Abstract
Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pulmonary disease with a median survival of 3–5 years after diagnosis. Recent evidence identifies mucins as key effectors in cell growth and tissue remodeling processes compatible with the processes observed in IPF. Mucins are classified in two groups depending on whether they are secreted (secreted mucins) or tethered to cell membranes (transmembrane mucins). Secreted mucins (MUC2, MUC5AC, MUC5B, MUC6-8 and MUC19) are released to the extracellular medium and recent evidence has shown that a promoter polymorphism in the secreted mucin MUC5B is associated with IPF risk. Otherwise, transmembrane mucins (MUC1, MUC3, MUC4, MUC12-17 and MUC20) have a receptor-like structure, sensing the external environment and activating intracellular signal transduction pathways essential for mucosal maintenance and damage repair. In this context, the extracellular domain can be released to the external environment by metalloproteinase action, increased in IPF, thus activating fibrotic processes. For example, several studies have reported increased serum extracellular secreted KL6/MUC1 during IPF acute exacerbation. Moreover, MUC1 and MUC4 overexpression in the main IPF cells has been observed. In this review we summarize the current knowledge of mucins as promising druggable targets for IPF.
Highlights
Interstitial lung diseases (ILDs) are a group of disorders characterized by cellular proliferation, interstitial inflammation, fibrosis, or a combination of these conditions within the alveolar wall [1]
idiopathic pulmonary fibrosis (IPF) biomarkers can be categorized into three groups, namely biomarkers associated with alveolar epithelial cell dysfunction (such as the Krebs von den Lungen-6 (KL-6) antigen, carbohydrate antigen (CA)15-3, CA125, the mucin MUC5B and surfactant proteins A and D), biomarkers associated with extracellular matrix remodelling and fibroproliferation (such as matrix metalloproteinase-1 (MMP-1) and -7 (MMP-7), lysyl oxidase-like 2 and periostin), and biomarkers related to immune dysfunction [5,6,7,8,9] (Table 1)
Several studies have reported increased serum KL-6 levels during acute IPF exacerbation and a recent study demonstrated that serial increases in serum KL-6 levels are associated with a rapid decline in predicted forced vital capacity (FVC), and further demonstrated that higher KL-6 levels are correlated with lower survival rates [11]
Summary
Interstitial lung diseases (ILDs) are a group of disorders characterized by cellular proliferation, interstitial inflammation, fibrosis, or a combination of these conditions within the alveolar wall [1]. Small protein mainly secreted by monocytes, macrophages and dendritic cells that acts as a chemoattractant [24] and has an important role stimulating fibroblasts to synthesise collagen in fibrotic lung diseases [25]. Several studies have reported increased serum KL-6 levels during acute IPF exacerbation and a recent study demonstrated that serial increases in serum KL-6 levels are associated with a rapid decline in predicted forced vital capacity (FVC), and further demonstrated that higher KL-6 levels are correlated with lower survival rates [11]. The use of MUC5B as an IPF biomarker is based on a common gain-of-function promoter variant (rs35705950) associated with IPF development. This polymorphism has been reported in 30%–35% of IPF patients [20]. This review summarizes the current state of lung mucin research related to pulmonary fibrosis and provides an assessment of the potential of mucins as treatment targets in this disease
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