Morphomolecular motifs of pulmonary neoangiogenesis in interstitial lung diseases

Abstract

The pathogenetic role of angiogenesis in interstitial lung diseases (ILDs) is controversial. This study represents the first investigation of the spatial complexity and molecular motifs of microvascular architecture in important subsets of human ILD. The aim of our study was to identify specific variants of neoangiogenesis in three common pulmonary injury patterns in human ILD.We performed comprehensive and compartment-specific analysis of 24 human lung explants with usual intersitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP) and alveolar fibroelastosis (AFE) using histopathology, microvascular corrosion casting, micro-comupted tomography based volumetry and gene expression analysis using Nanostring as well as immunohistochemistry to assess remodelling-associated angiogenesis.Morphometrical assessment of vessel diameters and intervascular distances showed significant differences in neoangiogenesis in characteristically remodelled areas of UIP, NSIP and AFE lungs. Likewise, gene expression analysis revealed distinct and specific angiogenic profiles in UIP, NSIP and AFE lungs.Whereas UIP lungs showed a higher density of upstream vascularity and lower density in perifocal blood vessels, NSIP and AFE lungs revealed densely packed alveolar septal blood vessels. Vascular remodelling in NSIP and AFE is characterised by a prominent intussusceptive neoangiogenesis, in contrast to UIP, in which sprouting of new vessels into the fibrotic areas is characteristic. The molecular analyses of the gene expression provide a foundation for understanding these fundamental differences between AFE and UIP and give insight into the cellular functions involved.

Demystifying morphomolecular alterations of vasculature in interstitial lung diseases

“…As ACKERMANN et al [12] described in the study, there are two types of angiogenesis: sprouting angiogenesis and intussusceptive angiogenesis [13]. Sprouting angiogenesis is characterised by a stereotypical series of steps including enzymatic degradation of the capillary basement membrane, endothelial cell proliferation, endothelial cell tube formation, vessel fusion, vessel pruning, and pericyte .…”

“…In this issue of the European Respiratory Journal, ACKERMANN et al [12] present histopathology, microvascular anatomy and gene expression in three main histopathological subtypes of interstitial lung disease: UIP/IPF; NSIP/iNSIP; and AFE/RAS, iPPFE. This is a comprehensive analysis with state-of-the-art technology focusing on remodelling-associated angiogenesis (figure 1).…”

“…The initial step is driven by hypoxia, which induces angiogenic stimuli, including vascular endothelial growth factor [14]. Given that insulin-like growth factor-1 (IGF-1) is also considered as an angiogenic stimulus for sprouting [15], it is interesting to see IGF1 was upregulated as a common dominator of AFE and UIP [12]. Indeed, ACKERMANN et al [16] previously showed that inhibition of IGF-1 could prevent sprouting angiogenesis in a tumour model.…”

“…The study of vascular alteration in interstitial lung diseases by ACKERMANN et al [12] raises several suggestions for future investigation. First, the study assessed mRNA expression in the explant lungs.…”

“…Second, a combined analysis of mass spectrometry-based tissue imaging with vessel structure would be informative for unveiling post-translational modification and extracellular matrix shifts in sites with vascular alterations. Third, as investigators discuss in the study [12], the canonical question "Angiogenesis in pulmonary fibrosis: too much or not enough?" raised by HANUMEGOWDA et al [22] cannot be easily addressed.…”