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.
Subject(s)
Enzyme Inhibitors/pharmacology , Peroxidase/antagonists & inhibitors , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/metabolism , Purines/therapeutic use , Smoking/adverse effects , Thiones/therapeutic use , Airway Remodeling/drug effects , Animals , Dinoprost/analogs & derivatives , Dinoprost/blood , Disease Models, Animal , Disease Progression , Female , Guinea Pigs , Hypertension, Pulmonary/etiology , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/prevention & control , Inflammation/etiology , Inflammation/metabolism , Inflammation/prevention & control , Lung/drug effects , Lung/metabolism , Oxidative Stress/drug effects , Peroxidase/metabolism , Pulmonary Disease, Chronic Obstructive/etiology , Thioxanthenes/antagonists & inhibitors , Thioxanthenes/metabolism , Tyrosine/analogs & derivatives , Tyrosine/drug effectsABSTRACT
The effects of the topical application of Dyphylline in concentrations of 1.0 mg/1.0 ml and 10 mg/1.0 ml Ringer's solution and 25 mg/1.0 ml, 0.065% NaCl solution (the content of ampoules in clinical use) were investigated on frog's heart in situ. Dyphylline in all of the above concentrations had a stimulatory effect on the frog's heart. Hycanthone methanesulphonate in concentration of 1.0 ml/1.0 ml when topically applied to the frog's heart had a depressant effect on both of the contractility and rhythmicity. The depressant effects of Hycanthone in concentration of 1:1 were compared before and after the topical application of Dyphylline in the above mentioned concentrations. It was found that Dyphylline in concentration of 1.0 mg/1.0 ml could partially antagonize the depressant effect of Hycanthone on the heart rate but not on the force of contraction. Dyphylline in concentration of 10 mg/1.0 ml could partially antagonize the depressant effects of Hycanthone on both of the heart rate and the force of contraction. Dyphylline in concentration of 25 mg/1.0 ml could completely antagonize the depressant effects of hycanthone on both of the heart rate and the force of contraction.
