40 Chapter 2 the recognized ECM fragments, including those discussed above, released from lung tissues has the potential to inform us about the fibrotic processes that are active in a patient. Such fragments can be considered as possible biomarkers for fibrotic lung disease. In a population-based multi-ethnic study, Madahar and colleagues reported that levels of two collagen fragments, carboxyl-terminal telopeptide of collagen type I (ICTP) and amino-terminal propeptide of procollagen type III (PIIINP), were associated with sub-clinical interstitial lung disease (interstitial lung abnormalities) detected through computed tomography screening [144]. These associations were not influenced by sex, race or smoking status. This report suggests that these ECM fragments represent a sensitive indication of fibrotic activity that can be detected well before lung function parameters can register disease activity. In the PROFILE study, ECM degradation markers were found to have significantly different levels between controls and IPF patients [145]. When assessed longitudinally, changes in the levels of six neoepitopes (MMP −degraded-collagen type I (C1M), −collagen type III (C3M), −collagen type VI (C6M) and −C-reactive protein (CRPM), collagen type III degraded by ADAMTS-1/4/8 (C3A) and citrullinated vimentin degraded by MMP-2/8 (VICM)) were indicative of IPF patients with a greater likelihood of disease progression compared to those with stable disease. The baseline levels of C1M and C3A were associated with increased mortality. The levels of markers of ECM synthesis, neoepitope of collagen type III (PRO-C3) and collagen type VI (PRO-C6), were also elevated in IPF patients compared to healthy controls and again were increased in progressive disease compared to stable [146]. In addition, during exacerbations, patients with idiopathic interstitial pneumonia, including IPF, had increased levels of MMP-degraded collagen type IV (C4M) and C6M but decreased levels of MMP7-degraded elastin (ELM7) and MMP-degraded versican (VCANM) compared to patients with stable disease. Lower VCANM levels during exacerbation were associated with increased mortality [147]. Serum levels of laminin, collagen type IV, PIIINP and hyaluronic acid were also higher in a cohort of IPF and connective tissue disease patients, compared to controls, and were associated with mortality [116]. The serial measurement of ECM fragment or neoepitope markers in serum has the potential to inform about parameters important for clinical management of disease in these patients. These markers may bring manifestation of precision medicine in pulmonary fibrosis one step closer.
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