Endotrophin, an extracellular hormone, in combination with neoepitope markers of von Willebrand factor improves prediction of mortality in the ECLIPSE COPD cohort

Abstract

Background: Lung epithelial damage, activation of the wound healing cascade, and remodeling of the extracellular matrix (ECM) play a major role in chronic obstructive pulmonary disease (COPD). The pro-peptide of type VI collagen has been identified as the hormone endotrophin. Endotrophin has been shown to promote fibrosis and inflammation, whereas von Willebrand factor (VWF) is a crucial part of wound healing initiation. Here, we assessed the released and activated form of VWF and endotrophin, the pro-peptide of type VI collagen, serologically to investigate their association with mortality in COPD subjects alone or in combination. Methods: One thousand COPD patients with 3 years of clinical follow-up from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort were included. Serum and heparin plasma were collected at 6 months and 1 year, respectively. Competitive ELISA utilizing specific monoclonal antibodies assessed endotrophin/ type VI collagen formation (PRO-C6), VWF release (VWF-N), and activated VWF (VWF-A). Biomarker levels were dichotomized into high and low as defined by receiver operating characteristic (ROC) curves based on mortality data. Kaplan-Meier analysis was used to determine hazard ratios for all-cause mortality for biomarkers alone or in combination. Results: High levels of PRO-C6, VWF-A, and VWF-N have previously been shown to be individually associated with a higher risk of mortality with hazard ratios of 5.6 (95% CI 2.4-13.1), 3.7 (1.8-7.6), and 4.6 (2.2-9.6), respectively. The hazard ratios increased when combining the biomarkers: PRO-C6*VWFA 8.8 (2.8-27.7) and PRO-C6*VWFN 13.3 (5.6-32.0). Notably, PRO-C6*VWF-N increased more than 2-fold.

Endotrophin is associated with chronic multimorbidity and all-cause mortality in a cohort of elderly women

“…Further studies in humans have substantiated this link. Yoldemir et al found endotrophin significantly associated with insulin resistance and upregulated in overweight individual [41] and several clinical studies have found endotrophin elevated in fibrotic conditions where it is produced by fibroblasts [12,13,15,16]. This correlates well with our findings where endotrophin levels were associated with both fibrotic and obesity-related clinical variables and chronic diseases.…”

“…In animal models, endotrophin has been shown to be involved in several biological processes, such as fibrosis, inflammation, angiogenesis, insulin resistance and epithelial-mesenchymal transition (EMT) [10,11]. In humans, endotrophin has been linked to chronic kidney disease (CKD) [12,13], breast cancer [14], chronic obstructive pulmonary disease (COPD) [15,16], diabetes [17,18] and death [19].…”

Chronic obstructive pulmonary disease risk assessment tools: is one better than the others?

“…Low concentrations of interleukin-15, a pleiotropic cytokine that induces proliferation of natural killer cells, and high concentrations of interleukin-8, a cytokine targeting neutrophils, have been associated with an increased risk of exacerbations [8]. High levels of endotrophin and von Willebrand factor as well as other markers of epithelial repair, alveolar destruction, and endothelial dysfunction have been correlated with higher morbidity and mortality in COPD [53 ▪ –56 ▪ ]. Low-serum IgG and free light chain levels have been linked to a higher risk of exacerbation and hospitalization, which suggests a potential role for intravenous immunoglobulin administration in COPD patients with recurrent exacerbations [57 ▪ –59 ▪ ].…”

Regulation of tumor immunity and immunotherapy by the tumor collagen extracellular matrix

“…The biological role of endothrophin in cancer is related to epithelial-to-mesenchymal transition and tumor fibrosis. Endothrophin is highly expressed in CAFs and is prognostic in a range of fibrotic diseases, including liver, lung, kidney, and skin fibrosis (31)(32)(33)(34)(35)(36). Understanding how collagens and collagen fragments actively bind and regulate immune receptors, in addition to functions described here, will be critical to link cancer matrix biology and immune oncology.…”