Evaluation of novel LOXL2-selective inhibitors in models of pulmonary fibrosis

Roberts, James; Tear, Victoria; Lunn, Kerry; Cao, Lucy; Murphy, James S.; Shimbori, Chiko; Imani, Jewel; Tandon, Karun; Ayaub, Ehab; Jones, Mark; Davies, Donna E.; Jarolimek, Wolfgang; Ask, Kjetil; Gauldie, Jack; Kolb, Martin; Monk, Phillip

doi:10.1183/1393003.congress-2017.pa3476

Cited by 3 publications

(3 citation statements)

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“…In addition, we identified Secreted protein acidic and rich in cysteine ( SPARC )[34], encoding a glycoprotein involved in fibrosis, as well as Follistatin-like 1 ( FSTL1 )[35–37], encoding a glycoprotein sequestering inhibitory ligands of TGF-β, and Serpin H1 (aka Hsp47 )[38], encoding a collagen specific molecular chaperone associated with increased collagen accumulation. Less known genes involved in fibrosis found in this list are Peroxidasin ( PXDN )[39], Growth arrest specific gene 6 ( GAS6 )[40,41], heparan sulfate proteoglycan ( HSPG2 aka Perlecan )[42], Alpha-1, 6-Mannosylglycopotein 6-Beta-N-Acetylglucosaminyltransferase ( MGAT5 )[43] as well as Lysyl oxidase-like 2 ( LOXL2 )[44,45], encoding an enzyme triggering the network of collagen fibers of the ECM, and Limb-Bud and Heart ( LBH )[46], encoding a transcription factor in the WNT/ β-catenin pathway.…”

Section: Resultsmentioning

confidence: 99%

Highlighting fibroblast plasticity in lung fibrosis: the WI-38 cell line as a model for investigating the myofibroblast and lipofibroblast switch

Pacheco,

Marega,

Lingampally

et al. 2023

Preprint

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BackgroundMyofibroblasts (MYFs) are generally considered the principal culprits in excessive extracellular matrix deposition and scar formation in the pathogenesis of lung fibrosis. Lipofibroblasts (LIFs), on the other hand, are defined by their lipid-storing capacity and are predominantly found in the alveolar regions of the lung. They have been proposed to play a protective role in lung fibrosis. We previously reported that a LIF to MYF reversible differentiation switch occurred during fibrosis formation and resolution. In this study, we tested whether WI-38 cells, a human embryonic lung fibroblast cell line, could be used to study fibroblast differentiation towards the LIF or MYF phenotype and whether this could be relevant for idiopathic pulmonary fibrosis (IPF).Methodsusing WI-38 cells, MYF differentiation was triggered using TGF-β1 treatment and LIF differentiation using Metformin treatment. We analyzed the LIF to MYF and MYF to LIF differentiation by pre-treating the WI-38 cells with TGF-β1 or Metformin first, followed by treatment with Metformin and TGF-β1, respectively. We used IF, qPCR and bulk RNA-Seq to analyze the phenotypic and transcriptomic changes in the cells. We correlated our in vitro transcriptome data from WI-38 cells (obtained via bulk RNA sequencing) with the transcriptomic signature of LIFs and MYFs derived from the IPF cell atlas as well as with our own single-cell transcriptomic data from IFP patients-derived lung fibroblasts (LF-IPF) culturedin vitro. We also carried out alveolosphere assays to evaluate the ability of the proposed LIF and MYF cells to support the growth of alveolar epithelial type 2 cells.ResultsWI-38 and LF-IPF display similar phenotypical and gene expression responses to TGF-β1 and Metformin treatment. Bulk RNA-Seq analysis of WI-38 and LF-IPF treated with TGF-β1, or Metformin indicate similar transcriptomic changes. We also show the partial conservation of the LIF and MYF signature extracted from the Habermann et al. scRNA-seq dataset in WI-38 cells treated with Metformin or TGF-β1, respectively. Alveolosphere assays indicate that LIFs enhance organoid growth, while MYFs inhibit organoid growth. Finally, we provide evidence supporting the LIF to MYF reversible switch using WI-38 cells.ConclusionsWI-38 cells represent a versatile and reliable model to study the intricate dynamics of fibroblast differentiation towards the MYF or LIF phenotype associated with lung fibrosis formation and resolution, providing valuable insights to drive future research.Graphical abstractin vitroapproach using WI-38 cells as a versatile and reliable model to study the MYF or LIF phenotype associated with lung fibrosis formation and resolution observedin vivo. WI-38 are providing valuable insights to drive future research on lung fibrosis.

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Section: Resultsmentioning

confidence: 99%

Highlighting fibroblast plasticity in lung fibrosis: the WI-38 cell line as a model for investigating the myofibroblast and lipofibroblast switch

Pacheco,

Marega,

Lingampally

et al. 2023

Preprint

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“…It is also possible that PXS-5505 inhibited the involvement of LOXL2 as a pro-fibrotic transcription factor at the nuclear level [ 34 ]. In fact, LOXL2 inhibition alone may be sufficient to alleviate mild to medium levels of pulmonary fibrosis in animal models and human IPF patients [ 35 ]. However, in the fibrotic condition as severe as SSc, where both LOX and LOXL2 are upregulated, pan-lysyl oxidase inhibition using PXS-5505 may be more efficacious by inhibiting all lysyl oxidase isoforms.…”

Section: Discussionmentioning

confidence: 99%

Pan-Lysyl Oxidase Inhibitor PXS-5505 Ameliorates Multiple-Organ Fibrosis by Inhibiting Collagen Crosslinks in Rodent Models of Systemic Sclerosis

Yao

Findlay

Stolp

et al. 2022

IJMS

Self Cite

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Systemic sclerosis (SSc) is characterised by progressive multiple organ fibrosis leading to morbidity and mortality. Lysyl oxidases play a vital role in the cross-linking of collagens and subsequent build-up of fibrosis in the extracellular matrix. As such, their inhibition provides a novel treatment paradigm for SSc. A novel small molecule pan-lysyl oxidase inhibitor, PXS-5505, currently in clinical development for myelofibrosis treatment was evaluated using in vivo rodent models resembling the fibrotic conditions in SSc. Both lysyl oxidase and lysyl oxidase-like 2 (LOXL2) expression were elevated in the skin and lung of SSc patients. The oral application of PXS-5505 inhibited lysyl oxidase activity in the skin and LOXL2 activity in the lung. PXS-5505 exhibited anti-fibrotic effects in the SSc skin mouse model, reducing dermal thickness and α-smooth muscle actin. Similarly, in the bleomycin-induced mouse lung model, PXS-5505 reduced pulmonary fibrosis toward normal levels, mediated by its ability to normalise collagen/elastin crosslink formation. PXS-5505 also reduced fibrotic extent in models of the ischaemia-reperfusion heart, the unilateral ureteral obstruction kidney, and the CCl4-induced fibrotic liver. PXS-5505 consistently demonstrates potent anti-fibrotic efficacy in multiple models of organ fibrosis relevant to the pathogenesis of SSc, suggesting that it may be efficacious as a novel approach for treating SSc.

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“…Serum LOXL2 levels are elevated in patients with IPF and are associated with increased risk of disease progression. 28 Despite promising preclinical studies, 29 a Phase II clinical trial with the LOXL2 inhibitor simtuzumab showed no effect on progression-free survival for patients with IPF. 30 More in-depth details on the ECM of the lung in healthy and diseased states have been provided in several previously published review articles.…”

Section: The Ecm Of the Lung And Mechanical Changes In Ipfmentioning

confidence: 99%