The role of IL -13 in pulmonary fibrosis.
Jakubzick, Claudia Virginia
2003
Abstract
Severe forms of idiopathic interstitial pneumonia (IIP) such as usual interstitial pneumonia (UIP) can be impervious to modern steroid and immunosuppressive treatment regimens thereby emphasizing the need for novel effective therapies. Research attention has been directed towards understanding the cytokine networks that may affect fibroblast activation and, hence, the progression of certain IIPs. This led us to investigate the role of IL-13 and IL-13 receptor subunits in this process. Our first studies demonstrated that IL-13 receptor subunits were differentially regulated, leading us to investigate whether the elimination of fibroblasts (and possibly other pulmonary cell types) that were highly responsive to IL-4 and IL-13 exerted a therapeutic effect into the murine models characterized by abnormal fibrotic responses. The murine models used in our studies were <italic>Schistosoma Mansoni</italic> egg-induced pulmonary granuloma and the bleomycin-induced pulmonary fibrosis model. Conventional and novel methods were used during these dissertation studies: ELISA, RT-PCR Real-time TAQMAN PCR, Immunohistochemistry, densitometry, [<super>3</super>H]thymidine proliferation assay, hemacytometer, fibroblast tissue culture, and gene array analysis. IL-4, IL-13 and their corresponding receptor subunits, IL-4Ralpha, IL-13Ralpha1 and IL-13Ralpha2 were maximally expressed at the mRNA and protein level in whole lung samples from murine models during the development of pulmonary fibrosis. The elimination of IL-4 and IL-13 responsive pulmonary cells using a chimeric IL-13-immunotoxin molecule (IL13-PE) at specific times significantly attenuated the fibrotic response in these mouse models. Using clinical surgical lung biopsies (SLBs), we addressed the hypothesis that IL-4 and IL-13 receptor expression profile in the pulmonary fibroblast, SLB and fibroblastic foci directly correlates with the fibrotic state of the lung during IIP. Our studies showed that IIP is characterized by the abnormal expression of the receptor subunits that bind IL-4 and IL-13. IL-4 and IL-13 receptor subunits were altered in IIP patient SLBs and fibroblasts grown from these biopsies. Most importantly, the high affinity IL-13R subunit was present in greater abundance in SLBs and fibroblasts from IIP patients compared with patients who exhibited no evidence of pulmonary fibrosis (non-IIP). Interestingly, IL13-PE selectively target human pulmonary fibroblasts grown from IIP, whereas it had a minimal effect on fibroblasts from non-IIP patients. These data demonstrated that IL-4 and IL-13 are required for the initiation and maintenance of pulmonary fibrosis, and highlight the importance of further investigation of anti-fibrotic therapeutics that target both cytokines during pulmonary fibrosis.Subjects
Il-13 Interstitial Pneumonia Pulmonary Fibrosis Role
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