Early granulocyte-macrophage colony-stimulating factor expression by alveolar inflammatory cells during bleomycin-induced rat lung fibrosis

Lab Invest. 1998 Dec;78(12):1493-502.

Abstract

Topical administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) into the subcutaneous tissue or in the pulmonary alveoli of the rat induces a fibrotic reaction characterized by the presence of alpha-smooth muscle actin-rich myofibroblasts, suggesting that GM-CSF plays a role in the development of fibrotic changes. A high level of expression of GM-CSF also has been demonstrated in epidermal cells during human atopic dermatitis. It is accepted that transforming growth factor beta1 (TGF-beta1) plays a key role in the modulation from fibroblast into myofibroblast, although it is not known how TGF-beta1 activity is stimulated. Up until now, no evidence of early GM-CSF expression during development of fibrosis has been reported. Herein we have studied, using RT-competitive PCR, the expression of GM-CSF mRNA during the early steps of pulmonary fibrosis development after intra-alveolar instillation of bleomycin, a well-established experimental model of this lesion. GM-CSF mRNA was already increased in the total lung at 6 hours and maximal at 12 hours after bleomycin instillation and returned to basal levels at 24 hours. This was followed by an increase of TGF-beta1 and TGF-beta receptor type II (but not of types I and III) mRNAs. Analyses of macrophages and polymorphonuclear neutrophils isolated by bronchoalveolar lavage 12 hours after bleomycin instillation indicated that they were responsible, at least in part, for the accumulation of GM-CSF mRNA. Our results show for the first time that GM-CSF is expressed, very early and temporarily, by inflammatory cells accumulating in the alveolus after bleomycin administration and before the appearance of TGF-beta1. Moreover, we have shown that GM-CSF induces the expression of TGF-beta1 mRNA by alveolar macrophages. Our data support the possibility that GM-CSF participates in the initial steps of the chain of events leading to fibrosis, perhaps through a stimulation of TGF-beta1 production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / analysis
  • Actins / genetics
  • Animals
  • Bleomycin / administration & dosage
  • Bleomycin / toxicity*
  • Dermatitis, Atopic / metabolism
  • Epidermis / metabolism
  • Female
  • Gene Expression Regulation / drug effects
  • Granulocyte-Macrophage Colony-Stimulating Factor / administration & dosage
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics*
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Humans
  • Instillation, Drug
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / metabolism
  • Protein-Serine-Threonine Kinases
  • Pulmonary Alveoli / drug effects
  • Pulmonary Alveoli / metabolism*
  • Pulmonary Alveoli / pathology
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / metabolism*
  • Pulmonary Fibrosis / pathology
  • Rats
  • Rats, Wistar
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription, Genetic / drug effects
  • Transforming Growth Factor beta / genetics

Substances

  • Actins
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Bleomycin
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II