Effects of a MAPK p38 inhibitor on lung function and airway inflammation in equine recurrent airway obstruction.
BACKGROUND
It has been suggested that many of the beneficial effects of corticosteroids are mediated through mitogen-activated protein kinase (MAPK) p38 inhibition.


OBJECTIVE
To investigate the efficacy of the MAPK p38 inhibitor compound MRL-EQ1 to either prevent (Phase 1) or treat (Phase 2) recurrent airway obstruction (RAO) in horses.


METHODS
MRL-EQ1 was administered i.v. at a dosage of 0.75-1.5 mg/kg bwt q. 12 h. In Phase 1, susceptible horses in clinical remission were divided into 2 groups (n = 5/group), based on historical values of respiratory mechanics. All horses were entered in the study in pairs (one control, one treated horse) and exposed to the same environmental challenge (stabling, mouldy hay and dusty conditions). The treatment group received MRL-EQ1 for 14 days while the control horses were untreated during the same period. In Phase 2, affected horses were ranked by severity of respiratory dysfunction and split randomly into either dexamethasone or MRL-EQ1 treatment groups (n = 5/group). Bronchoalveolar lavage fluid, respiratory mechanic measurements, MRL-EQ1 plasma concentration and tumour necrosis factor (TNF) whole blood activity were evaluated sequentially.


RESULTS
In Phase 1, MRL-EQ1 did not prevent the occurrence of clinical signs and pulmonary inflammation. However, treatment was associated with a reduction in severity and a delay in the onset of signs and a reduction in pulmonary neutrophilia. In Phase 2, plasma concentrations achieved resulted in ex vivo suppression of lipopolysaccharide-induced TNF production in equine blood. MRL-EQ1 did not improve airway inflammation or lung function and was associated in a dose dependent manner with behavioural (depression, excitability) and blood changes (neutrophilia, increased serum muscle enzyme concentrations).


CONCLUSIONS
Inhibition of p38 in the horse was partially effective in reducing clinical signs and airway inflammation when administered prior to, but not during clinical exacerbation in RAO.


CONCLUSIONS
Inhibitors of p38 MAPK with a better toxicity profile may be effective in the prevention or treatment of RAO.
Lavoie
J P
JP
Faculté de médecine vétérinaire, Université de Montréal, C.P 5000, Saint-Hyacinthe, Quebec J2S 7C6, Canada.
Thompson
D
D
Hamilton
E
E
Debrue
M
M
David
F
F
Hickey
G
G
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology*; D003907:Dexamethasone / Q000627:therapeutic use; D005260:Female; D006734:Horse Diseases / Q000188:drug therapy* / Q000517:prevention & control*; D006736:Horses; D007249:Inflammation / Q000188:drug therapy / Q000517:prevention & control / Q000662:veterinary; D007275:Injections, Intravenous / Q000662:veterinary; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008173:Lung Diseases, Obstructive / Q000188:drug therapy / Q000517:prevention & control / Q000662:veterinary*; D008297:Male; D012008:Recurrence; D012129:Respiratory Function Tests / Q000662:veterinary; D012720:Severity of Illness Index; D016896:Treatment Outcome; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000893:Anti-Inflammatory Agents; D003907:Dexamethasone; D048051:p38 Mitogen-Activated Protein Kinases