Repair of the lung after injury can restore normal gas exchange or produce a fibroproliferative disorder that leads to excessive scarring and impaired lung function. The long term goal of this proposal is to elucidate the molecular mechanisms that mediate fibrogenesis at the alveolar level. In rodent model of pulmonary fibrosis, a single inhalation exposure to asbestos fibers initiates the events that generate a fibrotic scar at the sites of fiber deposition in the lung. The preliminary data presented within this proposal demonstrate expression of the proliferating cell nuclear antigen (PCNA), an essential DNA replication and repair protein, at the sites of the developing fibrotic lesions within twenty four hours of inhalation exposure of rats or mice to chrysotile asbestos. To establish the molecular mechanisms leading to PCNA expression in the rodent model of asbestos-induced pulmonary fibrosis, we will compare expression of a transgene with wild-type and mutant forms of the human PCNA promoter after inhalation exposure to fibrogenic asbestos fibers. Our analysis of transgene expression in the asbestos-exposed animals will be compared to a simultaneous analysis of the endogenous mouse PCNA gene. PCNA functions as an auxiliary protein for DNA polymerases delta and epsilon during DNA replication and repair. These functions of PCNA would directly correlate with the regenerative capacity of the lung. Our published and preliminary data demonstrate transcriptional regulation of the PCNA promoter by the P53 tumor suppressor protein, an important mediator of the cellular response to DNA damage. We propose that p53- mediated activation of the PCNA promoter constitutes a cellular response to DNA damage. This inducer of growth arrest (p53) and mitogens (growth factors) are expressed simultaneously with PCNA in the developing lesion following asbestos exposure. Our immediate objective is to establish how these conflicting growth signals regulate PCNA expression in an animal model of fibrogenic lung disease.
| Nelson, A; Mendoza, T; Hoyle, G W et al. (2001) Enhancement of fibrogenesis by the p53 tumor suppressor protein in asbestos-exposed rodents. Chest 120:33S-34S |
