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Apoptosis signal-regulating kinase 1 inhibition attenuates human airway smooth muscle growth and migration in chronic obstructive pulmonary disease

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journal contribution
posted on 2023-05-19, 19:37 authored by Mathew Eapen, Kota, A, Vindin, H, McAlinden, K, Xenaki, D, Oliver, BG, Deshpande, DA, Sukhwinder SohalSukhwinder Sohal, Sharma, P
Increased airway smooth muscle (ASM) mass is observed in COPD which is correlated with disease severity and negatively impact lung function. Thus, there is clear unmet clinical need for finding new therapies which can target airway remodeling and disease progression in COPD. Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed mitogen-activated protein kinase kinase kinase activated by various stress stimuli, including reactive oxygen species, tumor necrosis factor-α, and lipopolysaccharide and is known to regulate cell proliferation. ASM cells from COPD patients are hyper-proliferative to mitogens in vitro. However, the role of ASK1 in ASM growth is not established. Here, we aim to determine the effects of ASK1 inhibition on ASM growth and pro-mitogenic signaling in COPD patients. We found greater expression of ASK1 in ASM-bundles of COPD lung when compared with non-COPD. Pre-treatment of ASM cells with selective ASK1 inhibitor, TCASK10 resulted in a dose-dependent reduction in mitogen (FBS, PDGF and EGF)-induced ASM growth as measured by CyQuant assay. Further, molecular targeting of ASK1 using siRNA in ASM cells prevented mitogen-induced cell growth. In addition, to anti-mitogenic potential, ASK1 inhibitor also prevented TGFb1-induced migration of ASM cells in vitro . Immunoblotting revealed that anti-mitogenic effects are mediated by JNK and p38MAP kinase-signaling pathways as evident by reduced phosphorylation of downstream effectors JNK1/2 and p38MAP kinases respectively with no effect on ERK1/2. 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.


Clifford Craig Foundation


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Clinical Science










School of Health Sciences


Portland Press

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59 Portland Place, London, England, W1N 3Aj

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Copyright 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society

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Clinical health not elsewhere classified

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