Superior anti-inflammatory effects of narrow-spectrum kinase inhibitors in airway smooth muscle cells from subjects with chronic obstructive pulmonary disease

Knobloch, Jürgen; Jungck, David; Charron, Catherine E.; Stoelben, Erich; Ito, Kazuhiro; Koch, Andrea

doi:10.1016/j.jaci.2017.09.026

Cited by 8 publications

(17 citation statements)

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“…TNFα-induced IL-8 is completely insensitive to dexamethasone and fluticasone in HASMCs of COPD subjects but sensitive to these corticosteroids in HASMCs from subjects without COPD [7,8]. LPS-induced IL-8 is almost insensitive to fluticasone in HASMCs of COPD patients but sensitive to fluticasone in HASMCs from patients without COPD [7].…”

Section: Introductionmentioning

confidence: 96%

“…COPD airway inflammation is perpetuated by the production of corticosteroid-sensitive and -insensitive cytokines and chemokines in response to inflammatory stimuli like TNFα and pathogen-associated molecular patterns (PAMPs) like lipopolysaccharide (LPS) from gram-negative bacteria [5][6][7][8]. The corticosteroid-insensitivity particularly applies to IL-8 (CXCL8), which is a central chemokine in non-type 2 (neutrophilic) airway inflammation that is present and critical in most likely all COPD phenotypes and disease stages and a target for therapeutic strategies [7][8][9][10]. The production of IL-8 and other COPD key cytokines are regulated by p38-mitogen-activated-protein kinase (p38MAPK) [7].…”

Section: Introductionmentioning

confidence: 99%

“…The corticosteroid-insensitivity particularly applies to IL-8 (CXCL8), which is a central chemokine in non-type 2 (neutrophilic) airway inflammation that is present and critical in most likely all COPD phenotypes and disease stages and a target for therapeutic strategies [7][8][9][10]. The production of IL-8 and other COPD key cytokines are regulated by p38-mitogen-activated-protein kinase (p38MAPK) [7]. All four p38MAPK isoforms (α, β, γ, δ) are expressed in the lung tissue of COPD subjects and might contribute to non-type 2 inflammation [11].…”

Section: Introductionmentioning

confidence: 99%

“…Promising future causal therapy strategies to neutralize non-type 2 airway inflammation are (1) the drug-induced reversion of its corticosteroid-resistance to improve the effects of ICS, and (2) therapeutic inhibition of the activity of pro-inflammatory protein kinases, e.g., with narrow spectrum kinase inhibitors (NSKIs) that target a certain panel of pro-inflammatory protein kinases including p38MAPKα and -γ [7,12].…”

Section: Introductionmentioning

confidence: 99%

“…We investigated whether LABAs and inhibitors of p38MAPK and related MAPK families (ERK, JNK) can reverse the corticosteroid-insensitivity in HASMCs of COPD. We induced the inflammatory IL-8 response in cultivated HASMCs with TNFα or LPS, representing culture models of non-type 2 airway inflammation in COPD [7]. TNFα is increased in the lungs of subjects with stable COPD, and HASMCs are permanently/repeatedly exposed to this pro-inflammatory factor.…”

Section: Introductionmentioning

confidence: 99%

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LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD

Knobloch

Jungck

Kronsbein

et al. 2019

JCM

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Airway inflammation in chronic obstructive pulmonary disease (COPD) is partially insensitive/resistant to inhaled corticosteroids (ICS). ICS plus bronchodilator therapy has been discussed for COPD phenotypes with frequent exacerbations and participation of corticosteroid-sensitive type 2/eosinophilic inflammation. Neutralization of non-type 2/IL-8-associated airway inflammation by reversion of its corticosteroid-resistance might be a future strategy for other phenotypes. Human airway smooth muscle cells (HASMCs) produce corticosteroid-insensitive IL-8 in response to TNFα or LPS in stable disease stages or bacteria-induced exacerbations, respectively. p38-mitogen-activated-protein-kinases (p38MAPKs) are alternative therapeutic targets. Hypothesis: long-acting-β2-agonists (LABAs) reverse the corticosteroid-insensitivity of IL-8 by p38MAPK inhibition in HASMCs. Cultivated HASMCs from COPD subjects were pre-incubated with formoterol, salmeterol, fluticasone-propionate, BIRB796 (p38MAPKα, -γ, -δ inhibitor), and/or SB203580 (p38MAPKα and -β inhibitor) before stimulation with TNFα or LPS. IL-8 and MAPK-activities were measured by ELISA. Formoterol, salmeterol, and fluticasone did not or hardly reduced TNFα- or LPS-induced IL-8. BIRB796 and SB203580 reduced TNFα-induced IL-8. SB203580 reduced LPS-induced IL-8. Fluticasone/formoterol, fluticasone/salmeterol, and fluticasone/BIRB796, but not fluticasone/SB203580 combinations, reduced TNFα-induced IL-8 stronger than single treatments. All combinations including fluticasone/SB203580 reduced LPS-induced IL-8 stronger than single treatments. TNFα induced p38MAPKα and -γ activity. LPS induced p38MAPKα activity. Formoterol reduced TNFα-induced p38MAPKγ and LPS-induced p38MAPKα activity. LABAs reverse the corticosteroid-insensitivity of IL-8 in airway smooth muscles via p38MAPKγ in stable disease and via p38MAPKα in exacerbations. Our pre-clinical data indicate a utility for also adding ICS in non-type 2 inflammatory COPD phenotypes to bronchodilator therapy. Depending on phenotype and disease stage, isoform-specific p38MAPK blockers might also reverse corticosteroid-resistance in COPD.

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Section: Introductionmentioning

confidence: 96%