
references: 18167491
references: Am J Physiol Heart Circ Physiol. 2010 Feb;298(2):H331-9
references: 19940079
references: Free Radic Biol Med. 2006 Jan 15;40(2):295-302
references: 16413411
references: Lancet. 1998 May 16;351(9114):1491-2
references: 9605813
references: Methods Mol Biol. 2010;610:309-21
references: 20013186
references: J Biol Chem. 1997 Jan 10;272(2):1276-82
references: 8995432
references: Lancet. 1995 Jul 1;346(8966):51-2
references: 7603160
references: Am J Physiol. 1994 Apr;266(4 Pt 1):L455-60
references: 7802762
references: J Clin Invest. 1994 Nov;94(5):2036-44
references: 7525653
references: FASEB J. 2004 Nov;18(14):1746-8
references: 15364894
references: Proc Soc Exp Biol Med. 1996 Jan;211(1):1-6
references: 8594612
references: Biochim Biophys Acta. 1999 May 5;1411(2-3):217-30
references: 10320659
references: J Clin Invest. 1993 Aug;92(2):736-42
references: 8349813
references: Circulation. 2005 Jun 14;111(23):3105-11
references: 15939821
references: N Engl J Med. 2005 Jul 7;353(1):13-22
references: 16000352
references: Circ Res. 1996 Feb;78(2):225-30
references: 8575065
references: Am J Physiol. 1999 Sep;277(3):L472-8
references: 10484454
references: Lung. 2001;179(4):233-43
references: 11891614
references: Clin Sci (Lond). 1999 Jul;97(1):99-102
references: 10369800
references: J Pathol. 1998 Jul;185(3):313-8
references: 9771486
references: Chest. 1996 Jun;109(6):1545-9
references: 8769509
references: Am J Physiol Lung Cell Mol Physiol. 2007 Jan;292(1):L15-7
references: 16980373
references: Eur J Pharmacol. 1990 Dec 15;189(6):347-53
references: 1963600
references: Am J Respir Crit Care Med. 1994 Feb;149(2 Pt 1):538-51
references: 7508323
references: Eur Heart J. 2004 Sep;25(18):1651-6
references: 15351165
references: Am J Physiol Lung Cell Mol Physiol. 2005 Mar;288(3):L450-9
references: 15591412
references: Arterioscler Thromb Vasc Biol. 2005 Jul;25(7):1414-8
references: 15860741
references: Thorax. 2003 Apr;58(4):289-93
references: 12668787
references: N Engl J Med. 1995 Dec 14;333(24):1642-4
references: 7477212
references: Am J Respir Crit Care Med. 2005 Apr 15;171(8):912-30
references: 15817806
references: Surgery. 1996 Jan;119(1):61-6
references: 8560388
references: Annu Rev Physiol. 2002;64:749-74
references: 11826287
references: Cell. 1992 Oct 2;71(1):1-4
references: 1356629
references: Am Rev Respir Dis. 1991 Mar;143(3):522-7
references: 2001061
references: Am J Physiol. 1990 Dec;259(6 Pt 2):H1921-7
references: 2260716
references: Circulation. 2002 Apr 9;105(14):1672-8
references: 11940546
references: Arterioscler Thromb Vasc Biol. 2006 Apr;26(4):697-705
references: 16424350
references: Cell. 1994 Sep 23;78(6):915-8
references: 7522969
references: Am J Physiol Lung Cell Mol Physiol. 2007 Jan;292(1):L18-24
references: 16891395
references: Annu Rev Physiol. 2005;67:99-145
references: 15709954
references: Am J Physiol. 1997 May;272(5 Pt 1):L903-7
references: 9176255
references: Circulation. 2007 Jul 17;116(3):238-48
references: 17606845
references: Circulation. 2002 May 21;105(20):2398-403
references: 12021227
references: Nat Med. 2004 Oct;10(10):1122-7
references: 15361865
references: Biochim Biophys Acta. 1993 Aug 18;1178(2):153-75
references: 7688574
references: Biochem Biophys Res Commun. 1992 Oct 15;188(1):409-15
references: 1384487
references: Expert Rev Respir Med. 2011 Apr;5(2):163-71
references: 21510727
references: J Clin Invest. 1998 Feb 1;101(3):660-6
references: 9449700
references: N Engl J Med. 1995 Jul 27;333(4):214-21
references: 7540722
references: J Card Fail. 2011 Apr;17(4):265-71
references: 21440863
