Pathogenesis of pulmonary fibrosis in interstitial lung disease. Alveolar macrophage PDGF(B) gene activation and up-regulation by interferon gamma.
Alveolar macrophages are believed to be central in orchestrating the fibrotic response in interstitial lung disease (ILD). To test the hypothesis that macrophages from patients with ILD were dedicated to growth factor production and that this was independent of other indices of macrophage activation, we measured the mRNA of the B chain of PDGF and TGF-beta, as well as HLA-DR-alpha in alveolar macrophages from patients with ILD and from normal control subjects. When alveolar macrophages were examined immediately after lavage, cells from patients with ILD had increased PDGF(B) but similar TGF-beta and HLA-DR-alpha mRNA when compared with control subjects. Discoordinate regulation of these genes was observed when alveolar macrophage PDGF(B) mRNA increased while TGF-beta and HLA-DR-alpha mRNA decreased after culture for 24 h. This response was not disease-related as these changes were similar in cells from patients with ILD and from control subjects. Because a lymphocytic alveolitis is present in many cases of ILD, we asked whether interferon gamma (IFN-gamma) modulated the activation of these genes. In both the patients and the control subjects, PDGF(B) and HLA-DR-alpha, but not TGF-beta, mRNA were increased after incubation with IFN-gamma. These results indicate that PDGF(B) mRNA may be increased in alveolar macrophages in ILD and that PDGF(B), TGF-beta, and HLA-DR-alpha are independently regulated genes in alveolar macrophages, but that IFN-gamma increases both PDGF(B) and HLA-DR-alpha mRNA. We speculate that IFN-gamma induced PDGF(B) gene activation may be an important mechanism by which lymphocytes promote pulmonary fibrosis.
Shaw
R J
RJ
Department of Medicine, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206.
Benedict
S H
SH
Clark
R A
RA
King
T E
TE
D000328:Adult; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010982:Platelet-Derived Growth Factor / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D020574:Proto-Oncogene Proteins c-sis; D011650:Pulmonary Alveoli / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000032:analysis; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D006684:HLA-DR Antigens; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma