PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, relieves airway hyperresponsiveness, mucus hypersecretion and inflammation in a murine asthma model.

Abstract

BACKGROUND: Tyrosine kinase and phosphoinositide kinase pathways play important roles in asthma formation. As a dual tyrosine and phosphoinositide kinase inhibitor, PP121 has shown anticancer efficacy in multiple tumors. However, the study of PP121 in pulmonary diseases is still limited. Herein, we investigated the therapeutic activities of PP121 in asthma treatment. METHODS: Tension measurements and patch clamp recordings were made to investigate the anticontractile characteristics of PP121 in vitro. Then, an asthma mouse model was established to further explore the therapeutic characteristics of PP121 via measurement of respiratory system resistance, histological analysis and western blotting. RESULTS: We discovered that PP121 could relax precontracted mouse tracheal rings (mTRs) by blocking certain ion channels, including L-type voltage-dependent Cachannels (L-VDCCs), nonselective cation channels (NSCCs), transient receptor potential channels (TRPCs), Na/Caexchangers (NCXs) and Kchannels, and accelerating calcium mobilization. Furthermore, PP121 relieved asthmatic pathological features, including airway hyperresponsiveness, systematic inflammation and mucus secretion, via downregulation of inflammatory factors, mucins and the mitogen-activated protein kinase (MAPK)/Akt signaling pathway in asthmatic mice. CONCLUSION: In summary, PP121 exerts dual anti-contractile and anti-inflammatory effects in asthma treatment, which suggests that PP121 might be a promising therapeutic compound and shed new light on asthma therapy.