title: Inflammatory responses of airway smooth muscle cells and effects of endothelin receptor antagonism.
abstract: Endothelin receptor antagonists (ETRAs), authorized for pulmonary hypertension, have failed to prove their utility in chronic lung diseases with corticosteroid-resistant airway inflammation when applied at late disease stages with emphysema/fibrosis. Earlier administration might prove effective by targeting the interaction between airway inflammation and tissue remodeling. We hypothesized that human airway smooth muscle cells (HASMCs) participate in linking inflammation with remodeling and that associated genes become differentially suppressed by ambrisentan (A-receptor selective ETRA) and bosentan (nonselective/dual ETRA). Inflammatory responses of ex vivo-cultivated HASMCs to TNF-α were investigated by whole-genome microarray analyses. qRT-PCR and ELISA were used to test inflammatory and remodeling genes for sensitivity to bosentan and ambrisentan and to investigate differential sensitivities mechanistically. ETRA and corticosteroid effects were compared in HASMCs from patients with chronic obstructive pulmonary disease. TNF-α induced the expression of 18 cytokines/chemokines and five tissue remodeling genes involved in severe, corticosteroid-insensitive asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and/or pulmonary hypertension. Thirteen cytokines/chemokines, MMP13, and WISP1 were suppressed by ETRAs. Eight genes had differential sensitivity to bosentan and ambrisentan depending on the endothelin-B receptor impact on transcriptional regulation and mRNA stabilization. Chemokine (C-C motif) ligands 2 and 5, granulocyte macrophage colony-stimulating factor, and MMP13 had increased sensitivity to bosentan or bosentan/dexamethasone combination versus dexamethasone alone. Suppression of cytokine and remodeling gene expression by ETRAs was confirmed in TNF-α-activated human bronchial epithelial cells. HASMCs and human bronchial epithelial cells participate in the interaction of inflammation and tissue remodeling. This interaction is targeted differentially by selective and nonselective ETRAs, which could be used in therapies of chronic lung diseases with corticosteroid-resistant airway inflammation at early disease stages to attenuate inflammation-induced airway remodeling.
authors.affiliation: Department of Internal Medicine III, University Hospital Bergmannsheil, Bochum, Germany. juergen.knobloch@bergmannsheil.de
authors.forename: Jürgen
authors.initials: J
authors.lastname: Knobloch
authors.forename: Yingfeng
authors.initials: Y
authors.lastname: Lin
authors.forename: Jürgen
authors.initials: J
authors.lastname: Konradi
authors.forename: David
authors.initials: D
authors.lastname: Jungck
authors.forename: Juergen
authors.initials: J
authors.lastname: Behr
authors.forename: Justus
authors.initials: J
authors.lastname: Strauch
authors.forename: Erich
authors.initials: E
authors.lastname: Stoelben
authors.forename: Andrea
authors.initials: A
authors.lastname: Koch
mesh_terms: D056151:Airway Remodeling; D000077300:Bosentan; D018925:Chemokines / Q000276:immunology; D065128:Endothelin Receptor Antagonists; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D053509:Matrix Metalloproteinase 13 / Q000276:immunology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010666:Phenylpropionates / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000473:pathology; D011724:Pyridazines / Q000494:pharmacology; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017466:Receptors, Endothelin / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology
chemical_list: D018925:Chemokines; D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D011724:Pyridazines; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C467894:ambrisentan; D000077300:Bosentan