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

Published byΟὐλίξης Κουβέλης Modified over 5 years ago

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Presentation on theme: "Superior anti-inflammatory effects of narrow-spectrum kinase inhibitors in airway smooth muscle cells from subjects with chronic obstructive pulmonary."— Presentation transcript:

1 Superior anti-inflammatory effects of narrow-spectrum kinase inhibitors in airway smooth muscle cells from subjects with chronic obstructive pulmonary disease  Jürgen Knobloch, PhD, David Jungck, MD, Catherine Charron, PhD, Erich Stoelben, MD, Kazuhiro Ito, PhD, Andrea Koch, MD  Journal of Allergy and Clinical Immunology  Volume 141, Issue 3, Pages e11 (March 2018) DOI: /j.jaci Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Effects of NSKIs vs BIRB796 and FP on TNF-α– and LPS-induced GM-CSF and CXCL8 in COPD HASMCs. COPD HASMCs (n = 6) were preincubated with NSKIs, BIRB796, or FP 2 hours before stimulation with TNF-α (20 ng/mL) or LPS (1 μg/mL) for 72 hours. GM-CSF and CXCL8 were measured in cell culture supernatants by ELISA. Data are presented as mean ± SEM. In B, D, F, and H, drug effects are presented as percent inhibition vs stimulation with TNF-α or LPS alone. Curves were calculated by nonlinear regression with sigmoidal curve fit. One-way repeated-measures ANOVA (A-H, P < .001) and post hoc Dunnett or Bonferroni test was used to analyze for differences across stimulations. B, D, F, and H, One-sample t tests were used to compare drug effects vs a hypothetical value of 0 (= no drug effect on TNF-α– or LPS-induced GM-CSF or CXCL8). The percent inhibition data of 10−7 mol/L for each drug were individually compared with 0 and between drugs. DMSO, Dimethyl sulfoxide. *P < .05, **P < .01, ***P < .001 vs unstimulated controls (Fig 1, A, C, E, and G) vs 0 (Fig 1, B, D, F, and H) or between values as indicated. §P < .05, §§P < .01, §§§P < .001 vs stimulation with TNF-α or LPS alone. Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig E1 Fluticasone reduces GM-CSF but not CXCL8 release in TNF-α– and in LPS-activated COPD HASMCs. COPD (left panels, n = 4) or non-COPD (right panels, n = 5 never-smokers) HASMCs were preincubated with FP 2 hours before stimulation with TNF-α (20 ng/mL) or LPS (1 μg/mL) for 72 hours. CXCL8 and GM-CSF were measured in cell culture supernatants by ELISA. Data are presented as mean ± SEM. One-way repeated-measures ANOVA (A-D, P < .001) and post hoc Bonferroni test: **P < .01, ***P < .001 vs unstimulated controls; §P < .05, §§P < .01, §§§P < .001 vs TNF-α or LPS stimulation. Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig E2 Effects of NSKIs vs SKIs on TNF-α–induced GM-CSF in non-COPD HASMCs. Non-COPD HASMCs (n = 5) were preincubated with NSKIs, SKIs, or SKI combinations at indicated concentrations (triangles in A indicate decreasing drug concentrations: 10−7, 10−8, and 10−9 mol/L) 2 hours before stimulation with TNF-α (20 ng/mL) for 72 hours. GM-CSF was measured in cell culture supernatants by ELISA. Data are presented as mean ± SEM. One-way repeated-measures ANOVA (A and B, P < .001) and post hoc Dunnett or Bonferroni test was used to analyze for differences across stimulations. BIRB, BIRB796; DAS, dasatinib. **P < .01, ***P < .001 vs unstimulated controls; §P < .05, §§P < .01, §§§P < .001 vs stimulation with TNF-α alone; #P < .05, ##P < .01, ###P < .001 between data as indicated. Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig E3 Effects of NSKIs vs SKIs on TNF-α–induced CXCL8 in non-COPD HASMCs. Non-COPD HASMCs (n = 5) were preincubated with NSKIs, SKIs, or SKI combinations at indicated concentrations (triangles in A indicate decreasing drug concentrations: 10−7, 10−8, and 10−9 mol/L) 2 hours before stimulation with TNF-α (20 ng/mL) for 72 hours. CXCL8 was measured in cell culture supernatants by ELISA. Data are presented as mean ± SEM. One-way repeated-measures ANOVA (A and B, P < .001) and post hoc Dunnett or Bonferroni test was used to analyze for differences across stimulations. BIRB, BIRB796; DAS, dasatinib. ***P < .001 vs unstimulated control; §P < .05, §§P < .01, §§§P < .001 vs stimulation with TNF-α alone; #P < .05, ##P < .01 between data as indicated. Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig E4 Effects of NSKIs vs SKIs on LPS-induced CXCL8 in non-COPD HASMCs. Non-COPD HASMCs (n = 4) (A) or (n = 5) (B) were preincubated with NSKIs, SKIs, or SKI combinations at indicated concentrations (triangles in Fig E4, A, indicate decreasing drug concentrations: 10−7, 10−8, and 10−9 mol/L) 2 hours before stimulation with LPS (1 μg/mL) for 72 hours. CXCL8 was measured in cell culture supernatants by ELISA. Data are presented as mean ± SEM. One-way repeated-measures ANOVA (Fig E4, A and B, P < .001) and post hoc Dunnett or Bonferroni test was used to analyze for differences across stimulations. BIRB, BIRB796; DAS, dasatinib. ***P < .001 vs unstimulated control; §§P < .01, §§§P < .001 vs stimulation with LPS alone. Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig E5 Effects of NSKIs vs. SKIs on LPS-induced GM-CSF in non-COPD HASMCs. Non-COPD HASMCs (n = 4) (A) or n = 5 (B) were preincubated with NSKIs, SKIs, or SKI combinations at indicated concentrations (triangles in Fig E5, A, indicate decreasing drug concentrations: 10−7, 10−8, and 10−9 mol/L) 2 hours before stimulation with LPS (1 μg/mL) for 72 hours. GM-CSF was measured in cell culture supernatants by ELISA. Data are presented as mean ± SEM. One-way repeated-measures ANOVA (A and B, P < .001) and post hoc Dunnett or Bonferroni test was used to analyze for differences across stimulations. BIRB, BIRB796; DAS, dasatinib. ***P < .001 vs unstimulated control; §P < .05, §§P < .01, §§§P < .001 vs stimulation with LPS alone; #P < .05 between data as indicated. Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig E6 RV1088 and RV568 inhibit cytokine gene transcription. HASMCs (A, C, D, n = 5; B, n = 3) were preincubated with RV1088 or RV568 each at 10−7 mol/L 2 hours before stimulation with TNF-α (Fig E6, A and C; 20 ng/mL) or LPS (Fig E6, B and D; 1 μg/mL) for 2 hours. RNA was isolated and subjected to quantitative RT-PCR with specific primers for CXCL8, GM-CSF, and GAPDH. Values for CXCL8 and GM-CSF were first normalized to the housekeeping gene and reference GAPDH and, second, to the unstimulated control, which was set to 1. Data are presented as mean ± SEM (Gaussian distribution) or as scatter with median (non-Gaussian distribution), as fold induction (top row), and as percent inhibition vs stimulation with TNF-α or LPS alone (bottom row). Top row: 1-way repeated-measures ANOVA or Friedmann (Fig E6, A-D, P ≤ .01) and post hoc Bonferroni or Dunn test; bottom row: paired t tests (comparison between drug effects) and 1-sample t tests (comparisons vs a hypothetical value of 0 [=no reduction]). GAPDH, Glyceraldehyde 3-phosphate dehydrogenase. *P < .05, **P < .01, ***P < .001 vs unstimulated control (top row), vs 0 or between data as indicated (bottom row); §P < .05, §§P < .01, §§§P < .001 vs stimulation with TNF-α or LPS alone; #P < .05 between data as indicated. Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig E7 NSKIs have posttranscriptional effects on CXCL8 in TNF-α– but not in LPS-activated HASMCs. HASMCs were stimulated for 48 hours with TNF-α (n = 9) or LPS (n = 7). After 6 hours of stimulation, actinomycin D was added at 5 μg/mL. After 6.5 hours of stimulation (30 minutes after actinomycin D), RV1088 or RV568 was added at 10−7 mol/L (postincubations). CXCL8 was measured in cell culture supernatants by ELISA. Data are presented as mean ± SEM. One-way repeated-measures ANOVA (A and B, P ≤ .01) and post hoc Bonferroni tests: *P < .05, **P < .01, ***P < .001 vs unstimulated control or between data as indicated. §§P < .01, §§§P < .001 vs stimulation with TNF-α or LPS alone. Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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