Elevated Expression of Growth Differentiation Factor-15 Is Associated With Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Abstract

BackgroundsGrowth differentiation factor 15 (GDF-15) is a highly divergent member of the TGF-β superfamily and has been implicated in various biological functions. However, the expression of GDF-15 in patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is unclear.MethodThe study included 47 AE-IPF patients, 61 stable IPF (S-IPF) subjects, and 31 healthy controls (HCs). Serum GDF-15 levels and their expression in the lung were measured. The correlation between serum GDF-15 and other clinical parameters and the risk factors for AE occurrence and the survival of IPF patients were analyzed.ResultsSerum GDF-15 levels were significantly elevated in AE-IPF patients (1279.22 ± 540.02 pg/ml) as compared with HCs (891.30 ± 479.90 pg/ml) or S-IPF subjects (107.82 ± 14.21 pg/ml) (both p < 0.001). The protein and mRNA expressions of GDF-15 in the lung of AE-IPF patients were significantly increased as compared with S-IPF cases (p = 0.007 and p = 0.026, respectively). The serum GDF-15 level was correlated with the clinical variables of inflammation, metabolism, and disease severity in IPF subjects (all p < 0.05). The GDF-15 serum concentration was significantly higher in decedents than in survivors (p = 0.005). A serum GDF-15 level above 989.3 pg/ml was a risk factor for AE occurrence (p = 0.04), and the level above 1,075.76 pg/ml was an independent predictor for survival in IPF cases (p = 0.007).ConclusionsThe GDF-15 level was significantly elevated in subjects with AE-IPF. GDF-15 could be a promising biomarker for AE occurrence and survival in IPF patients.

Predictive biomarkers of disease progression in idiopathic pulmonary fibrosis

“…Serum GDF15 is an independent risk factor for predicting the survival of patients with IPF. The survival rate of patients with GDF15 levels higher than 1075.76 pg/ml is significantly worse than that of patients with levels below this threshold [ 22 ]. Regarding the mechanism of GDF15 in IPF, research suggests that GDF15 promotes fibroblast differentiation into myofibroblasts, leading to extracellular matrix deposition.…”

“… Mikolasch TA, 2023 [ 21 ] NLR Multicenter, retrospective study Derivation cohort: n = 71 Internal validation cohort: n = 134 External additional cohort: n = 794 40 NLR is a widely available indicator that is significantly related to lung function and can predict the outcome of IPF patients. Cao M, 2022 [ 22 ] GDF-15 Single-center, case-control study AE-IPF: n = 47 S-IPF: n = 61 Control subjects: n = 31 – Significantly elevated level of GDF-15 in AE-IPF patients may predict the progression and survival rate of IPF patients. Forte G, 2021 [ 23 ] Trace elements (Cd, Cr, Cu, Pb) Single-center, case-control study IPF: n = 31 Control subjects: n = 30 – The concentration of certain trace elements in the sputum of IPF patients significantly increases.…”

GDF15 as a key disease target and biomarker: linking chronic lung diseases and ageing

“…The expression of GDF15 in the human IPF lung is increased, along with increased levels in the bronchoalveolar lavage fluid and plasma, with pulmonary epithelial cells proven to be the main source of GDF15 in this condition [ 35 , 88 ]. A study involving 108 patients with IPF and 31 healthy controls in China [ 90 ] found that the serum level of GDF15 in patients with acute exacerbation of IPF was elevated and that the protein and mRNA levels of GDF15 in IPF lung tissues were significantly increased. Additionally, immunohistochemical staining showed that GDF15 expression in the cytoplasm of type II alveolar epithelial cells was moderately positive.…”

Circulating markers of extracellular matrix remodelling in severe COVID‐19 patients

“…Thus, although YKL-40 (also known as Chitinase 3-like 1 [CHI3L1]) [9], S100A12 (S100 calcium-binding protein A12 also called ENRAGE) [10], osteopontin (OPN) [11,12] and cystatin B (CYSB) [13] are all known to be up-regulated in various pulmonary disorders, playing a role in ECM remodelling, fibrogenesis and inflammation, data in COVID-19 patients are scarce or even lacking. For 'comparison', we also included markers that are well known to be involved in ECM remodelling and where there are several publications in COVID-19 disease (>25 publications in PubMed), that is matrix metalloproteinase 9 (MMP-9) [14][15][16], galectin 3 (GAL-3) [17][18][19] and growth differentiation factor 15 (GDF-15) [20][21][22].…”

“…Furthermore, few studies have examined changes in mediators of ECM remodelling in relation to lung pathology beyond the acute phase; in addition, we there- GDF-15 Growth differentiation factor 15. Member of the TGF-β superfamily involved in ECM remodelling and inflammation in various tissues including the lung and the myocardium [20] fore also examined the levels of these markers 3-months after hospital admission in relation to pulmonary pathology at this time point. Finally, we also tested the ability of inactivated SARS-CoV-2 to directly regulate the examined mediators in different cell types with relevance to ECM remodelling.…”