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Research ArticleInflammation, Immunopharmacology, and Asthma

Endothelin Receptor Antagonists Attenuate the Inflammatory Response of Human Pulmonary Vascular Smooth Muscle Cells to Bacterial Endotoxin

Jürgen Knobloch, Maria Feldmann, Chiara Wahl, David Jungck, Jürgen Behr, Erich Stoelben and Andrea Koch
Journal of Pharmacology and Experimental Therapeutics August 2013, 346 (2) 290-299; DOI: https://doi.org/10.1124/jpet.112.202358
Jürgen Knobloch
Department of Internal Medicine III for Pneumology, Allergology, Sleep and Respiratory Medicine, University Hospital Bergmannsheil, Bochum, Germany (J.K., M.F., C.W., D.J., A.K.); Department Internal Medicine V, Comprehensive Pneumology Center, Member of the DLZ, University of Munich, Germany (J.B.); and Department of Thoracic Surgery, Lungenklinik Merheim, Kliniken der Stadt Köln, Cologne, Germany (E.S.)
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Maria Feldmann
Department of Internal Medicine III for Pneumology, Allergology, Sleep and Respiratory Medicine, University Hospital Bergmannsheil, Bochum, Germany (J.K., M.F., C.W., D.J., A.K.); Department Internal Medicine V, Comprehensive Pneumology Center, Member of the DLZ, University of Munich, Germany (J.B.); and Department of Thoracic Surgery, Lungenklinik Merheim, Kliniken der Stadt Köln, Cologne, Germany (E.S.)
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Chiara Wahl
Department of Internal Medicine III for Pneumology, Allergology, Sleep and Respiratory Medicine, University Hospital Bergmannsheil, Bochum, Germany (J.K., M.F., C.W., D.J., A.K.); Department Internal Medicine V, Comprehensive Pneumology Center, Member of the DLZ, University of Munich, Germany (J.B.); and Department of Thoracic Surgery, Lungenklinik Merheim, Kliniken der Stadt Köln, Cologne, Germany (E.S.)
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David Jungck
Department of Internal Medicine III for Pneumology, Allergology, Sleep and Respiratory Medicine, University Hospital Bergmannsheil, Bochum, Germany (J.K., M.F., C.W., D.J., A.K.); Department Internal Medicine V, Comprehensive Pneumology Center, Member of the DLZ, University of Munich, Germany (J.B.); and Department of Thoracic Surgery, Lungenklinik Merheim, Kliniken der Stadt Köln, Cologne, Germany (E.S.)
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Jürgen Behr
Department of Internal Medicine III for Pneumology, Allergology, Sleep and Respiratory Medicine, University Hospital Bergmannsheil, Bochum, Germany (J.K., M.F., C.W., D.J., A.K.); Department Internal Medicine V, Comprehensive Pneumology Center, Member of the DLZ, University of Munich, Germany (J.B.); and Department of Thoracic Surgery, Lungenklinik Merheim, Kliniken der Stadt Köln, Cologne, Germany (E.S.)
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Erich Stoelben
Department of Internal Medicine III for Pneumology, Allergology, Sleep and Respiratory Medicine, University Hospital Bergmannsheil, Bochum, Germany (J.K., M.F., C.W., D.J., A.K.); Department Internal Medicine V, Comprehensive Pneumology Center, Member of the DLZ, University of Munich, Germany (J.B.); and Department of Thoracic Surgery, Lungenklinik Merheim, Kliniken der Stadt Köln, Cologne, Germany (E.S.)
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Andrea Koch
Department of Internal Medicine III for Pneumology, Allergology, Sleep and Respiratory Medicine, University Hospital Bergmannsheil, Bochum, Germany (J.K., M.F., C.W., D.J., A.K.); Department Internal Medicine V, Comprehensive Pneumology Center, Member of the DLZ, University of Munich, Germany (J.B.); and Department of Thoracic Surgery, Lungenklinik Merheim, Kliniken der Stadt Köln, Cologne, Germany (E.S.)
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Abstract

