Late intervention with a myeloperoxidase inhibitor stops progression of experimental chronic obstructive pulmonary disease.

Abstract

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.

• Authors: Andrew Churg, Caroline V Marshall, Don D Sin, Sarah Bolton, Steven Zhou, Katherine Thain, Elaine B Cadogan, Justine Maltby, Matthew G Soars, Philip R Mallinder, Joanne L Wright
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 185 Issue 1 Pg. 34-43 (Jan 01 2012) ISSN: 1535-4970 [Electronic] United States
• PMID: 21997333 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-((tetrahydrofuran-2-yl)methyl)-2-thioxo-7H-purin-6-one
• Enzyme Inhibitors
• Purines
• Thiones
• Thioxanthenes
• 2-thioxanthene
• 8-epi-prostaglandin F2alpha
• Tyrosine
• Dinoprost
• dityrosine
• Peroxidase

Topics

• Airway Remodeling (drug effects)
• Animals
• Dinoprost (analogs & derivatives, blood)
• Disease Models, Animal
• Disease Progression
• Enzyme Inhibitors (pharmacology)
• Female
• Guinea Pigs
• Hypertension, Pulmonary (etiology, metabolism, prevention & control)
• Inflammation (etiology, metabolism, prevention & control)
• Lung (drug effects, metabolism)
• Oxidative Stress (drug effects)
• Peroxidase (antagonists & inhibitors, metabolism)
• Pulmonary Disease, Chronic Obstructive (drug therapy, etiology, metabolism)
• Purines (therapeutic use)
• Smoking (adverse effects)
• Thiones (therapeutic use)
• Thioxanthenes (antagonists & inhibitors, metabolism)
• Tyrosine (analogs & derivatives, drug effects)