Rapid activation of PDGF-A and -B expression at sites of lung injury in asbestos-exposed rats.
The development of interstitial pulmonary fibrosis is associated with a variety of inflammatory mediators, including peptide growth factors and cytokines. In the work presented here, we have asked whether or not platelet-derived growth factor (PDGF)-A and -B genes and proteins are expressed in anatomic and temporal patterns consistent with this factor playing a role in the disease process. Using an established rat model of asbestos-induced fibroproliferative lung disease, we demonstrate elevated levels of PDGF-A and -B mRNAs in total lung RNA immediately after a single 5-h exposure to approximately 1,000 fibers/ml of chrysotile asbestos. In situ hybridization revealed the PDGF-A and -B in RNAs primarily in macrophages and bronchiolar-alveolar epithelial cells at sites of initial fiber deposition and lung injury. There was clear evidence of PDGF-A and -B mRNAs in interstitial cells as well. The pattern of in situ hybridization was entirely consistent with the appearance (established by immunohistochemistry) of PDGF-A and -B proteins by 24 h post-exposure in the same cell types. Both mRNAs and proteins remained detectable at the fiber deposition sites for almost 2 wk post-exposures. These findings are consistent with our previous studies showing increased mesenchymal cell proliferation and fibroproliferative lesions that progress at the sites where PDGF-A and -B are expressed. Although it is clear that multiple growth factors are produced simultaneously at sites of initial injury, we suggest that the PDGF isoforms could be playing a central role in the disease process based upon their potent mitogenic effects upon mesenchymal cells.
Liu
J Y
JY
Department of Pathology, Tulane University Medical Center, New Orleans, Louisiana 70112, USA.
Morris
G F
GF
Lei
W H
WH
Hart
C E
CE
Lasky
J A
JA
Brody
A R
AR
D000818:Animals; D017632:Asbestos, Serpentine / Q000633:toxicity*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D020574:Proto-Oncogene Proteins c-sis; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014746:Vimentin / Q000378:metabolism
D017632:Asbestos, Serpentine; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D014746:Vimentin; C075278:platelet-derived growth factor A