Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal lung disease characterized by fibroblast proliferation and extracellular matrix deposition leading to irreversible destruction of lung architecture. Anti-inflammatory approaches to treating IPF are unsuccessful in most instances leading to a shift in the paradigm of pathogenesis from that of chronic inflammation to a dissociation between the inflammatory response and unrelenting tissue fibrosis. The pathogenic mechanisms in IPF are unknown and one hypothesis to explain the episodic nature of deterioration in patients with IPF is that an abnormal host response to injury exists in a susceptible host resulting in an exaggerated fibrotic response to a routine lung injury. One of the limitations in elucidating pathogenic mechanisms in progressive fibrosis is the lack of model systems to investigate unremitting fibrosis. We have identified a genetic deficiency in mice that leads to progressive fibrosis in the absence of increased lung inflammation following acute non-infectious lung injury. Mice deficient in CXCR3, the receptor for the interferon-gamma inducible CXC chemokines CXC9, 10 and 11 (Mig, IP-10 and ITAC) develop severe and progressive fibrosis after lung injury. This observation has led us to the hypothesis that an important component of progressive pulmonary fibrosis is a failure of endogenous host defense mechanisms to limit the extent of tissue remodeling. Our preliminary data suggest that interferon-gamma is produced as an early response to lung injury and requires the presence of CXCR3. We have identified CXCR3 as an important regulator of both the innate response to lung injury and the subsequent fibroproliferative response. The goals of this proposal are to elucidate the mechanisms leading to unremitting fibrosis in CXCR3 deficiency and identify the mechanisms of the protective effect of interferon-gamma on the fibroproliferative response to lung injury. Identifying mechanisms of progressive fibrosis and failures in host defense could lead to new therapeutic options in patients with IPF.
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