Complex regulation of pulmonary inflammation and fibrosis by CCL18

Am J Pathol. 2007 Aug;171(2):428-37. doi: 10.2353/ajpath.2007.061167. Epub 2007 Jun 14.


Elevated pulmonary levels of CCL18 have been associated with influx of T lymphocytes, collagen accumulation, and a decline in lung function in pulmonary fibrosis patients. We previously reported that overexpression of CCL18 in mouse lungs triggers selective infiltration of T lymphocytes and moderate lymphocyte-dependent collagen accumulation. We hypothesized that in combination with bleomycin injury, overexpression of CCL18 will worsen the severity of lung inflammation and fibrosis. Mice were infected with a replication-deficient adenovirus encoding CCL18 and then instilled with bleomycin; control mice were challenged with either CCL18 overexpression or bleomycin. Additive effects of CCL18 overexpression and bleomycin injury were observed on pulmonary inflammation, particularly on T-cell infiltration, and increased levels of tumor necrosis factor-alpha, interferon-gamma, matrix metalloproteinase (MMP)-2, and MMP-9. Despite the additive effect on inflammation, CCL18 overexpression unexpectedly attenuated the bleomycin-induced collagen accumulation. Pulmonary levels of active transforming growth factor-beta1 mirrored the changes in collagen levels. Depletion of T cells with antilymphocyte serum or pharmacological inhibition of MMPs with GM6001 abrogated accumulation of collagen and increases in the levels of tumor necrosis factor-alpha, interferon-gamma, and active transforming growth factor-beta1. Thus, CCL18-stimulated T-lymphocytic infiltration is by itself mildly profibrotic to a healthy lung, whereas it partially protects against lung fibrosis in an inflammatory profibrotic pulmonary milieu.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Antigens, CD / analysis
  • Bleomycin / pharmacology
  • Cells, Cultured
  • Chemokines, CC / genetics
  • Chemokines, CC / metabolism*
  • Chemokines, CC / pharmacology
  • Collagen / metabolism
  • Dipeptides / pharmacology
  • Dose-Response Relationship, Drug
  • Flow Cytometry
  • Genetic Vectors / genetics
  • Humans
  • Hydroxyproline / metabolism
  • Interferon-gamma / metabolism
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology*
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase Inhibitors
  • Mice
  • Mice, Inbred C57BL
  • Pneumonia / genetics
  • Pneumonia / metabolism
  • Pneumonia / pathology*
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / pathology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / pathology
  • Transfection / methods
  • Tumor Necrosis Factor-alpha / metabolism


  • Antibiotics, Antineoplastic
  • Antigens, CD
  • Chemokines, CC
  • Dipeptides
  • Matrix Metalloproteinase Inhibitors
  • N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide
  • Tumor Necrosis Factor-alpha
  • Bleomycin
  • Interferon-gamma
  • Collagen
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Hydroxyproline