Role of LTB₄ in the pathogenesis of elastase-induced murine pulmonary emphysema.
Exaggerated levels of the leukotriene B₄ (LTB₄) frequently coexist at sites of inflammation and tissue remodeling. Therefore, we hypothesize that the LTB₄ pathway plays an important role in the pathogenesis of neutrophilic inflammation that contributes to pulmonary emphysema. In this study, significant levels of LTB₄ were detected in human lung tissues with emphysema compared with lungs without emphysema (9,497 ± 2,839 vs. 4,142 ± 1,173 pg/ml, n = 9 vs. 10, P = 0.04). To further determine the biological role of LTB₄ in the pathogenesis of emphysema, we compared the lungs of wild-type (WT) and LTA₄ hydrolase-/- mice (LTB₄ deficient, LTA₄H-/-) exposed to intranasal elastase or vehicle control. We found that intranasal elastase induced accumulation of LTB₄ in the lungs and caused progressively worsening emphysema between 14 and 28 days after elastase exposure in WT mice but not in LTA₄H-/- mice. Premortem physiology documented increased lung compliance in elastase-exposed WT mice compared with elastase-exposed LTA₄H-/- mice as measured by Flexivent (0.058 ± 0.005 vs. 0.041 ± 0.002 ml/cmH₂O pressure). Postmortem morphometry documented increased total lung volume and alveolar sizes in elastase-exposed WT mice compared with elastase-exposed LTA₄H-/- mice as measured by volume displacement and alveolar chord length assessment. Furthermore, elastase-exposed LTA₄H-/- mice were found to have significantly delayed influx of the CD45(high)CD11b(high)Ly6G(high) leukocytes compatible with neutrophils compared with elastase-exposed WT mice. Mechanistic insights to these phenotypes were provided by demonstrating protection from elastase-induced murine emphysema with neutrophil depletion in the elastase-exposed WT mice and by demonstrating time-dependent modulation of cysteinyl leukotriene biosynthesis in the elastase-exposed LTA₄H-/- mice compared with elastase-exposed WT mice. Together, these findings demonstrated that LTB₄ played an important role in promoting the pathogenesis of pulmonary emphysema associated with neutrophilic pulmonary inflammation.
Shim
Y Michael
YM
Dept. of Medicine, Univ. of Virginia, Charlottesville, 22908-0546, USA. yss6n@virginia.edu
Paige
Mikell
M
Hanna
Halim
H
Kim
Su H
SH
Burdick
Marie D
MD
Strieter
Robert M
RM
D000368:Aged; D000818:Animals; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007975:Leukotriene B4 / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism; D010196:Pancreatic Elastase / Q000494:pharmacology*; D011656:Pulmonary Emphysema / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*
D007975:Leukotriene B4; D004851:Epoxide Hydrolases; D010196:Pancreatic Elastase; C043134:leukotriene A4 hydrolase
Arterioscler Thromb Vasc Biol. 2003 Oct 1;23(10):1761-7
12947016
Respir Physiol Neurobiol. 2009 Feb 28;165(2-3):229-36
19136080
J Clin Invest. 2000 Nov;106(9):1081-93
11067861
Exp Lung Res. 2004 Jul-Aug;30(5):383-404
15204830
N Engl J Med. 2004 Jun 24;350(26):2645-53
15215480
Nature. 1980 Jul 17;286(5770):264-5
6250050
Chest. 2005 May;127(5):1553-9
15888827
Am J Physiol Lung Cell Mol Physiol. 2007 Sep;293(3):L779-89
17586692
Ann Allergy Asthma Immunol. 1998 Jul;81(1):17-26; quiz 26-9
9690569
Nature. 1980 Dec 4;288(5790):484-6
6108512
Prostaglandins Leukot Essent Fatty Acids. 2009 Jan;80(1):1-7
19081714
Inflamm Res. 1997 Oct;46(10):420-2
9372316
Thorax. 2002 Aug;57(8):709-14
12149532
PLoS Med. 2004 Oct;1(1):e8
15526056
J Immunol. 2006 Feb 15;176(4):2538-45
16456015
J Clin Invest. 1991 Sep;88(3):891-7
1653278
J Appl Physiol (1985). 2007 Jan;102(1):459-67
16973815
Inflammation. 1993 Jun;17(3):353-60
8392493
Biol Chem. 2006 Jul;387(7):903-9
16913840
Acta Physiol Scand. 1980 Dec;110(4):449-51
6263048
Lung. 2007 Jul-Aug;185(4):191-201
17562108
J Appl Physiol (1985). 2001 Dec;91(6):2730-4
11717240
Int J Cancer. 2004 Dec 20;112(6):934-42
15386349
J Leukoc Biol. 2008 Jan;83(1):64-70
17884993
Am J Respir Crit Care Med. 1999 Dec;160(6):1968-75
10588615
Respir Care. 2001 Aug;46(8):798-825
11463370
J Immunol. 1999 Dec 15;163(12):6810-9
10586081
Arch Bronconeumol. 2006 Jul;42(7):332-7
16945263
Chest. 2002 Sep;122(3):1058-60
12226052
J Immunol. 2002 Mar 15;168(6):2953-62
11884467
J Clin Invest. 1989 Nov;84(5):1609-19
2553777
Chest. 2003 Apr;123(4):1240-7
12684317
FASEB J. 2001 Sep;15(11):2007-9
11511519
FEBS Lett. 2004 Jan 2;556(1-3):249-52
14706858
J Immunol. 1996 Dec 15;157(12):5221-4
8955165
Curr Gastroenterol Rep. 2006 Feb;8(1):14-20
16510030
Biochem Biophys Res Commun. 1998 Oct 9;251(1):307-12
9790952
Biomed Chromatogr. 2009 Aug;23(8):817-21
19353686
Am J Respir Crit Care Med. 1999 May;159(5 Pt 2):S41-63
10228145
Lab Invest. 1963 Feb;12:131-55
13999512
J Exp Med. 1981 Feb 1;153(2):482-7
6264017
Dis Model Mech. 2009 May-Jun;2(5-6):275-82
19380307
Am J Respir Crit Care Med. 1994 Dec;150(6 Pt 1):1646-52
7952628
J Immunol. 2006 Aug 1;177(3):1918-24
16849505
J Allergy Clin Immunol. 1989 Jul;84(1):19-26
2546985
J Allergy Clin Immunol. 2003 May;111(5):1032-40
12743568
J Clin Invest. 1999 Mar;103(6):779-88
10079098
J Clin Invest. 1996 Feb 1;97(3):806-13
8609238
Am Rev Respir Dis. 1990 Jul;142(1):112-9
2195930
Toxicology. 2009 May 2;259(1-2):84-9
19428947
Blood. 1981 Sep;58(3):658-61
6266432