A Serological Biomarker of Versican Degradation is Associated with Mortality Following Acute Exacerbations of Idiopathic Interstitial Pneumonia

Abstract

BackgroundIdiopathic interstitial pneumonia (IIP) is characterized by an increased rate of extracellular matrix (ECM) remodeling resulting in fibrosis. Acute exacerbations of IIP represent periods of increased disease activity, thus we hypothesized that ECM remodeling was altered during acute exacerbations and investigated this by serological neo-epitope biomarkers.MethodsPatients who were sequentially admitted to the hospital with acute exacerbations of IIP were retrospectively analyzed for ECM remodeling at time of exacerbation (AE-IIP) and at clinical stability (S-IIP). Biomarkers released by matrix metalloproteinase-mediated degradation of collagen type I (C1M), III (C3M), IV (C4M), and VI (C6M), elastin (ELM7), versican (VCANM), biglycan (BGM), and C-reactive protein (CRPM) were assessed in serum by competitive ELISAs utilizing neo-epitope specific monoclonal antibodies.ResultsSixty-eight patients at AE-IIP and 29 at S-IIP were included in this retrospective analysis. Of these, 28 and 11 patients, respectively, had idiopathic pulmonary fibrosis. At AE-IIP, serum levels of C4M (p = 0.002) and C6M (p = 0.024) were increased as compared with S-IIP, while ELM7 (p = 0.024) and VCANM (p < 0.0001) were decreased. Lower VCANM levels at AE-IIP were associated with increased risk of mortality (HR 0.64 [95% CI 0.43–0.94], p = 0.022).ConclusionsThe ECM remodeling profile was significantly altered during acute exacerbations of IIP, and a biomarker of versican degradation was related to mortality outcome. These results indicate that biomarkers of ECM remodeling may be useful in the non-invasive evaluation of acute exacerbations of IIP. Especially versican degradation, as measured serologically by VCANM, may have prognostic potential and help guide treatment for acute exacerbations.

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“…59 A range of biomarkers reflecting ECM remodelling and fibrosis were identified predicting the decline of the lung function. 37,55 Overactive fibroblasts (EPIC software output) are suspected of fibrillar collagens (type I, III, V collagens) production, which are not permeable to oxygen, unlike the networking collagens of the basement membrane (types IV and VIII). 36 To manage this condition, we propose MMP inhibitors as potential therapeutic agents for severe COVID-19 lung injury, including Aprotinin, a nonspecific protease inhibitor.…”

Can biomarkers of extracellular matrix remodelling and wound healing be used to identify high risk patients infected with SARS-CoV-2?: lessons learned from pulmonary fibrosis

“…Neoepitope markers of both fibrogenesis and fibrolysis were elevated in patients with IPF compared with healthy controls, and the change of these markers over a short period was significantly related to loss in lung function and increased mortality risk in IPF patients [25,26]. Furthermore, a versican neoepitope markerhas been reported to become elevated during acute exacerbations of interstitial pulmonary fibrosis [34].…”

Systematic review and meta-analysis of prognostic factors of acute exacerbation of idiopathic pulmonary fibrosis

“…The measure of hQOL was also described in one study. A total of eight research groups conducted multiple studies using the same cohort and published reports (Collard et al, 40 Kim et al, 50 Lee et al, 54 and Song et al 62 ; Kishaba et al 51 52 ; Enomoto et al [41][42][43] ; Furuya et al, 45 Isshiki et al, 46 Koyama et al, 53 and Sakamoto et al 59 ; Nikaido et al 55 and Sand et al 60 ; Kataoka et al, 48 Suzuki et al 64 and Yokoyama et al 71 ; Abe et al 35 and Atsumi et al 38 ; Tomioka et al 66 and Yamazoe et al 70 ; online supplementary e-table 1). Among these multiple research conducted by the same groups, the study with the largest sample size was prioritised and a total of 31 potential prognostic factors, which were investigated for their association with all-cause mortality, were identified and followed by further analysis (online supplementary e-table 2).…”