Lysyl oxidase like 2 is increased in asthma and contributes to asthmatic airway remodelling

Abstract

Airway smooth muscle cells (ASM) are fundamental to asthma pathogenesis, influencing bronchoconstriction, airway hyper-responsiveness, and airway remodelling. Extracellular matrix (ECM) can influence tissue remodelling pathways, however, to date no study has investigated the effect of ASM ECM stiffness and crosslinking on the development of asthmatic airway remodelling. We hypothesised that TGFβ activation by ASM is influenced by ECM in asthma and sought to investigate the mechanisms involved. This study combines in vitro and in vivo approaches: human ASM cells were used in vitro to investigate basal TGFβ activation and expression of ECM crosslinking enzymes. Human bronchial biopsies from asthmatic and non-asthmatic donors were used to confirm LOXL2 expression ASM. A chronic ovalbumin model of asthma was used to study the effect of LOXL2 inhibition on airway remodelling. We found that ASM cells from asthmatics activated more TGFβ basally than non-asthmatic controls and that diseased cell-derived ECM influences levels of TGFβ activated. Our data demonstrate that the ECM crosslinking enzyme LOXL2 is increased in asthmatic ASM cells and in bronchial biopsies. Crucially, we show that LOXL2 inhibition reduces ECM stiffness and TGFβ activation in vitro, and can reduce subepithelial collagen deposition and ASM thickness, two features of airway remodelling, in an ovalbumin mouse model of asthma. These data are the first to highlight a role for LOXL2 in the development of asthmatic airway remodelling and suggest that LOXL2 inhibition warrants further investigation as a potential therapy to reduce remodelling of the airways in severe asthma.

Prostaglandin E2 attenuates lung fibroblast differentiation via inactivation of yes‐associated protein signaling

“…In agreement, we observed a significant reduction in TGFβ1‐induced MRTF‐A by PGE 2 . Further, the inhibition of LOXL2 has been shown to inhibit airway remodeling during asthma 52 . Complementing these findings, we observed that PGE 2 attenuates TGFβ1‐induced LOXL2, but not LOX expression.…”

A high-throughput 3D cantilever array to model airway smooth muscle hypercontractility in asthma

“…We found several overlapping pathways in the TGF-β1 and IL-13-treated microtissues which could explain the similarities in phenotypic changes. In both treatment conditions, upregulation in gene expression of ECM components and modifiers, as well as enrichment of pathways involved in focal adhesions and cell-ECM interactions supports the argument that the smooth muscle cells under the influence of these cytokines would play a hand in remodeling the airway matrix 24,37 .…”

“…Both treatments resulted in an enrichment of pathways associated with protein digestion and absorption, focal adhesion, and extracellular matrix (ECM)-receptor interaction, which correlates with the observed phenotypic changes in the microtissues by the smooth muscle (Figure 3C and D). Closer observation of the top DEGs in both conditions show an upregulation in the expression of matrix proteins, including a variety of collagen subfamily proteins and elastin (ELN), as well as proteins involved in matrix modifications such as matrix metalloprotease 2 (MMP2) and lysyl oxidase (LOX), which can crosslink collagen fibers 24 and is upregulated in both conditions (Supplementary Figure 6). The two treatment conditions also show an enrichment in epithelial to mesenchymal transition (EMT), the myogenesis pathway, and IL-2/STAT5 signaling (Figure 3C and D).…”

Involvement of Cu-containing amine oxidases in the development of lung pathology in ovalbumin-induced bronchial asthma in guinea pigs

“…Increased ECM stiffness is associated with crosslinking of interstitial collagen and fibronectin via action of lysyl oxidase family enzymes (EC 1.4.3.14, LOX, and EC 1.4.3.13, LOXL 1-4), other members of Cu-AOs. In support of this, an increase in LOXL2 expression in asthma has recently been shown to promote airway remodeling [7]. Thus, the mechanisms of biochemical processes underlying the development of BA can be directly related to the…”