Targeting ASK1 in preventing airway smooth muscle growth: Implications for airway remodeling in COPD

Abstract

Airway remodeling is a hallmark feature of individuals with COPD. Increased airway smooth muscle (ASM) mass, and ASM thickness is correlated with severity of the disease and has been described to negatively impact lung function in COPD. Current medications control inflammation and reverse airway obstruction effectively yet have limited effect on remodeling. Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed MAPK kinase kinase (MAP3K), activated by various stress stimuli, including ROS, TNF-α, and LPS. ASK1 affects multiple cellular functions, including survival, differentiation, and the innate immune response and has been reported to be involved in the pathogenesis of various human diseases. However, no reported study has demonstrated a role for ASK1 in airway remodeling. In this study we aimed to determine the effects of ASK1 inhibition on ASM growth and pro-mitogenic signaling. We found expression of ASK1 on human lung tissue and primary human ASM cells. Pre-treatment of human ASM cells with potent and orally available ASK1 inhibitor, TCASK10 resulted in a dose-dependent reduction in mitogen (FBS, PDGF and EGF)-induced ASM growth as measured by CyQuant assay. Furthermore, the effectiveness of this pharmacological inhibition was established and replicated in gene silencing experiments where ASK1 siRNA inhibited mitogen-induced human ASM cell growth. Immunoblotting revealed that the anti-mitogenic effect of ASK1 inhibition or silencing is mediated by JNK-signaling pathway. Collectively, these findings establish the anti-mitogenic effect of ASK1 inhibition and identify a novel pathway that can be targeted to reduce or prevent excessive ASM mass in COPD.