Date Published: January 15, 2010
Publisher: Public Library of Science
Author(s): Rogério S. Rosada, Ana P. Moreira, Fabiani G. Frantz, Raj K. Puri, Aquilur Rahman, Theodore J. Standiford, Carlos R. Zárate-Bladés, Célio L. Silva, Cory M. Hogaboam, Mauricio Rojas. http://doi.org/10.1371/journal.pone.0008721
Abstract: We have previously explored a therapeutic strategy for specifically targeting the profibrotic activity of IL-13 during experimental pulmonary fibrosis using a fusion protein comprised of human IL-13 and a mutated form of Pseudomonas aeruginosa exotoxin A (IL13-PE) and observed that the intranasal delivery of IL13-PE reduced bleomycin-induced pulmonary fibrosis through its elimination of IL-13-responsive cells in the lung. The aim of the present study was to determine whether the presence of an immune response to P. aeruginosa and/or its exotoxin A (PE) would diminish the anti-fibrotic properties of IL13-PE.
Partial Text: Idiopathic pulmonary fibrosis (IPF) is a fatal, interstitial lung disease characterized by persistent tissue scarring for which there is no effective therapy. The diagnostic lesion of IPF is the fibroblastic foci comprised of a heterogeneous mix of epithelial cells and fibroblasts, which, it is postulated, forms as a result of an inappropriate wound healing response to an unknown injurious agent . Since the overall cytokine pattern in biopsies and alveolar macrophages from patients with interstitial pneumonia appears to be more Th2-type (i.e., IL-4 and IL-13) than Th1-type (i.e., IL-12 and IFN-γ) , , , , a highly anticipated antifibrotic strategy within the lung entails the targeted inhibition of both IL-4 and IL-13. Although transgenic over-expression of IL-13 alone in the lung leads to the development of pulmonary fibrosis , , both IL-4 and IL-13 appear to contribute to the development of pulmonary fibrosis , , presumably due to their ability to act directly on pulmonary fibroblasts  and mononuclear cells/macrophages . IL-4Rα and IL-13Rα1 form a functional receptor complex that binds both ligands , . IL-13, but not IL-4 , also binds with 100-fold higher affinity for IL-13Rα2 than IL-13Rα1 . IL-13R subunits are expressed on a variety of immune and nonimmune cells, including B cells, NK cells, monocytes, mast cells, endothelial cells, and fibroblasts , , , , .
The bleomycin model is one of the best-characterized models of fibrosis since this chemotherapeutic invokes a highly reproducible inflammatory response that ultimately leads to fibroblast proliferation and collagen deposition , . IL-13 is one of the dominant pro-fibrotic cytokines produced during the development of fibrosis in the bleomycin model since it directly activates fibroblasts . Puri and colleagues ,  have previously shown that tumor cells expressing IL-13Rα2 are susceptible to the cytotoxic effects of IL13-PE making this chimeric protein a highly effective anti-tumor agent, and we have extended these findings to show that targeting IL-13 responsive cells such as fibroblasts is also highly effective in treating established fibrotic responses in the lung . Prior to further development of IL13-PE as a therapeutic in clinical disease we undertook the present study in order to evaluate whether prior exposure to P. aeruginosa pathogen or IL13-PE altered the therapeutic potential of IL-13 immunotoxin. Our study highlighted two important findings: 1) immune responses to Pseudomonas and/or its exotoxin actually protect mice from bleomycin-induced pulmonary fibrosis; 2) neutralizing antibodies against Pseudomonas and/or its exotoxin do not hamper the therapeutic effect of IL13-PE delivered into the fibrotic lung.