title: Smooth muscle cells relay acute pulmonary inflammation via distinct ADAM17/ErbB axes.
abstract: In acute pulmonary inflammation, danger is first recognized by epithelial cells lining the alveolar lumen and relayed to vascular responses, including leukocyte recruitment and increased endothelial permeability. We supposed that this inflammatory relay critically depends on the immunological function of lung interstitial cells such as smooth muscle cells (SMC). Mice with smooth muscle protein-22α promotor-driven deficiency of the disintegrin and metalloproteinase (ADAM) 17 (SM22-Adam17(-/-)) were investigated in models of acute pulmonary inflammation (LPS, cytokine, and acid instillation). Underlying signaling mechanisms were identified in cultured tracheal SMC and verified by in vivo reconstitution experiments. SM22-Adam17(-/-) mice showed considerably decreased cytokine production and vascular responses in LPS- or acid-induced pulmonary inflammation. In vitro, ADAM17 deficiency abrogated cytokine release of primary SMC stimulated with LPS or supernatant of acid-exposed epithelial cells. This was explained by a loss of ADAM17-mediated growth factor shedding. LPS responses required ErbB1/epidermal growth factor receptor transactivation by TGFα, whereas acid responses required ErbB4 transactivation by neuregulins. Finally, LPS-induced pulmonary inflammation in SM22-Adam17(-/-) mice was restored by exogenous TGFα application, confirming the involvement of transactivation pathways in vivo. This highlights a new decisive immunological role of lung interstitial cells such as SMC in promoting acute pulmonary inflammation by ADAM17-dependent transactivation.
authors.affiliation: Institute of Pharmacology and Toxicology, Rheinisch-Westfaelische Technische Hochschule Aachen University, 52074 Aachen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Dreymueller
authors.forename: Christian
authors.initials: C
authors.lastname: Martin
authors.forename: Julian
authors.initials: J
authors.lastname: Schumacher
authors.forename: Esther
authors.initials: E
authors.lastname: Groth
authors.forename: Julia Katharina
authors.initials: JK
authors.lastname: Boehm
authors.forename: Lucy Kathleen
authors.initials: LK
authors.lastname: Reiss
authors.forename: Stefan
authors.initials: S
authors.lastname: Uhlig
authors.forename: Andreas
authors.initials: A
authors.lastname: Ludwig
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D018739:Oncogene Proteins v-erbB / Q000235:genetics / Q000378:metabolism*; D011014:Pneumonia / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D066247:Receptor, ErbB-4; D015533:Transcriptional Activation / Q000235:genetics; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D008840:Microfilament Proteins; D009124:Muscle Proteins; D018739:Oncogene Proteins v-erbB; C058992:Tagln protein, mouse; D016211:Transforming Growth Factor alpha; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse