The p38 MAPK inhibitor doramapimod attenuates airway inflammation and remodeling while improving functional features in experimental allergic airway disease

Allergic airway diseases, including allergic asthma, involve a complex interplay between inflammation and structural remodeling, leading to impaired airway function. The p38 mitogen-activated protein kinase (p38 MAPK) pathway is a key regulator of inflammatory signaling; however, its role in airway function and remodeling remains incompletely understood. This study investigated the effects of the p38 MAPK inhibitor doramapimod in an ovalbumin-induced guinea pig model of allergic airway inflammation. Doramapimod (1 and 3 mg/kg, intraperitoneally) significantly attenuated airway hyperresponsiveness, reduced cough responses, and increased tracheal ciliary beat frequency. Treatment also reduced levels of selected type 2-associated cytokines, including interleukin-4, interleukin-5, interleukin-13, as well as interferon gamma. In addition, doramapimod reduced inflammatory cell infiltration, decreased the number of MUC5AC-positive epithelial cells, and reduced collagen deposition. Collagen type III levels were reduced, whereas transforming growth factor beta 1 levels remained unchanged. Notably, doramapimod did not affect histamine- or carbachol-induced contractile responses in isolated tracheal rings obtained from healthy guinea pigs. These findings demonstrate that treatment with doramapimod, a p38 MAPK inhibitor, attenuates airway inflammation and remodeling while improving functional features of allergic airway disease. Together, these results support further investigation of p38 MAPK inhibition as a potential therapeutic strategy for allergic airway disease.