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Updated: May 28, 2026
Generation of a Chronic Obstructive Pulmonary Disease Model in Mice by Repeated Ozone Exposure
Published on: August 25, 2017
Late intervention with a myeloperoxidase inhibitor stops progression of experimental chronic obstructive pulmonary
Andrew Churg1, Caroline V Marshall, Don D Sin
1Department of Pathology and UBC James Hogg Research Centre, Institute for Heart and Lung Health, University of British Columbia, Vancouver, British Columbia, Canada. achurg@interchange.ubc.ca
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-κB 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.
Insights
Inhibition of myeloperoxidase (MPO) stopped chronic obstructive pulmonary disease (COPD) progression in a guinea pig model. This MPO inhibitor reduced inflammation and oxidative stress, offering a potential new therapy for COPD.
Area of Science:
- Pulmonary Medicine
- Pharmacology
- Oxidative Stress Research
Background:
- Cigarette smoke exposure is a primary cause of COPD, involving inflammation and oxidative stress.
- Myeloperoxidase (MPO) contributes to inflammatory reactions and tissue oxidation, exacerbating COPD.
- MPO is an enzyme produced by neutrophils and macrophages.
Purpose of the Study:
- To investigate the role of MPO in the development and progression of COPD.
- To evaluate the therapeutic potential of an MPO inhibitor in a cigarette smoke-induced COPD model.
Main Methods:
- Guinea pigs were exposed to cigarette smoke for 6 months.
- An MPO inhibitor (AZ1) was administered either from the start or after 3 months of smoke exposure.
- Physiological, morphological, and biochemical markers of COPD were assessed.
Main Results:
- MPO inhibition halted smoke-induced increases in inflammatory cells and ameliorated physiological changes.
- Treatments prevented or reversed emphysema and small airway remodeling.
- MPO inhibition reduced markers of oxidative stress (dityrosine, 8-isoprostane) and inflammatory mediators.
Conclusions:
- Inhibition of MPO can halt COPD progression, even with delayed treatment.
- MPO inhibitors show therapeutic potential for COPD by reducing oxidative damage and inflammation.
- Targeting MPO may offer a novel treatment strategy for COPD patients.
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