Pathognomonic remodeling of blood and lymphatic capillaries in idiopathic pulmonary fibrosis.

Abstract

Numerous studies have been published investigating the pathologic alterations in various interstitial pneumonias, particularly in idiopathic pulmonary fibrosis (IPF). However, the few existing studies on capillary remodeling, which does not seem to have priority for pathologic diagnosis, are contradictory, with some reporting increased and others reduced vascularization. We hypothesized that these discrepancies were due to the temporal heterogeneity of the lesions in IPF. We subsequently developed original techniques for evaluating vascular density within the alveolar septa and discovered, for the first time, a heterogeneous increase in alveolar capillaries in the lungs of IPF patients. Notably, we consistently found that the fibrotic lesions in IPF lungs, which are composed mainly of dense collagen with myofibroblasts, featured a reduction in capillaries. This finding provides a plausible explanation for the intractability of IPF, as this reduced vascularization would result in poor delivery of anti-fibrotic agents to these lesions. We also reported the disappearance of subpleural and interlobular lymphatics in IPF lungs, which likely results in poor alveolar clearance in the diseased lungs. Finally, we assessed the autopsied lungs of patients with IPF who died because of acute exacerbation and observed increased and dilated alveolar capillaries. These capillaries are likely to be "leaky" owing to exposure to VEGF produced by regenerated alveolar type II epithelial cells. Furthermore, poor alveolar clearance may prolong the high mobility group box 1 (HMGB1)-induced lung injury in acute exacerbation of IPF. Our data obtained from the assessment of blood and lymphatic capillary alterations in IPF provide novel pathogenetic insights and may provide the basis for new therapeutic strategies targeting IPF.