Abstract
In idiopathic pulmonary fibrosis (IPF), the fibroblast focus is a key histological feature representing active fibroproliferation. On standard 2D pathologic examination, fibroblast foci are considered small, distinct lesions, although they have been proposed to form a highly interconnected reticulum as the leading edge of a “wave” of fibrosis. Here, we characterized fibroblast focus morphology and interrelationships in 3D using an integrated micro-CT and histological methodology. In 3D, fibroblast foci were morphologically complex structures, with large variations in shape and volume (range, 1.3 × 104 to 9.9 × 107 μm3). Within each tissue sample numerous multiform foci were present, ranging from a minimum of 0.9 per mm3 of lung tissue to a maximum of 11.1 per mm3 of lung tissue. Each focus was an independent structure, and no interconnections were observed. Together, our data indicate that in 3D fibroblast foci form a constellation of heterogeneous structures with large variations in shape and volume, suggesting previously unrecognized plasticity. No evidence of interconnectivity was identified, consistent with the concept that foci represent discrete sites of lung injury and repair.
Highlights
Idiopathic pulmonary fibrosis (IPF) is the prototypic fibrotic lung disease in which progressive scarring of the lungs leads to death by respiratory failure [1]
Our work demonstrates the potential for 3D imaging methodologies to further inform concepts of the underlying pathogenesis of fibrotic lung diseases and reveals that, in contrast to current understanding from standard pathology of 2D tissue sections, in 3D fibroblast foci form a constellation of heterogeneous structures, with large variations in shape and volume, suggesting previously unrecognized plasticity
While idiopathic pulmonary fibrosis (IPF) remains an idiopathic disease, there have been several proposals regarding mechanisms of pathogenesis, one of which is that fibroblast foci form a highly complex and interconnected reticulum extending from the pleura to the lung parenchyma as a “wave” of progressive fibroproliferation [13, 28, 29]
Summary
Idiopathic pulmonary fibrosis (IPF) is the prototypic fibrotic lung disease in which progressive scarring of the lungs leads to death by respiratory failure [1]. Aggregates of proliferating fibroblasts and myofibroblasts, termed “fibroblast foci,” are a key histological diagnostic feature of UIP thought to represent areas of active fibrosis [7]. On standard 2D pathologic examination fibroblast foci are considered small, distinct lesions, and their profusion has been reported to be of prognostic significance, study findings vary [8,9,10,11,12]. They have been proposed to be linked in a complex reticulum that is highly interconnected and extends from the pleura insight.jci.org doi:10.1172/jci.insight.86375
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