The fibroproliferative response to acute lung injury is characterized by fibroblast proliferation and rapid accumulation of collagen, the main extracellular matrix macromolecule in the lung. Efforts to modulate the process of excessive fibrosis of injured lung could shorten the recovery period from ARDS and reduce the extent of permanent lung damage. This project builds on two observations that have identified mechanisms of potential importance in the fibroproliferative response to lung injury. First, the NH2-terminal propeptide of type I procollagen (Col 1) is capable of feedback regulation of procollagen synthesis. Second, mitogenic and fibrogenic cytokines are up-regulated after acute lung injury induced by bleomycin in experimental animals. The objective of this project is to evaluate further these mechanisms in the context of lung remodeling after acute lung injury with the long-term goal of developing strategies that could eventually be the basis of therapeutic intervention. The hypotheses to be examined and experimental approaches are as follows. 1. Increased lung collagen synthesis after lung injury can be directly downregulated by administration of the Col 1 gene in a plasmic vector. To test this hypothesis we will use in vitro models including cultured fibroblasts and intact lung parenchymal cultures to develop approaches that optimize gene transfer to lung target cells and maximize expression of the Col 1 gene product. These strategies will be adapted to directly test the effect of Col 1 gene transfer on lung collagen synthesis after bleomycin-induced injury in experimental animals. 2. The fibroproliferative response to acute lung injury can be inhibited by specifically blocking the action of pivotal mitogenic and fibrogenic cytokines. We will examine collagen synthesis and cellular proliferation after administration of neutralizing antibodies to PDGF after bleomycin-induced lung injury. To elucidate the direct effects of local growth factor production and the potential role of systemic inflammatory cell recruitment, we will examine the effects of growth factor neutralization on fibroproliferation if both animals with bleomycin-induced injury and intact lung parenchymal cultures obtained at intervals after injury. 3. Markers of excessive lung collagen synthesis and cytokine production will identify a subset of patients with ARDS who are at risk for progressive disease associated with fibrosis, restrictive impairment, and increased mortality. Since the long-term therapeutic efficacy of interventions aimed at modifying the fibroproliferative response will be dependent upon identifying patients with ARDS who are at risk for excessive fibrosis, we will determine if markers of excessive lung collagen synthesis (i.e., type III procollagen propeptide) or cytokine production are associated with progressive disease, restrictive impairment and mortality. As intervention trials are initiated within SCOR projects, we will evaluate these factors as predictors of response to intervention.
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