title: Nitric oxide exerts protective effects against bleomycin-induced pulmonary fibrosis in mice.
abstract: BACKGROUND
  Increased expression of nitric oxide synthase (NOS) and an increase in plasma nitrite plus nitrate (NOx) have been reported in patients with pulmonary fibrosis, suggesting that nitric oxide (NO) plays an important role in its development. However, the roles of the entire NO and NOS system in the pathogenesis of pulmonary fibrosis still remain to be fully elucidated. The aim of the present study is to clarify the roles of NO and the NOS system in pulmonary fibrosis by using the mice lacking all three NOS isoforms.
  
  
  METHODS
  Wild-type, single NOS knockout and triple NOS knockout (n/i/eNOS-/-) mice were administered bleomycin (BLM) intraperitoneally at a dose of 8.0 mg/kg/day for 10 consecutive days. Two weeks after the end of the procedure, the fibrotic and inflammatory changes of the lung were evaluated. In addition, we evaluated the effects of long-term treatment with isosorbide dinitrate, a NO donor, on the n/i/eNOS-/- mice with BLM-induced pulmonary fibrosis.
  
  
  RESULTS
  The histopathological findings, collagen content and the total cell number in bronchoalveolar lavage fluid were the most severe/highest in the n/i/eNOS-/- mice. Long-term treatment with the supplemental NO donor in n/i/eNOS-/- mice significantly prevented the progression of the histopathological findings and the increase of the collagen content in the lungs.
  
  
  CONCLUSIONS
  These results provide the first direct evidence that a lack of all three NOS isoforms led to a deterioration of pulmonary fibrosis in a BLM-treated murine model. We speculate that the entire endogenous NO and NOS system plays an important protective role in the pathogenesis of pulmonary fibrosis.
authors.forename: Shingo
authors.initials: S
authors.lastname: Noguchi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yatera
authors.forename: Ke-Yong
authors.initials: KY
authors.lastname: Wang
authors.forename: Keishi
authors.initials: K
authors.lastname: Oda
authors.forename: Kentarou
authors.initials: K
authors.lastname: Akata
authors.forename: Kei
authors.initials: K
authors.lastname: Yamasaki
authors.forename: Toshinori
authors.initials: T
authors.lastname: Kawanami
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishimoto
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Toyohira
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yanagihara
authors.forename: Masato
authors.initials: M
authors.lastname: Tsutsui
authors.affiliation: Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishiku, Kitakyusyu, 807-8555, Fukuoka, Japan. hmukae@med.uoeh-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mukae
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000627:therapeutic use*; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*
chemical_list: D001761:Bleomycin; D009569:Nitric Oxide
references.citation: Cardiovasc Res. 2010 Sep 1;87(4):675-82
references.pmid: 20304785
references.citation: Am J Respir Cell Mol Biol. 1996 Mar;14(3):272-8
references.pmid: 8845178
references.citation: Mol Cell Biol. 2013 Sep;33(17):3482-93
references.pmid: 23816882
references.citation: J Pharmacol Sci. 2006 Oct;102(2):147-54
references.pmid: 17031076
references.citation: Am J Physiol Lung Cell Mol Physiol. 2007 Jul;293(1):L212-21
references.pmid: 17496059
references.citation: J Biol Chem. 1996 Jul 26;271(30):17779-84
references.pmid: 8663511
references.citation: Nitric Oxide. 2004 Sep;11(2):156-65
references.pmid: 15491848
references.citation: Laryngoscope. 2014 Jan;124(1):E1-7
references.pmid: 23686840
references.citation: J Immunol. 2012 Sep 1;189(5):2234-45
references.pmid: 22844117
references.citation: Circ J. 2010 Nov;74(12):2681-92
references.pmid: 20966596
references.citation: Am J Respir Cell Mol Biol. 2003 Sep;29(3 Pt 1):375-80
references.pmid: 12676806
references.citation: Nitric Oxide. 2011 Aug 1;25(2):138-44
references.pmid: 21440655
references.citation: J Pathol. 2013 Jan;229(2):242-9
references.pmid: 23097221
references.citation: Intensive Care Med. 2004 Mar;30(3):489-95
references.pmid: 14767587
references.citation: Am J Respir Crit Care Med. 1997 May;155(5):1763-9
references.pmid: 9154889
references.citation: Kidney Int. 2002 Aug;62(2):401-11
references.pmid: 12110001
references.citation: Respir Res. 2010 Mar 20;11:34
references.pmid: 20302663
references.citation: J Pathol. 2011 Jan;223(1):37-45
references.pmid: 20845411
references.citation: Hypertension. 2007 Sep;50(3):519-24
references.pmid: 17646574
references.citation: Am J Respir Crit Care Med. 2005 Aug 15;172(4):417-22
references.pmid: 15894605
references.citation: Arterioscler Thromb Vasc Biol. 2005 Sep;25(9):2005-11
references.pmid: 16020745
references.citation: Am J Physiol Lung Cell Mol Physiol. 2004 May;286(5):L1038-44
references.pmid: 15064241
references.citation: Am J Respir Cell Mol Biol. 1997 Sep;17(3):279-83
references.pmid: 9308913
references.citation: Am J Respir Cell Mol Biol. 1999 Jul;21(1):128-36
references.pmid: 10385601
references.citation: Thorax. 2013 Oct;68(10):938-48
references.pmid: 23739137
references.citation: Am J Pathol. 1998 Dec;153(6):1861-72
references.pmid: 9846976
references.citation: Biochem Soc Trans. 2009 Aug;37(Pt 4):886-91
references.pmid: 19614613
references.citation: Am J Respir Cell Mol Biol. 2013 Oct;49(4):536-43
references.pmid: 23642017
references.citation: Nitric Oxide. 2011 Oct 30;25(3):350-9
references.pmid: 21767657
references.citation: Free Radic Biol Med. 2007 Mar 1;42(5):599-607
references.pmid: 17291983
references.citation: Shock. 1997 Apr;7(4):235-46
references.pmid: 9110408
references.citation: Am J Pathol. 2013 Feb;182(2):597-609
references.pmid: 23178077
references.citation: Respirology. 2006 Sep;11(5):546-56
references.pmid: 16916326
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10616-21
references.pmid: 16024729
references.citation: Eur J Pharmacol. 2008 Aug 20;590(1-3):400-8
references.pmid: 18598692
references.citation: Chest. 2002 Dec;122(6 Suppl):334S-339S
references.pmid: 12475811
references.citation: Am J Respir Crit Care Med. 2007 Jul 1;176(1):78-89
references.pmid: 17431224
references.citation: Physiol Rev. 2004 Jul;84(3):731-65
references.pmid: 15269335
references.citation: J Exp Med. 2000 Sep 18;192(6):857-69
references.pmid: 10993916
references.citation: Am J Clin Pathol. 2002 Jan;117(1):132-42
references.pmid: 11789718
references.citation: Respir Res. 2005 Jun 14;6:58
references.pmid: 15955252
references.citation: J Immunol. 2000 Mar 1;164(5):2745-51
references.pmid: 10679116
references.citation: N Engl J Med. 1999 Oct 21;341(17):1264-9
references.pmid: 10528036
references.citation: Circulation. 2002 Mar 5;105(9):1110-5
references.pmid: 11877364