Late Intervention with a Myeloperoxidase Inhibitor Stops Progression of Experimental Chronic Obstructive Pulmonary Disease

被引:96
作者
Churg, Andrew [1 ,2 ]
Marshall, Caroline V. [4 ]
Sin, Don D. [3 ]
Bolton, Sarah [4 ]
Zhou, Steven [1 ,2 ]
Thain, Katherine [3 ]
Cadogan, Elaine B. [4 ]
Maltby, Justine [4 ]
Soars, Matthew G. [4 ]
Mallinder, Philip R. [4 ]
Wright, Joanne L. [1 ,2 ]
机构
[1] Univ British Columbia, Dept Pathol, Vancouver, BC V6T 2B5, Canada
[2] Univ British Columbia, UBC James Hogg Res Ctr, Inst Heart & Lung Hlth, Vancouver, BC V6T 2B5, Canada
[3] Univ British Columbia, Div Resp Med, Dept Med, Vancouver, BC V6T 2B5, Canada
[4] AstraZeneca Res & Dev, Charnwood, Loughborough, Leics, England
基金
加拿大健康研究院;
关键词
cigarette smoke; chronic obstructive pulmonary disease; emphysema; small airway remodeling; myeloperoxidase; SMOKE-INDUCED EMPHYSEMA; CIGARETTE-SMOKE; LUNG INFLAMMATION; GUINEA-PIG; LIPID-PEROXIDATION; PREVENTS EMPHYSEMA; NADPH OXIDASE; MICE; EXPRESSION; ELASTASE;
D O I
10.1164/rccm.201103-0468OC
中图分类号
R4 [临床医学];
学科分类号
100218 [急诊医学];
摘要
Rationale: Inflammation and oxidative stress are linked to the deleterious effects of cigarette smoke in producing chronic obstructive pulmonary disease (COPD). Myeloperoxidase (MPO), a neutrophil and macrophage product, is important in bacterial killing, but also drives inflammatory reactions and tissue oxidation. Objectives: To determine the role of MPO in COPD. Methods: We treated guinea pigs with a 2-thioxanthine MPO inhibitor, AZ1, in a 6-month cigarette smoke exposure model, with one group receiving compound from Smoking Day 1 and another group treated after 3 months of smoke exposure. Results: At 6 months both treatments abolished smoke-induced increases in lavage inflammatory cells, largely ameliorated physiological changes, and prevented or stopped progression of morphologic emphysema and small airway remodeling. Cigarette smoke caused a marked increase in immunohistochemical staining for the myeloperoxidase-generated protein oxidation marker dityrosine, and this effect was considerably decreased with both treatment arms. Serum 8-isoprostane, another marker of oxidative stress, showed similar trends. Both treatments also prevented muscularization of the small intrapulmonary arteries, but only partially ameliorated smoke-induced pulmonary hypertension. Acutely, AZ1 prevented smoke-induced increases in expression of cytokine mediators and nuclear factor-kappa B binding. Conclusions: We conclude that an MPO inhibitor is able to stop progression of emphysema and small airway remodeling and to partially protect against pulmonary hypertension, even when treatment starts relatively late in the course of long-term smoke exposure, suggesting that inhibition of MPO may be a novel and useful therapeutic treatment for COPD. Protection appears to relate to inhibition of oxidative damage and down-regulation of the smoke-induced inflammatory response.
引用
收藏
页码:34 / 43
页数:10
相关论文
共 47 条
[1]
The myeloperoxidase system of human phagocytes generates Nε-(carboxymethyl)lysine on proteins:: a mechanism for producing advances glycation end products at sites of inflammation [J].
Anderson, MM ;
Requena, JR ;
Crowley, JR ;
Thorpe, SR ;
Heinecke, JW .
JOURNAL OF CLINICAL INVESTIGATION, 1999, 104 (01) :103-113
[3]
BRIDGES RB, 1985, EUR J RESPIR DIS, V67, P84
[4]
Cantin Andre M, 2010, Proc Am Thorac Soc, V7, P368, DOI 10.1513/pats.201001-014AW
[5]
FREE-RADICAL CHEMISTRY OF CIGARETTE-SMOKE AND ITS TOXICOLOGICAL IMPLICATIONS [J].
CHURCH, DF ;
PRYOR, WA .
ENVIRONMENTAL HEALTH PERSPECTIVES, 1985, 64 :111-126
[6]
Tumor necrosis factor-α drives 70% of cigarette smoke-induced emphysema in the mouse [J].
Churg, A ;
Wang, RD ;
Tai, H ;
Wang, XS ;
Xie, CS ;
Wright, JL .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2004, 170 (05) :492-498
[7]
CHURG A, AM J RESP C IN PRESS
[8]
CHURG A, EUR RESP J IN PRESS
[9]
Mechanisms of cigarette smoke-induced COPD: insights from animal models [J].
Churg, Andrew ;
Cosio, Manuel ;
Wright, Joanne L. .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2008, 294 (04) :L612-L631
[10]
Treatment of COPD: the sooner the better? [J].
Decramer, Marc ;
Cooper, Christopher B. .
THORAX, 2010, 65 (09) :837-841