A vicious circle of alveolar macrophages and fibroblasts perpetuates pulmonary fibrosis via CCL18.
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.
Prasse
Antje
A
Department of Pneumology, University Hospital, Killianstr. 5, 79106 Freiburg, Germany. prasse@medizin.ukl.uni-freiburg.de
Pechkovsky
Dmitri V
DV
Toews
Galen B
GB
Jungraithmayr
Wolfgang
W
Kollert
Florian
F
Goldmann
Torsten
T
Vollmer
Ekkehard
E
Müller-Quernheim
Joachim
J
Zissel
Gernot
G
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
C111792:CCL18 protein, human; D019742:Chemokines, CC; D024042:Collagen Type I; D016207:Cytokines; D012333:RNA, Messenger