Blocking LOXL2 and TGFβ1 signalling induces collagen I turnover in precision-cut lung slices derived from patients with idiopathic pulmonary fibrosis

Abstract

We recently identified epigallocatechin gallate (EGCG), a trihydroxyphenolic compound, as a dual inhibitor of lysyl oxidase-like2 and transforming growth factor-β1 (TGFβ1) receptor kinase that when given orally to patients with idiopathic pulmonary fibrosis (IPF) reversed profibrotic biomarkers in their diagnostic biopsies. Here, we extend these findings to advanced pulmonary fibrosis using cultured precision-cut lung slices from explants of patients with IPF undergoing transplantation. During these experiments, we were surprised to discover that not only did EGCG attenuate TGFβ1 signalling and new collagen accumulation but also activated matrix metalloproteinase-dependent collagen I turnover, raising the possibility of slow fibrosis resolution with continued treatment.

Dysregulated overexpression of Sox9 induces fibroblast activation in pulmonary fibrosis

“…Notably, SOX9 regulates the expression of LOXL2 an important ECM organizing enzyme that plays a crucial role in matrix remodeling and fibrogenesis (28). Previous studies have demonstrated that LOXL2 is a marker for IPF progression, and its inhibition resulted in the slower progression of the disease (28)(29)(30).…”

“…Notably, SOX9 regulates the expression of LOXL2, an important ECM-organizing enzyme that plays a crucial role in matrix remodeling and fibrogenesis ( 27 ). Previous studies have demonstrated that LOXL2 is a marker for IPF progression, and its inhibition resulted in the slower progression of the disease ( 27 – 29 ). SOX9 is well recognized as a transcriptional regulator for various ECM-related genes based on studies related to chondrogenesis and cancer cell types ( 30 , 31 ).…”

Fibrosis in Mesothelioma: Potential Role of Lysyl Oxidases

“…Moreover, the nuclear localization of LOXL2 protein has been associated with the progression of lung fibrosis [ 45 ] and suggests a dynamic regulatory role ( Table 1 ). In this regard, inhibition of LOXL2 in ex vivo lung explants from patients with IPF was shown to induce collagen turnover [ 46 ] ( Table 1 ). LOXL1 and LOXL3 have also been identified in the pathogenesis of IPF [ 41 , 43 , 47 ] ( Table 1 ).…”

Targeting Alveolar Repair in Idiopathic Pulmonary Fibrosis

“…Both pirfenidone and nintedanib have recently been shown to have an effect on epithelial-cell phenotypes when evaluated in an ex vivo precision-cut lung slice (PCLS) model with induction of early fibrotic remodeling via a cocktail of growth factors ( 152 , 153 ); however, how similar this injury model is to IPF is not yet known. Alternatively, other work has evaluated potential compounds in explanted IPF tissue, representing end-stage disease ( 154 , 155 ). How relevant either the PCLS approach or even the use of TGF-β stimulation alone on PCLSs might be in predicting clinical efficacy remains unknown.…”