Excessive lung collagen is a fundamental abnormality associated with diffuse pulmonary fibrosis in man as well as bleomycin-induced pulmonary fibrosis in experimental animals. However, mechanisms involved in regulation of collagen accumulation in the extracellular matrix of fibrotic lung are incompletely understood. A central premise of this proposal is that lung collagen accumulation depends on both collagen production rate and extracellular deposition of collagen. Experiments are planned to identify factors that influence these pivotal steps in lung collagen accumulation. In the first part of the proposed research, cultured lung fibroblasts will be studied as a model of collagen accumulation. These in vitro systems have provided useful insights into mechanisms that are potentially important in vivo, but fundamental questions regarding the biology of this relatively simple model remain unanswered. Thus, the initial phase of this research will be directed toward characterizing the kinetics of collagen accumulation in vitro and examining the influence of culture conditions on rat lung fibroblast procollagen production, proteolytic processing of procollagen, and deposition of newly synthesized collagen into extracellular matrix. Regulation of collagen production and matrix formation within this in vitro system will then be studied. One series of studies will examine the role of substances that are endogenously produced by fibroblasts (i.e., prostaglandins, cycli nucleotides, and polyamines) and appear to represent fundamental mechanisms for regulation of cell metabolism. A second series of in vitro studies will examine the influence of exogenous substances produced by bronchoalvelor macrophages on fibroblast collagen production and matrix formation. Finally, the concepts derived from these in vitro studies will extended to more complex biological systems. In these studies, collagen synthesis and extracellular processing and deposition of newly-synthesized collagen will be examined in lung explant cultures from normal animals as well as animals with bleomycin-induced pulmonary fibrosis. The proposed studies, designed to elucidate cellular and biochemical mechanisms involved in modulation of lung collagen content, may be useful in understanding the pathogenesis of diffuse pulmonary fibrosis and may ultimately provide a basis for rational diagnostic and staging procedures, as well as therapeutic intervention in fibrotic lung diseases.
| Clark, J G; Greenberg, J (1987) Modulation of the effects of alveolar macrophages on lung fibroblast collagen production rate. Am Rev Respir Dis 135:52-6 |