Bacterial infections induce exacerbations in chronic lung diseases, e.g., chronic obstructive pulmonary disease (COPD), by enhancing airway inflammation. Exacerbations are frequently associated with right heart decompensation and accelerate disease progression. Endothelin receptor antagonists (ERAs) might have therapeutic potential as pulmonary vasodilators and anti-inflammatory agents, but utility in exacerbations of chronic lung diseases is unknown. We hypothesized that cytokine releases induced by lipopolysaccharide (LPS), the major bacterial trigger of inflammation, are reduced by ERAs in pulmonary vascular smooth muscle cells (PVSMCs). Ex vivo cultivated human PVSMCs were preincubated with the endothelin-A-receptor selective inhibitor ambrisentan, with the endothelin-B-receptor selective inhibitor BQ788 [sodium (2R)-2-{[(2S)-2-({[(2R,6S)-2,6-dimethyl-1-piperidinyl]carbonyl}amino)-4,4-dimethylpentanoyl][1-(methoxycarbonyl)-d-tryptophyl]amino}hexanoate], or with the dual blocker bosentan before stimulation with smooth LPS (S-LPS), rough LPS (Re-LPS), or a mixture of long and short forms (M-LPS). Expression of cytokines and LPS receptors (TLR4, CD14) were analyzed via enzyme-linked immunosorbent assay (ELISA) and/or quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). All LPS forms induced interleukin (IL)-6-, IL-8-, and granulocyte macrophage–colony stimulating factor (GM-CSF) release. Bosentan and BQ788 inhibited M-LPS-induced release of all cytokines and soluble CD14 (sCD14) but not TLR4 expression. Ambrisentan blocked M-LPS-induced IL-6 release but not IL-8, GM-CSF, or LPS receptors. IL-8 release induced by S-LPS, which requires CD14 to activate TLR4, was blocked by bosentan and BQ788. IL-8 release induced by Re-LPS, which does not require CD14 to activate TLR4, was insensitive to both bosentan and BQ788. In conclusion, PVSMCs contribute to inflammation in bacteria-induced exacerbations of chronic lung diseases. Inhibition of the endothelin-B receptor suppresses cytokine release induced by long/smooth LPS attributable to sCD14 downregulation. ERAs, particularly when targeting the endothelin-B receptor, might have therapeutic utility in exacerbations of chronic lung diseases.

Footnotes

    • Received December 12, 2012.
    • Accepted May 17, 2013.
  • This work was funded by Actelion Pharmaceuticals, Germany. Actelion Pharmaceuticals was not involved in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

  • dx.doi.org/10.1124/jpet.112.202358

  • J.K. has received travel grants from Actelion Pharmaceuticals. D.J. has received travel grants from Actelion Pharmaceuticals and from GlaxoSmithKline. J.B. has received travel grants, fees for speaking and research grants from Actelion Pharmaceuticals, fees for speaking from GlaxoSmithKline, and has served as consultant/advisor for Actelion Pharmaceuticals and GlaxoSmithKline. A.K. has received travel grants from Actelion Pharmaceuticals and from GlaxoSmithKline and research funding from Actelion Pharmaceuticals.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 346 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 346, Issue 2
1 Aug 2013
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Research ArticleInflammation, Immunopharmacology, and Asthma

Endothelin Receptor Antagonists Suppress LPS Responses

Jürgen Knobloch, Maria Feldmann, Chiara Wahl, David Jungck, Jürgen Behr, Erich Stoelben and Andrea Koch
Journal of Pharmacology and Experimental Therapeutics August 1, 2013, 346 (2) 290-299; DOI: https://doi.org/10.1124/jpet.112.202358

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Research ArticleInflammation, Immunopharmacology, and Asthma

Endothelin Receptor Antagonists Suppress LPS Responses

Jürgen Knobloch, Maria Feldmann, Chiara Wahl, David Jungck, Jürgen Behr, Erich Stoelben and Andrea Koch
Journal of Pharmacology and Experimental Therapeutics August 1, 2013, 346 (2) 290-299; DOI: https://doi.org/10.1124/jpet.112.202358
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