of Work: Fibroproliferative lung disease develops in a large number of patients who undergo treatment with high-dose chemotherapy. We hypothesize that platelet-derived growth factor (PDGF), an important lung cytokine that has potent chemotactic and proliferative effects on lung mesenchymal cells, plays an important role in the pathogenesis of this disease. We are collecting blood, bronchoalveolar lavage (BAL) fluid, and transbronchial biopsy specimens from patients before/after receiving chemotherapy in order to study differences in the following: (a) serum and BAL fluid PDGF levels; (b) PDGF receptor expression on lung mesenchymal cells; (c) capacity of BAL fluid and BAL cell conditioned medium to stimulate proliferation of human lung fibroblasts in vitro; and (d) expression of other cytokines (e.g. Interleukin-1_) and lipid mediators (e.g. Prostaglandin E2) that modulate PDGF receptor expression. We are also attempting to localize expression of PDGF isoforms and PDGF receptor subtypes in lungs of patients with/without disease by immunohistochemistry and in situ hybridization. BAL fluid isolated from a patient who developed fibroproliferative lung disease after chemotherapy stimulates thymidine incorporation in 34Lu cultured human lung fibroblasts in vitro. This proliferative effect is blocked by inhibitory antibodies to PDGF implicating the PDGF/PDGF-receptor pathway in the pathogenesis of the disease. 125I PDGF-AA binding assays reveal that cultured human lung fibroblasts constitutively express high levels of PDGF-_ receptor. Interestingly, pretreatment of cells with PGE2 decreases PDGF-AA binding suggesting that this lipid mediator may play a role in limiting the fibroproliferative response to lung injury in humans. Current efforts are focused on delineating the mechanisms whereby PGE2 may modulate PDGF-_ receptor expression. We hope that this study will provide insight into basic cellular, molecular, and biochemical mechanisms responsible for initiating and perpetuating the fibroproliferative response in patients exposed to environmental lung toxins and will set the stage for a second study aimed at novel therapeutic and preventative strategies for fibroproliferative lung disease.
| Scarborough, P E; Ma, J; Qu, W et al. (1999) P450 subfamily CYP2J and their role in the bioactivation of arachidonic acid in extrahepatic tissues. Drug Metab Rev 31:205-34 |
