Nitric oxide synthase 3 contributes to ventilator-induced lung injury.
Nitric oxide synthase (NOS) depletion or inhibition reduces ventilator-induced lung injury (VILI), but the responsible mechanisms remain incompletely defined. The aim of this study was to elucidate the role of endothelial NOS, NOS3, in the pathogenesis of VILI in an in vivo mouse model. Wild-type and NOS3-deficient mice were ventilated with high-tidal volume (HV(T); 40 ml/kg) for 4 h, with and without adding NO to the inhaled gas. Additional wild-type mice were pretreated with tetrahydrobiopterin and ascorbic acid, agents that can prevent NOS-generated superoxide production. Arterial blood gas tensions, histology, and lung mechanics were evaluated after 4 h of HV(T) ventilation. The concentration of protein, IgM, cytokines, malondialdehyde, and 8-isoprostane were measured in bronchoalveolar lavage fluid (BALF). Myeloperoxidase activity, total and oxidized glutathione levels, and NOS-derived superoxide production were measured in lung tissue homogenates. HV(T) ventilation induced VILI in wild-type mice, as reflected by decreased lung compliance, increased concentrations of protein and cytokines in BALF, and oxidative stress. All indices of VILI were ameliorated in NOS3-deficient mice. Augmenting pulmonary NO levels by breathing NO during mechanical ventilation did not increase lung injury in NOS3-deficient mice. HV(T) ventilation increased NOS-inhibitable superoxide production in lung extracts from wild-type mice but not in those from NOS3-deficient mice. Administration of tetrahydrobiopterin and ascorbic acid ameliorated VILI in wild-type mice. Our results indicate that NOS3 contributes to ventilator-induced lung injury via increased production of superoxide.
Vaporidi
Katerina
K
Anesthesia Center for Critical Care Research, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston Massachusetts, USA.
Francis
Roland C
RC
Bloch
Kenneth D
KD
Zapol
Warren M
WM
D000818:Animals; D001205:Ascorbic Acid / Q000627:therapeutic use; D001708:Biopterins / Q000031:analogs & derivatives / Q000627:therapeutic use; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007075:Immunoglobulin M / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D013481:Superoxides / Q000378:metabolism; D055397:Ventilator-Induced Lung Injury / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control
D016207:Cytokines; D007075:Immunoglobulin M; D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C003402:sapropterin; D001205:Ascorbic Acid
J Appl Physiol (1985). 2003 Oct;95(4):1385-93
12807894
J Biol Chem. 2003 Jun 20;278(25):22546-54
12692136
Cardiovasc Res. 2005 Mar 1;65(4):768-9
15721855
Circulation. 2001 Mar 6;103(9):1282-8
11238274
Am J Physiol Lung Cell Mol Physiol. 2006 Jun;290(6):L1078-86
16399791
J Immunol. 2005 Sep 1;175(5):3369-76
16116230
Crit Care Med. 2002 Apr;30(4):868-73
11940761
Am J Respir Crit Care Med. 2002 Dec 15;166(12 Pt 2):S4-8
12471082
Biochem Biophys Res Commun. 2002 Aug 30;296(4):847-56
12200125
Microvasc Res. 2009 Jan;77(1):26-34
19041330
Eur Respir J. 2007 Dec;30(6):1216-26
18055706
J Clin Invest. 1999 Nov;104(10):1421-9
10562304
Antioxid Redox Signal. 2007 Nov;9(11):2003-12
17822361
Am J Respir Crit Care Med. 2008 Sep 15;178(6):605-17
18658108
Biochem J. 1984 Aug 15;222(1):1-15
6383353
J Clin Invest. 1986 Dec;78(6):1513-22
2431002
Am J Respir Crit Care Med. 2005 Aug 15;172(4):470-9
15937288
Hypertension. 1994 Jun;23(6 Pt 2):1121-31
7515853
Anesthesiology. 1999 Dec;91(6):1744-53
10598618
Circulation. 2006 Sep 12;114(11):1193-201
16940192
J Appl Physiol (1985). 1996 Mar;80(3):782-8
8964737
Antioxid Redox Signal. 2003 Dec;5(6):723-30
14588145
Anesthesiology. 2002 Oct;97(4):887-95
12357155
Am J Physiol Lung Cell Mol Physiol. 2003 May;284(5):L791-8
12562562
Acta Pharmacol Sin. 2010 Feb;31(2):175-83
20139900
Circulation. 2006 Apr 4;113(13):1708-14
16585403
Am J Physiol Lung Cell Mol Physiol. 2007 Nov;293(5):L1300-5
17720871
J Biol Chem. 1993 Oct 5;268(28):21120-9
7691806
Am J Physiol Lung Cell Mol Physiol. 2006 Jul;291(1):L119-27
16443642
J Appl Physiol (1985). 2002 Feb;92(2):795-801
11796694
Circulation. 2008 May 20;117(20):2626-36
18474817
Antioxid Redox Signal. 2009 Jul;11(7):1651-67
19186986
Arterioscler Thromb Vasc Biol. 2006 Nov;26(11):2439-44
16946131
Mamm Genome. 2002 Aug;13(8):429-37
12226708
Am J Respir Crit Care Med. 1999 May;159(5 Pt 1):1469-76
10228113
Biochim Biophys Acta. 2003 Sep 1;1639(1):17-26
12943964
Am J Physiol Lung Cell Mol Physiol. 2008 Dec;295(6):L1056-65
18849438
Nature. 2003 Apr 3;422(6931):531-4
12673252
Eur J Pharmacol. 2006 May 24;538(1-3):108-14
16647052
J Clin Invest. 2003 Apr;111(8):1201-9
12697739
Crit Care. 2003 Jun;7(3):233-41
12793874
Am J Physiol Lung Cell Mol Physiol. 2006 Sep;291(3):L345-53
16632522