Using mouse genomics to understand idiopathic interstitial fibrosis

Abstract

Idiopathic interstitial pneumonia represents a broad category of lung disorders characterized by scarring or fibrosis of the lung accompanied by varying degrees of inflammation. A number of important hypotheses based on clinical observations have substantially contributed to our understanding of the pathogenesis of the most insidious and devastating of the idiopathic interstitial pneumonias, idiopathic interstitial fibrosis (IIF). Patients with IIF usually present late in the course of their illness; thus, animal models of the early, preclinical stage of these diseases are needed. Although no model faithfully recapitulates the clinical course of disease or the histopathology observed in humans, all result in scarring of the lung and may therefore be used to understand the biological processes that contribute to this scarring. The purpose of this article is to summarize the application of mouse genetic and genomic tools to these models to advance our understanding of IIF and to describe emerging agnostic approaches to identifying genes important to the fibroproliferative component of IIF.

Figure 1.

Cluster analysis of a publicly available dataset, obtained from the Gene Expression Omnibus website (series accession number, GSE485), demonstrating that there are subsets of genes associated with an inflammatory and a fibrotic phase.

Figure 2.

Cluster analysis (left) of genes that are differentially expressed in 19 patients with idiopathic pulmonary fibrosis compared with six normal control subjects at a 5% false discovery rate and with greater than twofold over- or underexpression (Table 1). (Right) Expression changes observed in the mouse homologs of these genes over the course of a bleomycin exposure experiment in mice (data obtained from the Gene Expression Omnibus [series accession number, GSE485]); the genes have been clustered (grouped by similarity in expression) into two clusters to highlight the large fraction of genes observed to be up-regulated toward the late stage of the bleomycin exposure (contrast with the early/sustained inflammatory response shown in Figure 1). The graph (bottom right) shows this component of expression from a different perspective to illustrate the stronger response seen in sensitive versus resistant mice. Red bars, Balb/C saline; orange bars, Balb/C bleomycin; green bars, C57BL/6 saline; black bars, C57BL/6 bleomycin.

Figure 3.

Venn diagram of the intersection between LPS- and bleomycin-responsive gene list.