references: Mol Immunol. 1995 Sep;32(13):965-73
references: 7477002
references: Am J Respir Crit Care Med. 1994 Aug;150(2):337-41
references: 8049812
references: J Biol Chem. 1992 Dec 25;267(36):25722-9
references: 1281471
references: Am J Physiol. 1994 Nov;267(5 Pt 1):C1405-13
references: 7977701
references: Proc Natl Acad Sci U S A. 1987 Dec;84(24):9265-9
references: 2827174
references: J Biol Chem. 1994 May 13;269(19):13725-8
references: 7514592
references: Circulation. 2012 Jan 17;125(2):324-34
references: 22128226
references: Eur Heart J. 1993 Nov;14 Suppl I:16-21
references: 7507437
references: Herz. 1992 Oct;17(5):291-9
references: 1335437
references: J Thorac Cardiovasc Surg. 2006 Jul;132(1):58-65
references: 16798303
references: Respir Med. 2010 Apr;104(4):481-96
references: 20004088
references: FASEB J. 2005 Jul;19(9):1175-7
references: 15827267
references: Am J Physiol Lung Cell Mol Physiol. 2009 Jun;296(6):L1042-50
references: 19346433
references: J Am Coll Cardiol. 2007 Apr 10;49(14):1566-71
references: 17418297
references: J Exp Biol. 2003 Jun;206(Pt 12):2083-7
references: 12756290
references: Hypertension. 1996 Mar;27(3 Pt 2):823-6
references: 8613247
references: Biochem Biophys Res Commun. 1994 Sep 15;203(2):1160-7
references: 7916569
references: Circulation. 2009 Jan 20;119(2):298-305
references: 19118254
references: Circulation. 1991 Jun;83(6):2038-47
references: 2040056
references: Am J Respir Cell Mol Biol. 2001 Apr;24(4):414-8
references: 11306434
references: Am J Respir Crit Care Med. 1997 Mar;155(3):869-74
references: 9117019
references: Expert Opin Investig Drugs. 2011 Apr;20(4):567-76
references: 21391889
references: Cardiovasc Res. 1996 Jan;31(1):55-62
references: 8849589
references: Eur Respir J. 2008 Oct;32(4):881-91
references: 18550612
references: Circulation. 1997 Jul 15;96(2):689-97
references: 9244244
references: Free Radic Biol Med. 2004 Oct 1;37(7):1010-7
references: 15336317
references: J Crit Care. 2004 Mar;19(1):48-53
references: 15101006
references: J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S3-S9
references: 19555856
references: Am Rev Respir Dis. 1989 Dec;140(6):1623-30
references: 2690706
references: N Engl J Med. 2006 Jul 27;355(4):343-53
references: 16870913
references: Biol Neonate. 2004;85(3):195-202
references: 14707432
references: N Engl J Med. 2006 Jul 27;355(4):404-6
references: 16870920
references: J Heart Lung Transplant. 2008 Dec;27(12):1326-32
references: 19059113
references: Proc Natl Acad Sci U S A. 1990 Nov;87(21):8612-6
references: 2236071
references: Eur Respir J. 2010 Oct;36(4):792-9
references: 20530034
references: Nat Rev Mol Cell Biol. 2005 Feb;6(2):150-66
references: 15688001
references: Blood. 2008 Oct 1;112(7):2636-47
references: 18596228
references: Am J Respir Crit Care Med. 2005 Jul 1;172(1):105-13
references: 15817798
references: Lancet. 1991 Nov 9;338(8776):1173-4
references: 1682593
references: Pediatr Res. 2005 Sep;58(3):531-6
references: 16148069
references: Ann Intern Med. 1987 Aug;107(2):216-23
references: 3605900
references: Lancet. 2002 Sep 21;360(9337):886-7
references: 12354465
references: FASEB J. 1993 Feb 1;7(2):328-38
references: 7680013
references: Chest. 2010 Sep;138(3):682-92
references: 20822990
references: Am J Physiol Lung Cell Mol Physiol. 2008 Dec;295(6):L979-87
references: 18790993
references: Biochem J. 2001 Aug 1;357(Pt 3):593-615
references: 11463332
references: Adv Enzymol Relat Areas Mol Biol. 1992;65:287-346
references: 1373932
references: Am J Respir Crit Care Med. 1996 Nov;154(5):1370-4
references: 8912750
references: Physiol Rev. 2004 Jul;84(3):731-65
