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

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 Ca2+ channels (L-VDCCs), nonselective cation channels (NSCCs), transient receptor potential channels (TRPCs), Na+/Ca2+ exchangers (NCXs) and K+ channels, 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.

 

Comments:

That's an intriguing study! It appears that PP121, acting as a dual tyrosine and phosphoinositide kinase inhibitor, demonstrates promising effects in asthma treatment. Its ability to relax precontracted mouse tracheal rings by influencing various ion channels and modulating calcium mobilization is quite noteworthy.

Additionally, the findings indicating PP121's potential to alleviate asthmatic features like airway hyperresponsiveness, inflammation, and mucus secretion by downregulating inflammatory factors, mucins, and the MAPK/Akt signaling pathway in asthmatic mice are significant.

The dual nature of PP121, showcasing both anti-contractile and anti-inflammatory effects, positions it as a promising therapeutic candidate for asthma. This research potentially opens new avenues for asthma therapy, offering a novel approach to address the condition's underlying mechanisms.

Further exploration of PP121's safety profile, potential side effects, and its efficacy in different asthma models could be valuable for its development as a treatment option. If this compound continues to show promise, it might pave the way for more targeted and effective therapies for asthma patients.