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 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.

Vandetanib as a prospective anti-inflammatory and anti-contractile agent in asthma

“…Male BALB/c mice (sexually mature) were obtained from the Hubei Provincial Center for Disease Control and Prevention (Wuhan, China). All animal experiments were designed and conducted in a specific pathogen-free (SPF)-grade laboratory as previously described with minor revision (Shi et al, 2020;Li et al, 2023;Peng et al, 2023). First, we established acute asthmatic mouse models as previously described (Li et al, 2023;Peng et al, 2023).…”

“…All animal experiments were designed and conducted in a specific pathogen-free (SPF)-grade laboratory as previously described with minor revision (Shi et al, 2020;Li et al, 2023;Peng et al, 2023). First, we established acute asthmatic mouse models as previously described (Li et al, 2023;Peng et al, 2023). 6-week-old mice were randomly divided into the following four groups: (1) control group, (2) asthma group, (3) vandetanib group, and 4) dexamethasone group.…”

“…Experimental mice (control group, asthma group, vandetanib group and dexamethasone group) were anesthetized by IP administration of 1% sodium pentobarbital (10 mg/kg), and tracheostomized as previously described (Shi et al, 2020;Li et al, 2023;Peng et al, 2023). The anesthetized mice were ventilated with a flexiVent system (SCIREQ, Montreal, PQ, Canada).…”

“…Histological experiments were conceived and carried out as previously described (Shi et al, 2020;Li et al, 2023;Peng et al, 2023). Briefly, tracheal and left lung samples were isolated from experimental groups (control, asthma, dexamethasone and vandetanib).…”

“…After the homogenization of the right lungs of mice, total RNA was extracted, and cDNA was synthesized. Real-time PCR was then run using SYBR Green qPCR Mix on an Applied Biosystems 7500 Fast Real-Time PCR System (Foster City, CA, United States) in standard mode as described previously (Shi et al, 2020;Li et al, 2023;Peng et al, 2023). The mRNA expressions of related genes were normalized with 2 −ΔΔCt method.…”