references: 15269335
references: Nature. 1987 Jun 11-17;327(6122):524-6
references: 3495737
references: Circ Res. 2005 Mar 4;96(4):442-50
references: 15692087
references: Cell. 1998 Dec 23;95(7):939-50
references: 9875848
references: Mol Pharmacol. 1995 Dec;48(6):1068-77
references: 8848007
references: Exp Lung Res. 2011 Feb;37(1):26-34
references: 21077779
references: Lancet. 2010 Jul 31;376(9738):346-54
references: 20655106
references: Pharmacol Rev. 1991 Jun;43(2):109-42
references: 1852778
references: N Engl J Med. 1992 Jul 9;327(2):76-81
references: 1603139
references: Nat Med. 1995 Apr;1(4):370-3
references: 7585069
references: Circulation. 2009 Jun 9;119(22):2894-903
references: 19470885
references: Annu Rev Pharmacol Toxicol. 2006;46:235-76
references: 16402905
references: J Surg Res. 1995 Sep;59(3):337-43
references: 7643591
references: Nat Med. 1995 Aug;1(8):804-9
references: 7585184
references: Am J Respir Crit Care Med. 2005 Aug 15;172(4):453-9
references: 15901605
references: J Med Genet. 2000 Oct;37(10):741-5
references: 11015450
references: Clin Exp Allergy. 2005 Sep;35(9):1175-9
references: 16164444
references: Circ Res. 2003 Aug 22;93(4):280-91
references: 12933699
references: Am J Respir Crit Care Med. 2001 Sep 1;164(5):834-9
references: 11549542
references: Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3030-4
references: 1557408
references: Circ Res. 1997 Jul;81(1):34-41
references: 9201025
references: Am J Respir Crit Care Med. 2003 Jul 1;168(1):63-9
references: 12626350
references: Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7583-7
references: 7519783
references: Am J Physiol Endocrinol Metab. 2010 Jun;298(6):E1131-9
references: 20215577
references: N Engl J Med. 1993 Dec 30;329(27):2002-12
references: 7504210
references: Free Radic Biol Med. 2001 Dec 1;31(11):1360-7
references: 11728807
references: N Engl J Med. 2005 Nov 17;353(20):2148-57
references: 16291984
references: Nat Rev Cardiol. 2011 Jun 21;8(8):443-55
references: 21691314
references: Nitric Oxide. 2001 Apr;5(2):187-97
references: 11292368
references: Am J Respir Crit Care Med. 1999 Jun;159(6):1925-32
references: 10351941
references: J Biol Chem. 1994 Apr 1;269(13):9405-8
references: 7511585
references: Am J Respir Crit Care Med. 2005 May 15;171(10):1077-82
references: 15709050
references: Circulation. 2006 Jul 4;114(1 Suppl):I181-5
references: 16820570
references: Circulation. 2000 Dec 5;102(23):2880-5
references: 11104748
references: J Biol Chem. 2011 Sep 23;286(38):33134-40
references: 21808054
references: Am J Respir Crit Care Med. 2000 May;161(5):1443-9
references: 10806137
references: J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S78-S84
references: 19555861
references: Adv Pharmacol. 1994;26:19-33
references: 7913616
references: J Clin Invest. 1995 Feb;95(2):669-76
references: 7532188
references: Zhongguo Yao Li Xue Bao. 1997 Nov;18(6):550-2
references: 10322920
references: Cell. 1994 Sep 23;78(6):919-25
references: 7923361
references: Arterioscler Thromb Vasc Biol. 2007 Sep;27(9):1877-85
references: 17541026
references: Am J Respir Crit Care Med. 2001 Mar;163(4):887-91
references: 11282761
references: Br J Anaesth. 1967 May;39(5):388-92
references: 6025380
references: Thorax. 2005 Apr;60(4):265-7
references: 15790976
references: J Clin Invest. 1993 Apr;91(4):1367-73
references: 7682570
references: Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2622-7
references: 11226289
references: N Engl J Med. 2006 Jul 27;355(4):354-64
references: 16870914
references: Am J Physiol Lung Cell Mol Physiol. 2009 Sep;297(3):L506-11
references: 19617312