Effect of the 5‐lipoxygenase inhibitor, fenleuton, on antigen‐induced neutrophil accumulation and lung function changes in horses with chronic obstructive pulmonary disease

Abstract

The leukotrienes (LT) LTD4 and LTB4 have been shown to cause bronchoconstriction and neutrophil accumulation, respectively, in horse lungs. Such changes are characteristic of the equine allergic respiratory disease, chronic obstructive pulmonary disease (COPD). To further investigate the role of these putative mediators in the pathogenesis of equine COPD the effect of a 5-lipoxygenase inhibitor, fenleuton, on antigen-induced changes in horses with this condition has been examined. Six horses with COPD underwent a series of four antigen challenges, one month apart, with placebo pre-treatment on three occasions and fenleuton (4 days oral dosing 5 mg/kg) pre-treatment on one occasion. Three horses received fenleuton prior to the second challenge and three horses received the drug prior to the fourth antigen challenge. Changes in radiolabelled neutrophil distribution, lung function and peripheral leucocyte counts were monitored on each occasion for 7 h following the start of antigen challenge. Antigen challenge caused an increase in radioactive counts over the lungs and a decrease in peripheral leucocyte count. Neither response was affected by fenleuton pre-treatment. Mean maximal changes in pleural pressure (delta Pplmax) and respiratory rate were also unaffected by fenleuton pre-treatment. However, in the two horses which responded to antigen-challenge with a particularly marked increase in delta Pplmax (> 15 cm H2O), prior administration of fenleuton reduced the response by 64 and 63%. These results suggest that 5-lipoxygenase inhibitors warrant further investigation as bronchodilators in equine COPD.

Comparison of effects of dexamethasone and the leukotriene D4 receptor antagonist L-708,738 on lung function and airway cytologic findings in horses with recurrent airway obstruction

“…p Similarly, administration of a 5-LO inhibitor prior to allergen challenge in affected horses did not reduce pulmonary neutrophilia and did not significantly improve their lung function. 16 However, in the 2 horses that responded severely to the challenge, there was a marked reduction in lung function associated with drug administration. 16 While these findings indicated an overall poor therapeutic benefit of these agents for the prevention of heaves, they also suggested that LT contribute in some circumstances to the airway obstruction seen in heaves.…”

“…The use of a 5-LO inhibitor and a FLAP antagonist in affected horses has been investigated and led to equivocal results. 16,p In a preliminary study in which a FLAP antagonist was administered to horses with heaves prior to allergen challenge, no improvement in airway function and inflammation was observed. p Similarly, administration of a 5-LO inhibitor prior to allergen challenge in affected horses did not reduce pulmonary neutrophilia and did not significantly improve their lung function.…”

Assessment of leukotriene B4 production in leukocytes from horses with recurrent airway obstruction

“…37 Our enthusiasm for suggesting a role of LTB 4 in RAO is tempered somewhat by the observation that the 5-lipoxygenase inhibitor fenleuton did not diminish the accumulation of neutrophils in the lungs of horses with chronic obstructive pulmonary disease. 38 …”

Heaves, an asthma‐like disease of horses

“…Airway neutrophils are present in large numbers in the airways of horses with heaves and may contribute to the disease through the release of several inflammatory mediators. They are recruited 3–5 h following the beginning of exposure to stable dust, the process is reversible within 4 days after the cessation of a short exposure (5–7 h), 125–127 and up to 3 weeks or more under more natural conditions 79 . Resolution of airway inflammation coincides with neutrophil apoptosis and phagocytosis by alveolar macrophages 125 .…”

“…Other mediators increased during heaves exacerbation, including serotonin, endothelin‐1, histamine and leukotriene D 4 , potentiate the response of equine smooth muscle cells to acetylcholine, or increase its release. However, while they may contribute to increased cholinergic airway tone, cysteinyl leukotrienes are not believed to be major contributors to bronchospasm as leukotriene antagonists are ineffective for the treatment of heaves 127,161,191 …”