Abstract
Interstitial lung disease (ILD) encompasses a group of heterogeneous diseases characterised by varying degrees of aberrant inflammation and fibrosis of the lung parenchyma. This may occur in isolation, such as in idiopathic pulmonary fibrosis (IPF) or as part of a wider disease process affecting multiple organs, such as in systemic sclerosis. Anti-Vascular Endothelial Growth Factor (anti-VEGF) therapy is one component of an existing broad-spectrum therapeutic option in IPF (nintedanib) and may become part of the emerging therapeutic strategy for other ILDs in the future. This article describes our current understanding of VEGF biology in normal lung homeostasis and how changes in its bioavailability may contribute the pathogenesis of ILD. The complexity of VEGF biology is particularly highlighted with an emphasis on the potential non-vascular, non-angiogenic roles for VEGF in the lung, in both health and disease.
Highlights
The term ‘fibrotic lung disease’ or interstitial lung disease (ILD) encompasses a group of more than 100 heterogeneous diseases characterized by similar clinical and radio-pathological patterns of aberrant inflammation and fibrosis of the lung parenchyma despite a wide variety of potential triggers and prognoses [1]
This review describes our current understanding of Vascular Endothelial Growth Factor (VEGF) biology, highlighting its potential role in normal lung homeostasis and in ILD pathogenesis, with a particular focus in acute respiratory distress syndrome (ARDS), Idiopathic Pulmonary Fibrosis (IPF), Hypersensitivity Pneumonitis (HP) and connective tissue disorders (CTD)-ILD
VEGFR2 ( known as kinase domain region (KDR) or fetal liver kinase-1 (FLK-1)) is considered by many as the main signalling receptor for VEGF bioactivity [22,23]. It is abundantly expressed in the vascular bed where it appears to be critical for normal development [24], but several non-endothelial cells, including lung macrophages [3] and alveolar epithelial type II (ATII) cells [25] have been shown to express VEGFR2
Summary
The term ‘fibrotic lung disease’ or interstitial lung disease (ILD) encompasses a group of more than 100 heterogeneous diseases characterized by similar clinical and radio-pathological patterns of aberrant inflammation and fibrosis of the lung parenchyma despite a wide variety of potential triggers and prognoses [1]. This review describes our current understanding of VEGF biology, highlighting its potential role in normal lung homeostasis and in ILD pathogenesis, with a particular focus in ARDS, IPF, HP and CTD-ILD. Differential splicing of the VEGF gene at the distal splice site with exon 8; 66 bp distal to the VEGF-Axxxa acceptor-site, produces a second family of isoforms, the VEGF-Axxxb proteins which have the same number of amino acids as the conventional VEGF-Axxxa isoforms but have an alternative amino acid sequence at their carboxy-terminal (C-terminal) domain: Ser-Leu-Thr-Arg-Lys-Asp (SLTRKD) instead of Cys-Asp-Lys-Pro-Arg-Arg (CDKPRR) in VEGF-Axxxa isoforms (Figure 1) [8]. The most widely studied of these isoforms, VEGF-A165b, has been shown to act as an inhibitor of VEGF-A165a [8,9] through competitive interference with the VEGFR2-NP1 complex and activation of different downstream receptor phosphorylation sites [10]. When PlGF is produced in the same population of cells with VEGF, it can act as a natural occurring competitive inhibitor [20,21]
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