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.
Highlights
Idiopathic interstitial pneumonia (IIP) is characterized by an increased rate of extracellular matrix (ECM) remodeling resulting in fibrosis
We have previously shown that serological levels of neo-epitope biomarkers are associated with the presence of an acute exacerbation of chronic obstructive pulmonary disease (COPD) [7, 8]
idiopathic pulmonary fibrosis (IPF) was diagnosed using the definition in the 2011 ATS/ ERS/JRS/ALAT joint statement [12] based on a pattern of usual interstitial pneumonia (UIP) on high resolution computed tomography (HRCT)
Summary
Idiopathic interstitial pneumonia (IIP) is characterized by an increased rate of extracellular matrix (ECM) remodeling resulting in fibrosis. A hallmark of IIP, is characterized by extracellular matrix (ECM) deposition in the parenchyma (i.e. the interstitial matrix) and uncontrolled tissue remodeling It results from an increased rate of ECM remodeling and a shift in the balance between protein synthesis and degradation, leading to ECM accumulation [4, 5]. We have previously shown that serological levels of neo-epitope biomarkers are associated with the presence of an acute exacerbation of chronic obstructive pulmonary disease (COPD) [7, 8] This indicates that rate of ECM remodeling is significantly altered during acute exacerbations of a chronic lung disease and that the group of serological neoepitope biomarkers may be reflecting acute changes in disease activity. The association with disease activity is supported by the significant association of neo-epitope biomarkers with progression and mortality of IPF shown by Jenkins et al in the PROFILE study [9]
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