Rapid Activation of PDGF-A and -B Expression at Sites of Lung Injury in Asbestos-exposed Rats

Abstract

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.

Specific Inhibitors of Platelet-Derived Growth Factor or Epidermal Growth Factor Receptor Tyrosine Kinase Reduce Pulmonary Fibrosis in Rats

“…Asbestos fibers also stimulate the secretion of PDGF isoforms and TGF-␣ in vitro and in vivo in rodent models. 10,12,30 Due to the potent mitogenic effect of these growth factors, these studies suggest a role for PDGF and EGF receptor ligands in causing a fibrotic response. However, they do not clearly establish a link between PDGF-or EGF-mediated cell proliferation and the subsequent deposition of collagen, which defines the fibrotic lesion.…”

Leptin receptor expression in fetal lung increases in late gestation in the baboon: a model for human pregnancy

“…Immunohistochemistry was performed according to the technique of Liu et al (1997), as adapted for use in our laboratory. Fetal baboon lung was fixed in 10% buffered formalin, paraffin imbedded and 5 mm sections cut.…”

Interstitial fibrosis and growth factors.

“…For (18). The proliferating epithelium has been identified as a producer of these molecules as well (19,20). In addition, the mesenchymal cells, fibroblasts and myofibroblasts, not only release matrix but also produce significant amounts of the very molecules that control their proliferation and synthesis of the connective tissue components (21)(22)(23).…”

“…Both PDGF-A and -B chain mRNA and peptide are upregulated at the sites of developing asbestos-induced fibrotic lesions ( 19).…”