Emphysema, a form of chronic obstructive lung disease, is a major cause of morbidity and mortality particularly in the smoking population. The disease develops slowly over many years and is difficult to diagnose before irreverible, clinically significant alterations have occurred in the lung. Studies of human pathology and animal models of the disease strongly suggest that destruction of lung elastic fibers plays a key role in the pathogenesis of the disease in which elastic recoil is lost. This degradation is probably mediated by release of elastase into the diseastitium by newtrophils or macrophages which overwhelms the local antiproteinase activity. We have evidence that peptides released from elastin fibers during the destructive process appear in the seru. This project is devided into two sections. In the first part, involving human subjects, studies on the measurement of serum levels of elastin-derived peptides and their relationship to cigarette smoking and emphysema are proposed. The major objective of these studies is to determine whether immunologic assays of elastin-derived peptides in the sera can be used to evaluate the progression and severity of emphysema. A corollary of this goal is the identification of those individuals who have a high risk of developing emphysema before significant clinical symptoms or pulmonary function abnormalities occur. We have developed an enzyme-linked immunsosorbent assay for human elastin peptides and will use this assay first to determine factors which influence serum elastin in peptide levels in non-smokers. We will then determine whether there is a relationship between the intensity of smoking and serum elastin peptide levels and whether these levels are related to the development of spirometric evidence of airflow limitation. In these studies we will be collaborating with ongoing epidemiologic programs at the University of Arizona and the University of Oregon. In the second part of the project, we will administer elastase intratracheally to hamsters and determine whether immunologic quantitation of elastin peptides in the serum can be used to follow the course of emphysema development by correlating these peptide levels with histopathologic measurements. We will than use the elastin-treated hamster model to test agents and regimens which may be potentially useful in the treatment of emphysema.
NIH ExPorter
NIH ExPorter