title: A vicious circle of alveolar macrophages and fibroblasts perpetuates pulmonary fibrosis via CCL18.
abstract: BACKGROUND
  Recently, models of macrophage activation have been revised. Macrophages stimulated with Th2 cytokines have been classified as alternatively activated.
  
  
  OBJECTIVE
  This article examines the expression and regulation of CC chemokine ligand 18 (CCL18), a marker of alternative activation, by human alveolar macrophages (AMs).
  
  
  METHODS
  AM were obtained from bronchoalveolar lavage (BAL) fluid of patients with idiopathic pulmonary fibrosis, sarcoidosis, or hypersensitivity pneumonitis (n = 69) and healthy volunteers (n = 22). Expression of CCL18 was determined by quantitative reverse transcriptase-polymerase chain reaction, in situ hybridization, flow cytometry, and immunohistochemistry, respectively.
  
  
  RESULTS
  Spontaneous CCL18 production by BAL-derived cells was markedly increased in patients with pulmonary fibrosis and correlated negatively with pulmonary function test parameters. CCL18 gene expression and protein production were up-regulated in normal AMs after Th2 cytokine stimulation and/or coculture with human lung fibroblasts. Native collagen significantly up-regulated CCL18 expression in normal AMs activated with Th2 cytokines via a mechanism mediated by beta2-integrin/ scavenger receptor(s). Culture supernatants of AMs from patients with idiopathic pulmonary fibrosis increased collagen production by normal lung fibroblasts partly mediated via CCL18.
  
  
  CONCLUSIONS
  Our findings suggest that AMs from patients with pulmonary fibrosis disclose a phenotype of alternative activation and might be a part of a positive feedback loop with lung fibroblasts perpetuating fibrotic processes.
authors.affiliation: Department of Pneumology, University Hospital, Killianstr. 5, 79106 Freiburg, Germany. prasse@medizin.ukl.uni-freiburg.de
authors.forename: Antje
authors.initials: A
authors.lastname: Prasse
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Pechkovsky
authors.forename: Galen B
authors.initials: GB
authors.lastname: Toews
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jungraithmayr
authors.forename: Florian
authors.initials: F
authors.lastname: Kollert
authors.forename: Torsten
authors.initials: T
authors.lastname: Goldmann
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Vollmer
authors.forename: Joachim
authors.initials: J
authors.lastname: Müller-Quernheim
authors.forename: Gernot
authors.initials: G
authors.lastname: Zissel
mesh_terms: D001706:Biopsy; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002460:Cell Line; D019742:Chemokines, CC / Q000235:genetics*; D024042:Collagen Type I / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C111792:CCL18 protein, human; D019742:Chemokines, CC; D024042:Collagen Type I; D016207:Cytokines; D012333:RNA, Messenger