The central rationale underlying this proposal is that inflammatory reactions in the lung usually resolve. Accordingly, the progressive inflammatory and fibrotic reactions seen as interstitial lung diseases would represent some alteration or defect of this resolution process. We will study resolution and progression of pulmonary inflammation by comparing self- limiting, subacute or progressive and fibrotic reactions in the rabbit. Radiolabelled neutrophils and monocytes will be used to investigate mechanisms by which the accumulation of these cell types ceases or progresses. Routes and rates of clearance of inflammatory cells from the lung will be studied, thus providing data on the inflammatory cell load at any one time. Additionally, since senescent neutrophils have been shown to be ingested by fibroblasts in vitro, we will determine if this represents a route of clearance in vivo, and in particular if such ingestion alters the function of the fibroblasts. Investigation of progression of pulmonary inflammation will focus on mechanisms by which inflammatory cell emigration is maintained. In particular we will examine the possibility that fragmentation of connective tissue proteins provides a persistent source of chemoattractants for monocyte. Finally, two possibilities relating inflammatory processes to fibrosis will be tested: 1) that neutrophil influx is profibrogenic and 2) that the extent of deepithelialization induced by the inflammation or initial injurious factor, dictates the degree of fibrosis. The use of methodology in this project for detailed examination of inflammatory cell trafficking, biochemical and physiologic assessment, lavage, histology and morphometry will also allow specific intervention studies to be carried out in such a fashion as to determine not only their effect on outocome but also on the earlier pathogenetic events which led to this. The project involves extensive interaction with all the other portions of the SCOR and makes major use of the Morphology Core. In particular we hope to define mechanisms and methodology in the experimental animal which we will extend into the patients with project 1 a) to determine elements of pathogenesis and b) to assess the stage of the disease and thus provide rationale or appropriate therapy.
Showing the most recent 10 out of 220 publications
