Effects of a MAPK p38 inhibitor on lung function and airway inflammation in equine recurrent airway obstruction.
Authors: Lavoie J P, Thompson D, Hamilton E, Debrue M, David F, Hickey G
Journal: Equine veterinary journal
Summary
# Editorial Summary Recurrent airway obstruction (RAO) in horses shares inflammatory pathways with human asthma, and corticosteroids' effectiveness has been attributed partly to mitogen-activated protein kinase (MAPK) p38 inhibition; this study investigated whether directly blocking p38 could offer similar benefits without corticosteroid side-effects. Researchers tested the p38 inhibitor MRL-EQ1 (0.75–1.5 mg/kg intravenously twice daily) in two phases: prevention in susceptible horses during environmental challenge (stabling, mouldy hay, dusty conditions) and treatment in acutely affected horses, measuring respiratory mechanics, bronchoalveolar lavage fluid inflammation, and tumour necrosis factor activity. When given prophylactically, MRL-EQ1 delayed symptom onset and reduced airway neutrophilia severity, though it failed to prevent clinical signs entirely; conversely, during active disease flare-ups, the inhibitor produced no improvement in lung function or inflammation despite achieving plasma concentrations that suppressed TNF production in vitro, and dose-dependent adverse effects (depression, excitability, neutrophilia, elevated muscle enzymes) emerged. These results suggest p38 inhibition holds promise as a preventative strategy for RAO-susceptible horses facing known triggers, but current compounds lack the therapeutic efficacy and safety profile needed for acute exacerbation management, pointing toward the need for improved inhibitors before clinical application becomes viable.
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Practical Takeaways
- •p38 MAPK inhibitors may have potential for preventing RAO in susceptible horses during high-risk periods, but current formulations are not suitable for treating active disease episodes
- •Toxicity concerns with MRL-EQ1 (behavioral and hematologic side effects) limit clinical utility; safer p38 inhibitors would be needed before recommending this class for equine respiratory disease
- •Corticosteroids remain superior to p38 inhibitors for treating acute RAO exacerbations based on this evidence
Key Findings
- •MRL-EQ1 (p38 MAPK inhibitor) reduced severity and delayed onset of RAO clinical signs in Phase 1 prevention study but did not prevent occurrence of disease
- •In Phase 2 treatment phase, MRL-EQ1 failed to improve airway inflammation or lung function during clinical exacerbation despite achieving plasma concentrations that suppressed TNF production ex vivo
- •Treatment was associated with dose-dependent adverse effects including behavioral changes (depression, excitability) and blood abnormalities (neutrophilia, elevated serum muscle enzymes)
- •p38 MAPK inhibition showed partial effectiveness only when administered prior to clinical exacerbation, not during active disease