LXA4 inhibits TGF-β1-induced airway smooth muscle cells proliferation and migration by suppressing the Smad/YAP pathway

The aims of the present study were to examine the signaling mechanisms for transforming growth factor-beta 1 (TGF beta 1)-induced rat airway smooth muscle cells (ASMCs) proliferation and migration and to determine the effect of lipoxin A4 (LXA4) on TGF-beta 1-induced rat ASMCs proliferation and migration and its underlying mechanisms. TGF-beta 1 upregulated transcriptional coactivator Yes-associated protein (YAP) expression by activating Smad2/3 and then upregulated cyclin D1, leading to rat ASMCs proliferation and migration. This effect was reversed after treatment with the TGF-beta 1 receptor inhibitor SB431542. YAP is a critical mediator of TGF-beta 1-induced ASMCs proliferation and migration. Knockdown of YAP disrupted the pro-airway remodeling function of TGF-beta 1. Preincubation of rat ASMCs with LXA4 blocked TGF-beta 1-induced activation of Smad2/3 and changed its downstream targets, YAP and cyclin D1, resulting in the inhibition of rat ASMCs proliferation and migration. Our study suggests that LXA4 suppresses Smad/YAP signaling to inhibit rat ASMCs proliferation and migration and therefore has potential value in the prevention and treatment of asthma by negatively modulating airway remodeling.

Automated summary

The present study aimed to investigate the signaling mechanisms of TGF beta 1-induced rat ASMCs proliferation and migration and the effect of LXA4 on this process. TGF-beta 1 upregulated YAP expression by activating Smad2/3, leading to ASMCs proliferation and migration. The effect was reversed by the TGF-beta 1 receptor inhibitor SB431542. Knockdown of YAP disrupted the pro-airway remodeling function of TGF-beta 1. Preincubation of rat ASMCs with LXA4 inhibited TGF-beta 1-induced activation of Smad2/3 and suppressed ASMCs proliferation and migration.