title: Endothelin-1 induces proliferation of human lung fibroblasts and IL-11 secretion through an ET(A) receptor-dependent activation of MAP kinases.
abstract: Endothelin-1 (ET-1) is implicated in the fibrotic responses characterizing interstitial lung diseases, as well as in the airway remodeling process occurring in asthma. Within such a context, the aim of our study was to investigate, in primary cultures of normal human lung fibroblasts (NHLFs), the ET-1 receptor subtypes, and the intracellular signal transduction pathways involved in the proliferative effects of this peptide. Therefore, cells were exposed to ET-1 in the presence or absence of an overnight pre-treatment with either ET(A) or ET(B) selective receptor antagonists. After cell lysis, immunoblotting was performed using monoclonal antibodies against the phosphorylated, active forms of mitogen-activated protein kinases (MAPK). ET-1 induced a significant increase in MAPK phosphorylation pattern, and also stimulated fibroblast proliferation and IL-6/IL-11 release into cell culture supernatants. All these effects were inhibited by the selective ET(A) antagonist BQ-123, but not by the specific ET(B) antagonist BQ-788. The stimulatory influence of ET-1 on IL-11, but not on IL-6 secretion, was prevented by MAPK inhibitors. Therefore, such results suggest that in human lung fibroblasts ET-1 exerts a profibrogenic action via an ET(A) receptor-dependent, MAPK-mediated induction of IL-11 release and cell proliferation.
authors.affiliation: Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Gallelli
authors.forename: Girolamo
authors.initials: G
authors.lastname: Pelaia
authors.forename: Bruno
authors.initials: B
authors.lastname: D'Agostino
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cuda
authors.forename: Alessandro
authors.initials: A
authors.lastname: Vatrella
authors.forename: Donatella
authors.initials: D
authors.lastname: Fratto
authors.forename: Vincenza
authors.initials: V
authors.lastname: Gioffrè
authors.forename: Umberto
authors.initials: U
authors.lastname: Galderisi
authors.forename: Marilisa
authors.initials: M
authors.lastname: De Nardo
authors.forename: Claudio
authors.initials: C
authors.lastname: Mastruzzo
authors.forename: Elisa Trovato
authors.initials: ET
authors.lastname: Salinaro
authors.forename: Mauro
authors.initials: M
authors.lastname: Maniscalco
authors.forename: Matteo
authors.initials: M
authors.lastname: Sofia
authors.forename: Nunzio
authors.initials: N
authors.lastname: Crimi
authors.forename: Francesco
authors.initials: F
authors.lastname: Rossi
authors.forename: Mario
authors.initials: M
authors.lastname: Caputi
authors.forename: Francesco S
authors.initials: FS
authors.lastname: Costanzo
authors.forename: Rosario
authors.initials: R
authors.lastname: Maselli
authors.forename: Serafino A
authors.initials: SA
authors.lastname: Marsico
authors.forename: Carlo
authors.initials: C
authors.lastname: Vancheri
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D017370:Interleukin-11 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000166:cytology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000235:genetics; D013997:Time Factors
chemical_list: D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D017370:Interleukin-11; D015850:Interleukin-6; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D020928:Mitogen-Activated Protein Kinases