Role of diminished epithelial GM-CSF in the pathogenesis of bleomycin-induced pulmonary fibrosis.
Evidence derived from human and animal studies strongly supports the notion that dysfunctional alveolar epithelial cells (AECs) play a central role in determining the progression of inflammatory injury to pulmonary fibrosis. We formed the hypothesis that impaired production of the regulatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) by injured AECs plays a role in the development of pulmonary fibrosis. To test this hypothesis, we used the well-characterized model of bleomycin-induced pulmonary fibrosis in rats. GM-CSF mRNA is expressed at a constant high level in the lungs of untreated or saline-challenged animals. In contrast, there is a consistent reduction in expression of GM-CSF mRNA in the lung during the first week after bleomycin injury. Bleomycin-treated rats given neutralizing rabbit anti-rat GM-CSF IgG develop increased fibrosis. Type II AECs isolated from rats after bleomycin injury demonstrate diminished expression of GM-CSF mRNA immediately after isolation and in response to stimulation in vitro with endotoxin compared with that in normal type II cells. These data demonstrate a defect in the ability of type II epithelial cells from bleomycin-treated rats to express GM-CSF mRNA and a protective role for GM-CSF in the pathogenesis of bleomycin-induced pulmonary fibrosis.
Christensen
P J
PJ
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan School of Medicine and Veterans Affairs Medical Center, Ann Arbor, Michigan 48105, USA. pchriste@umich.edu
Bailie
M B
MB
Goodman
R E
RE
O'Brien
A D
AD
Toews
G B
GB
Paine
R
R
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001761:Bleomycin; D002478:Cells, Cultured; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006909:Hydroxyproline / Q000378:metabolism; D008297:Male; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D000906:Antibodies; D012333:RNA, Messenger; D001761:Bleomycin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006909:Hydroxyproline