A Vicious Circle of Alveolar Macrophages and Fibroblasts Perpetuates Pulmonary Fibrosis via CCL18

Am J Respir Crit Care Med. 2006 Apr 1;173(7):781-92. doi: 10.1164/rccm.200509-1518OC. Epub 2006 Jan 13.

Abstract

Rationale: Recently, models of macrophage activation have been revised. Macrophages stimulated with Th2 cytokines have been classified as alternatively activated.

Objectives: 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.

Measurements and main 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biopsy
  • Bronchoalveolar Lavage Fluid / cytology
  • Cell Line
  • Chemokines, CC / genetics*
  • Collagen Type I / metabolism
  • Cytokines / pharmacology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Gene Expression*
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • In Vitro Techniques
  • Macrophage Activation / drug effects
  • Macrophage Activation / physiology*
  • Macrophages, Alveolar / drug effects
  • Macrophages, Alveolar / metabolism*
  • Macrophages, Alveolar / pathology
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / metabolism*
  • Pulmonary Fibrosis / pathology
  • RNA, Messenger / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • CCL18 protein, human
  • Chemokines, CC
  • Collagen Type I
  • Cytokines
  • RNA, Messenger