The factors that initiate and maintain chronic idiopathic interstitial pneumonias (lIP) remain enigmatic thereby severely limiting the treatment options available to these patients. Pulmonary biopsies from lIP patients exhibit several unique characteristics not shared by similar biopsies from non-lIP patients, one of which is the exaggerated presence of type-2 cytokines such as interleukin-4 (IL-4) and IL-13. Experimental data suggest that both cytokines are potent pro-fibrotic mediators in the lung. Preliminary data provided in this proposal shows that primary lIP pulmonary fibroblasts derived from surgical lung biopsies (SLBs) and transbronchial biopsies (TBBs) exhibit increased levels of receptor subunits that bind IL-4 and IL-13. In addition, lIP pulmonary fibroblasts exhibit heightened responsive to both ligands as evidenced by exuberant fibroblast activation, proliferation and fibrosis. Few strategies currently exist that concomitantly modulate the in vivo activities of both type-2 cytokines, aside from a chimeric protein comprised of IL-13 and a truncated version of the Pseudomonas exotoxin A (IL13-PE). IL13-PE and other immunotoxins have been employed clinically to specifically eliminate brain tumor cells over-expressing receptors for IL-4 and IL-13. The working hypothesis of the present proposal is that an effective treatment strategy in lIP involves employing IL13-PE to eliminate IL-4- and IL-13-responsive lIP pulmonary cells, primarily fibroblasts, consequently ridding the lung of instigators of pulmonary remodeling. This hypothesis will be addressed by focusing on SLB and TBBs, and primary pulmonary SLB- and TBB-derived fibroblast lines from IIP and non-IIP patients, and demonstrating the specificity, safety and therapeutic efficacy of IL13-PE clinically. Specific areas to be addressed in this proposal include: 1) to characterize the IL-4 and IL-13 receptor subunits in primary fibroblast lines from IIP and non-IIP patients and determine the effects of IL13-PE on these cell lines; 2) to characterize the cellular expression of IL-4 and IL-13 and their respective receptor subunits in SLBs and TBBs from IIP and non-IIP patients; 3) To characterize the IL-4, IL-13, IL-4Ra, IL-13Ra1, and IL-13Ra2 expression profiles in fibrotic foci in lung biopsies (SLBs) from IIP patients.; 4) to determine the safety of aerosolized IL13-PE treatment in a consenting and informed IIP patient population. The proposed studies will critically evaluate a pathophysiologic paradigm in IIP that has not been thoroughly examined to date.
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