Abstract
The extracellular matrix (ECM) in idiopathic pulmonary fibrosis (IPF) drives fibrosis progression; however, the ECM composition of the fibroblastic focus (the hallmark lesion in IPF) and adjacent regions remains incompletely defined. Herein, we serially sectioned IPF lung specimens constructed into tissue microarrays and immunostained for ECM components reported to be deregulated in IPF. Immunostained sections were imaged, anatomically aligned, and 3D reconstructed. The myofibroblast core of the fibroblastic focus (defined by collagen I, α-smooth muscle actin, and procollagen I immunoreactivity) was associated with collagens III, IV, V, and VI; fibronectin; hyaluronan; and versican immunoreactivity. Hyaluronan immunoreactivity was also present at the fibroblastic focus perimeter and at sites where early lesions appear to be forming. Fibrinogen immunoreactivity was often observed at regions of damaged epithelium lining the airspace and the perimeter of the myofibroblast core but was absent from the myofibroblast core itself. The ECM components of the fibroblastic focus were distributed in a characteristic and reproducible manner in multiple patients. This information can inform the development of high-fidelity model systems to dissect mechanisms by which the IPF ECM drives fibrosis progression.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a lethal disease characterized by deposition of a pathological extracellular matrix (ECM) that establishes a positive feedback loop that mediates fibrosis progression [1]
Low-magnification images of 2 IPF specimens illustrate that regions of collagen I expression overlap with αSMA and procollagen I immunoreactivity (Figure 1A); higher-magnification images of 3 IPF specimens show that both αSMA and procollagen I are present in the collagen I–rich myofibroblast core (Figure 1B, red dotted lines outline the myofibroblast core)
Our present knowledge supports the inference that the fibroblastic focus is a dynamic structure, where, in time, the mesenchymal progenitor cell population invades adjacent normal alveolar interstitium, differentiates into fibrogenic myofibroblasts, and gives rise to new fibroblastic foci, leaving behind a highly remodeled ECM
Summary
Idiopathic pulmonary fibrosis (IPF) is a lethal disease characterized by deposition of a pathological extracellular matrix (ECM) that establishes a positive feedback loop that mediates fibrosis progression [1]. IPF ECM increases ribosome recruitment to hundreds of stromal transcripts, indicative of increased translation [4]. Some of these effects can be explained by the ability of IPF ECM to decrease Dicer, a core component of the microRNA-processing machinery [5], which suppresses biogenesis of microRNA-29, a master negative regulator of stromal genes. Left unknown is the identity of those components of the IPF ECM that promote fibrosis progression. To understand how the ECM might drive fibrosis progression, an important step will be to characterize the ECM in the specific regions where collagen is being actively synthesized. A landmark study by Kuhn and McDonald identified the fibroblastic focus, the hallmark lesion in IPF, as the locus of active ECM deposition [10]. There are no studies that have systematically registered each of these ECM components to one another in and around the fibroblastic focus
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