Lung injury can lead to respiratory distress and eventual fibrosis in both adults (eg. ARDS) and infants (eg. Bronchopulmonary Dysplasia). Inflammation with influx of neutrophils and macrophages and production of cytokines are early events following injury in both humans and in animal models. In the rat model of intratracheal instillation of bleomycin, an early inflammatory response is seen with increased expression of cytokines such as TGF-beta1 and TNF-A. Our recent data show a selective deficiency of surfactant proteins-B and -C (SP-B,SP-C) and surfactant dysfunction after bleomycin injury. Increased long concentrations of hyaluronan (hyaluronic acid, HA) are observed in human lung diseases and also after bleomycin injury in rats. In this model, treatment with an HA-binding peptide (predicted to sequester HA and thereby competitively block receptor action) inhibits alveolar macrophage motility in vitro and blunts the inflammatory response after lung injury. Further, we hypothesize that elaboration of cytokines by accumulating macrophages inhibits the expression of SP-B and SP-C, resulting of respiratory distress, and also promotes fibrosis.
The first aim of the proposed studies will examine the effects of various blocking strategies to determine the sequence of events following acute lung injury. Thus, HA blockers and anti-cytokine antibodies will be examine din separate experiments to determine their effects on HA content, inflammatory infiltrate, cytokine levels, decreased SP gene expression and increased collagen accumulation after injury. Experiments in the second aim will investigate the mechanisms of cytokine inhibition of SP- B and SP-C expression using rat lung explants and cultured type II cells addressing the relative contributions of transcription and message stability. Further, growth factor-mediated cytoplasmic trapping of critical transcription factors (TTF-1/HNF-3) will be examined in injured lungs, lung explants and cultured type II cells. Transcriptional regulation of SP- B after injury and the effect of blocking strategies will be tested in mice expressing a reporter gene drive by the SP-B promoter In the third aim, the relative contributions of the HA receptors CD44 and RHAMM in the response to bleomycin injury will be examined suing either CD44+ mice, or mice with a macrophage-specific RHAMM knock-out. These studies will determine the role of HA and its major receptor in inflammation after lung injury, and the role of cytokines in altered surfactant function. The findings of these studies may have future therapeutic application in limiting inflammation and respiratory distress occurring after lung injury in humans.
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| McDevitt, Theresa M; Gonzales, Linda W; Savani, Rashmin C et al. (2007) Role of endogenous TGF-beta in glucocorticoid-induced lung type II cell differentiation. Am J Physiol Lung Cell Mol Physiol 292:L249-57 |
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| Casey, John; Kaplan, Jennifer; Atochina-Vasserman, Elena N et al. (2005) Alveolar surfactant protein D content modulates bleomycin-induced lung injury. Am J Respir Crit Care Med 172:869-77 |
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