Serial KL-6 analysis in patients with idiopathic pulmonary fibrosis treated with nintedanib

Bergantini, Laura; Bargagli, Elena; Cameli, Paolo; Cekorja, Behar; Lanzarone, Nicola; Pianigiani, Lucrezia; Vietri, Lucia; Bennett, David; Sestini, Piersante; Rottoli, Paola

doi:10.1016/j.resinv.2019.02.001

Cited by 35 publications

(38 citation statements)

References 5 publications

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“…Moreover, KL-6 has been confirmed to be a reliable prognostic biomarker indicative of the response to nintedanib treatment in IPF patients. Particularly, IPF patients treated with nintedanib for 12 months maintain stable FVC values and KL-6 levels [12]. KL-6 mechanism of action is not yet well understood.…”

Section: Mucins As Potential Idiopathic Pulmonary Fibrosis (Ipf) Dmentioning

confidence: 99%

Mucins as a New Frontier in Pulmonary Fibrosis

Ballester

Milara

Cortijo

2019

JCM

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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.

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Section: Mucins As Potential Idiopathic Pulmonary Fibrosis (Ipf) Dmentioning

confidence: 99%

Mucins as a New Frontier in Pulmonary Fibrosis

Ballester

Milara

Cortijo

2019

JCM

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“…S-1D) 22 . This observation prompted us to quantify KL-6 trends after nintedanib treatment 23 . We found a decreasing trend of protein abundance in serum.…”

Section: Discussionmentioning

confidence: 99%

“…5). The proteins of Group B (light blue bars) were associated with "liver regeneration" and "descending colon inflammation" (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25).…”

Section: Proteomic Analysis Of Sera From Ipf Patients Before and Aftementioning

confidence: 99%

Idiopathic Pulmonary Fibrosis Serum proteomic analysis before and after nintedanib therapy

Landi

Bergantini²,

Cameli³

et al. 2020

Sci Rep

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Idiopathic pulmonary fibrosis (IPF) is a fatal progressive disease with a median survival of 2-5 years. Nintedanib is a small tyrosine kinase inhibitor that reduces IPF progression, significantly slowing the annual decline in Forced Vital Capacity (FVC). Very little data is available on the molecular mechanisms of this treatment in IPF, despite a growing interest in the definition of IPF pathogenesis and target therapy. A functional proteomic approach was applied to the analysis of serum samples from IPF patients in order to highlight differential proteins potentially indicative of drug-induced molecular pathways modifications and response to therapy. Twelve serum samples were collected from six IPF patients in care at Siena Regional Referral Center for Interstitial Lung Diseases (ILDs) and treated with nintedanib for one year. Serum samples were analyzed at baseline (T0 before starting therapy) and after one year of treatment (T1) and underwent differential proteomic and bioinformatic analysis. Proteomic analysis revealed 13 protein species that were significantly increased after one year of treatment. When the targets of nintedanib (VEGFR, FGFR and PDGFR) were added, enrichment analysis extracted molecular pathways and process networks involved in cell differentiation (haptoglobin and albumin), coagulation (antithrombin III), epithelial mesenchymal transition, cell proliferation and transmigration. PI3K and MAPK induced up-regulation of apolipoprotein C3. Proteomic study found 13 protein species up-regulated in IPF patients after one year of nintedanib treatment. Haptoglobin, a central hub of our analysis was validated by 2D-WB and ELISA as theranostic marker in a more numerous populations of patients.

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“…Krebs von den Lungen‐6 (KL‐6), an aberrantly glycosylated form of MUC1 which either carries the sialylated T antigen (MUC1‐ST) or a longer sialylated core 2 structure, or a mixture of both, shows increased levels of expression on airway epithelial cells in IPF . Injured AT2 cells release KL‐6, and measuring serum KL‐6 levels forms the basis of a biomarker used in Japan to assess disease progression and treatment response . The MUC1 intracellular cytoplasmic tail has also been shown to be activated in type 2 epithelial cells and fibroblasts both in animal models of pulmonary fibrosis and in the human disease.…”

Section: Disease Associationsmentioning

confidence: 99%

“…58 Injured AT2 cells release KL-6, and measuring serum KL-6 levels forms the basis of a biomarker used in Japan to assess disease progression and treatment response. 59 The MUC1 intracellular cytoplasmic tail has also been shown to be activated in type 2 epithelial cells and fibroblasts both in animal models of pulmonary fibrosis and in the human disease. Phosphorylation of the cytoplasmic tail results in formation of a MUC1/beta-catenin nuclear complex that promotes epithelial to mesenchymal and fibroblast to myofibroblast transition.…”

Section: Mucins In Pulmonary Fibrosismentioning

confidence: 99%

Mucins and their receptors in chronic lung disease

et al. 2020

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There is growing recognition that mucus and mucin biology have a considerable impact on respiratory health, and subsequent global morbidity and mortality. Mucins play a critical role in chronic lung disease, not only by providing a physical barrier and clearing pathogens, but also in immune homeostasis. The aim of this review is to familiarise the reader with the role of mucins in both lung health and disease, with particular focus on function in immunity, infection and inflammation. We will also discuss their receptors, termed glycan‐binding proteins, and how they provide an attractive prospect for therapeutic intervention.

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Serial KL-6 analysis in patients with idiopathic pulmonary fibrosis treated with nintedanib

Cited by 35 publications

References 5 publications

Mucins as a New Frontier in Pulmonary Fibrosis

Mucins as a New Frontier in Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis Serum proteomic analysis before and after nintedanib therapy

Mucins and their receptors in chronic lung disease

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