IPF is a fatal form of interstitial lung disease (ILD) of unknown etiology and for which there is no proven medical therapy. The median post diagnosis survival time is three years. While there are an estimated 5 million people affected by IPF world-wide, the prevalence continues to escalate. In the United States alone the incidence of IPF has increased considerably from a reported 50,000 people in 2000 to current estimates closer to 200,000. IPF is characterized by extensive parenchymal fibrosis which ultimately destroys the lungs' architecture and function. This fibrosis results from an unremitting accumulation of fibroblasts concomitant with their relentless deposition of extra cellular matrix, predominantly in the form of type 1 collagen. In light of this, the fibroblast is arguably the effector cell of the IPF phenotype. With no effective therapy available and over 40,000 individuals dying annually, as many as die from breast cancer, there is clearly an immediate need to expand our understanding of IPF, and specifically---the fibroblast. This dissertation (1) presents a novel isolation method of the pulmonary fibroblast cell population from IPF and normal lungs derived without long-term tissue culture; (2) comprehensively characterizes the genomic phenotype of these non-cultured isolated pulmonary fibroblasts in IPF in comparison to normal controls, and (3) documents the evolution and in vitro de-differentiation of this fibroblast model system. This model is then compared to the current in vitro explant-derived fibroblast model system The insights gleaned from these studies will further our understanding of the contribution of the fibroblast to the pathogenesis of IPF in addition to providing a platform for systematically investigating aberrant pathways. Moreover, the findings herein will promote and facilitate development of a more strategic approach to our investigations of this aberrant promoter of IPF progression---the fibroblast.
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