Abstract
Increased airway smooth muscle (ASM) mass is observed in chronic obstructive pulmonary disease (COPD) which is correlated with disease severity and negatively impact lung function in these patients. 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 (MAP3K) activated by various stress stimuli, including reactive oxygen species (ROS), tumor necrosis factor (TNF)-α, and lipopolysaccharide (LPS) 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 using ASM cells from 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 highly selective ASK1 inhibitor, TCASK10 resulted in a dose-dependent reduction in mitogen (FBS, PDGF and EGF; 72 hours)-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 TGFβ1-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.
Highlights
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease that represents one of the most significant global healthcare problems
We examined the effect of Apoptosis signal-regulating kinase 1 (ASK1) inhibition on cell growth and migration in airway smooth muscle (ASM) cells from COPD patients
Using both pharmacological and molecular approaches we demonstrate that ASK1 inhibition can lead to reduction in mitogen-induced ASM cell growth
Summary
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease that represents one of the most significant global healthcare problems. Vulnerable smokers develop epithelial squamous metaplasia, mucus hypersecretion, smooth muscle hypertrophy and small airway fibrosis, that causes narrowing and obliteration, accompanied by “bronchitis” and structural changes throughout the airways [3,4,5,6]. Up to fifty percent of the patients go on to suffer from varying degree of emphysematous lung destruction which adds to airflow obstructions and symptoms. In pathological conditions multiple cell types participate in airway remodeling largely through increased extracellular matrix (ECM) deposition and vasculature changes (reviewed in [7, 8]), our study here will focus on the contribution of airway smooth muscle (ASM) cells in disease manifestation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
