Mast cell generated cyclooxygenase products protect from airway hyperresponsiveness in a model of chronic asthma

The cyclooxygenase (COX) product prostaglandin (PG) E2 is known to act bronchoprotective in asthmatics. Recent preclinical studies identified the COX-terminal microsomal PGE synthase-1 to contribute to the formation of protective PGE2. This study investigated whether the release of bronchoprotective COX products is mast cell (MC) dependent. Chronic allergic airway inflammation in mice was induced by ovalbumin/alum injections and repeated challenges during 90 days. COX-inhibition with diclofenac (DFC) was performed. Airway hyperresponsiveness (AHR) was assessed applying forced-oscillation technique in response to methacholine. Contribution of MC-COX-products to AHR was resolved by comparing Wsh (MC-deficient) to C57BL/6 wildtype (WT) mice (MCs around central airway). Central airway resistance, R n was pronounced in allergen-challenged WT mice and increased in WT-DFC [cmH2O/s*mL, mean± SEM: 1.3±0.1 vs 1.6±0.2, p=0.04]. Wsh displayed comparable resistance [1.7±0.1] as WT-DFC. R n in Wsh was not changed after treatment [1.9±0.2]. Both mouse strains lack MCs in peripheral lung tissue. Consequently, tissue resistance was not changed in WT and Wsh [8.5±0.5 vs 7.8±0.6], nor after treatment [WT-DFC 7.8±0.5, Wsh-DFC 7.6±0.6]. Although a shift in baseline tissue elastance was observed between WT and Wsh [21.9±1.4 vs 17.7±0.4, p=0.02], treatment did not affect baseline [WT-DFC 21.4±1.2; Wsh-DFC 17.6±0.9], nor was the reactivity changed. The data indicates that the bronchoprotective role of PGE2 is MC dependent. It remains to be seen if this is due to PGE2 or other COX products released by MCs, or if modulating COX products are released by other cells in response to MC activation.