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

Author

Eapen MS, Kota A, Vindin H, McAlinden KD, Xenaki D, Oliver BG, Deshpande DA, Sohal SS, and Sharma P

Subjects
Cell Movement drug effects, Cell Proliferation drug effects, Cells, Cultured, Enzyme Inhibitors pharmacology, Humans, Lung cytology, MAP Kinase Kinase Kinase 5 antagonists & inhibitors, MAP Kinase Kinase Kinase 5 metabolism, MAP Kinase Signaling System drug effects, MAP Kinase Signaling System genetics, Mitogens pharmacology, Muscle, Smooth cytology, Myocytes, Smooth Muscle cytology, Myocytes, Smooth Muscle drug effects, Pulmonary Disease, Chronic Obstructive metabolism, Pulmonary Disease, Chronic Obstructive pathology, RNA Interference, Transforming Growth Factor beta1 pharmacology, Cell Movement genetics, Cell Proliferation genetics, Lung metabolism, MAP Kinase Kinase Kinase 5 genetics, Myocytes, Smooth Muscle metabolism, Pulmonary Disease, Chronic Obstructive genetics
Abstract

Increased airway smooth muscle (ASM) mass is observed in chronic obstructive pulmonary disease (COPD), which is correlated with disease severity and negatively affects 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 (MAPK) 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 hyperproliferative 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, TC ASK 10 resulted in a dose-dependent reduction in mitogen (FBS, PDGF, and EGF; 72 h)-induced ASM growth as measured by CyQUANT assay. Further, molecular targetting 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 C-Jun N-terminal kinase (JNK) and p38MAP kinase-signaling pathways as evident by reduced phosphorylation of downstream effectors JNK1/2 and p38MAP kinases, respectively, with no effect on extracellular signal-regulated kinase (ERK) 1/2 (ERK1/2). Collectively, these findings establish the anti-mitogenic effect of ASK1 inhibition and identify a novel pathway that can be targetted to reduce or prevent excessive ASM mass in COPD., (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Published
2018
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2. Apoptosis signal-regulating kinase 1 inhibition attenuates human airway smooth muscle growth and migration in chronic obstructive pulmonary disease

Author

Eapen, MS, Kota, A, Vindin, H, McAlinden, KD, Xenaki, D, Oliver, BG, Deshpande, DA, Sohal, SS, and Sharma, P

Subjects
MAP Kinase Signaling System, Myocytes, Smooth Muscle, Muscle, Smooth, respiratory system, MAP Kinase Kinase Kinase 5, respiratory tract diseases, Transforming Growth Factor beta1, Pulmonary Disease, Chronic Obstructive, Cardiovascular System & Hematology, Cell Movement, Humans, RNA Interference, Mitogens, Enzyme Inhibitors, Lung, Cells, Cultured, Cell Proliferation
Abstract

© 2018 The Author(s). Increased airway smooth muscle (ASM) mass is observed in chronic obstructive pulmonary disease (COPD), which is correlated with disease severity and negatively affects 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 (MAPK) 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 hyperproliferative 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, TC ASK 10 resulted in a dose-dependent reduction in mitogen (FBS, PDGF, and EGF; 72 h)-induced ASM growth as measured by CyQUANT assay. Further, molecular targetting 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 C-Jun N-terminal kinase (JNK) and p38MAP kinase-signaling pathways as evident by reduced phosphorylation of downstream effectors JNK1/2 and p38MAP kinases, respectively, with no effect on extracellular signal-regulated kinase (ERK) 1/2 (ERK1/2). Collectively, these findings establish the anti-mitogenic effect of ASK1 inhibition and identify a novel pathway that can be targetted to reduce or prevent excessive ASM mass in COPD.

Published
2018

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