Interstitial lung disease (Il-D) encompasses a group of pulmonary inflammatory disorders that are characterized by excessive tissue injury and progressive fibrosis. Clinical and laboratory evidence suggest that ILD is a consequence of a poorly regulated pulmonary inflammatory process because of the persistence of one or several inflammatory signals. Recent experimental data suggest that the lung fibroblast is not a bystander during chronic inflammatory responses in the lung, rather this structural cell has a very specialized role in the recruitment and regulation of immune cells that infiltrate the interstitial space. The role of the fibroblast during ILD has expanded because of the recent recognition that this cell markedly increases the generation of chemotactic proteins (chemokines) and directly responds to these factors through the expression of high-specialized chemokine receptors. Chemokines affect both the proliferation and synthetic capacity of pulmonary fibroblasts. Although increased chemokine levels during ILD have been reported, little is known about changes in the chemokine and chemokine receptor expression in the fibroblast during ILD, nor is it known whether the temporal pattern of expression of chemokine receptors by these cells may aid in differentiating the various pathologically distinct types of ILD or success of ILD treatment. Thus, the overall aim of this proposal is to characterize the pattern of chemokine and chemokine receptor expression associated with non-specific interstitial pneumonia (NSIP)-cellular, NSIP-fibrotic, usual interstitial pneumonia (UIP)-discordent, and UIP-cordent in open lung biopsies (OLB), fibrotic foci and cultured fibroblasts from OLB and transbronchial biopsies. The following specific aims will be addressed using powerful new techniques including TAQMAN quantitative polymerase chain reaction (PCR) and laser capture microscopy: 1) to characterize the chemokine and chemolcine receptor profile in OLB from patients at the time of ILD diagnosis, and specifically identify the chemokine receptor profile in fibrotic foci from histological samples. 2) to characterize the chemokine and chemokine receptor profile in fibroblasts cultured from open lung biopsies at the time of ILD diagnosis. 3) to examine changes in the chemokine and chemokine receptor profile in cultured transbronchial biopsy fibroblasts at defined intervals after initial ILD diagnosis and during a defined ILD treatment regimen. Taken together, these studies entail an examination of the expression of chemokines and their receptors in OLB, fibrotic foci and cultured lung fibroblasts at the time of diagnosis and during ILD treatment.
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