Antithrombin III as predictive indicator of survival in idiopathic pulmonary fibrosis (IPF) patients treated with nintedanib: a preliminary study

Bergantini, Laura; d’Alessandro, Miriana; Cameli, Paolo; Carleo, Alfonso; Landi, Claudia; Vietri, Lucia; Lanzarone, Nicola; Pieroni, Maria; Sestini, Piersante; Bargagli, Elena

doi:10.1111/imj.14768

Cited by 12 publications

(10 citation statements)

References 23 publications

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“…Indeed, in diabetic retinopathy, RAAS is an effector of vascular epithelial growth factor (VEGF) that drive the leakage of retinal blood vessels [ 50 ]. VEGF is also well known to be one of the major players in IPF onset and its receptor is one of the targets of nintedanib treatment [ 11 , 51 ].…”

Section: Metabolic Alterations In Ipfmentioning

confidence: 99%

“…There is an urgent need for reliable biomarkers for early diagnosis and to monitor progression. Recent studies have identified potentially useful peripheral and bronchoalveolar lavage (BAL) biomarkers, including chemokines, cytokines, genes and proteins [ 10 , 11 , 12 , 13 , 14 , 15 ], but the 2018 International Guidelines for the Clinical Diagnosis of IPF do not include recommendations, due to insufficient evidence [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

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Metabolic Dysregulation in Idiopathic Pulmonary Fibrosis

Bargagli

Refini

d’Alessandro

et al. 2020

IJMS

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Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative disorder limited to the lung. New findings, starting from our proteomics studies on IPF, suggest that systemic involvement with altered molecular mechanisms and metabolic disorder is an underlying cause of fibrosis. The role of metabolic dysregulation in the pathogenesis of IPF has not been extensively studied, despite a recent surge of interest. In particular, our studies on bronchoalveolar lavage fluid have shown that the renin–angiotensin–aldosterone system (RAAS), the hypoxia/oxidative stress response, and changes in iron and lipid metabolism are involved in onset of IPF. These processes appear to interact in an intricate manner and to be related to different fibrosing pathologies not directly linked to the lung environment. The disordered metabolism of carbohydrates, lipids, proteins and hormones has been documented in lung, liver, and kidney fibrosis. Correcting these metabolic alterations may offer a new strategy for treating fibrosis. This paper focuses on the role of metabolic dysregulation in the pathogenesis of IPF and is a continuation of our previous studies, investigating metabolic dysregulation as a new target for fibrosis therapy.

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Section: Metabolic Alterations In Ipfmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metabolic Dysregulation in Idiopathic Pulmonary Fibrosis

Bargagli

Refini

d’Alessandro

et al. 2020

IJMS

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“…Our proteomic analysis also highlighted the abundance of antithrombin III in serum after one year of nintedanib treatment 28 . This protein is one of the most important serine protease inhibitor in plasma where it regulates the clotting cascade by inhibiting thrombin, matriptase-3/TMPRSS7, and clotting factors IXa, Xa and XIa.…”

Section: Discussionmentioning

confidence: 73%

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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“…Transient activation of platelets induces pro-inflammatory and pro-fibrotic effects [ 42 ]. While the role of platelets in IPF is unknown [ 43 , 44 ], platelet trapping in the lungs of mice following intravenous bleomycin administration showed a strong correlation with subsequent collagen deposition, suggesting a role in fibrogenesis in this animal model [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicle Surface Signatures in IPF Patients: A Multiplex Bead-Based Flow Cytometry Approach

d’Alessandro

Soccio

Bergantini

et al. 2021

Cells

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Background: Extracellular vesicles (EVs) are secreted by cells from their membrane within circulation and body fluids. Knowledge of the involvement of EVs in pathogenesis of lung diseases is increasing. The present study aimed to evaluate the expression of exosomal surface epitopes in a cohort of idiopathic pulmonary fibrosis (IPF) patients followed in two Italian Referral Centres for Interstitial Lung Diseases, comparing them with a group of healthy volunteers. Materials and Methods: Ninety IPF patients (median age and interquartile range (IQR) 71 (66–75) years; 69 males) were selected retrospectively. Blood samples were obtained from patients before starting antifibrotic therapy. A MACSPlex Exosome Kit, human, (Miltenyi Biotec, Bergisch-Gladbach, Germany), to detect 37 exosomal surface epitopes, was used. Results: CD19, CD69, CD8, and CD86 were significantly higher in IPF patients than in controls (p = 0.0023, p = 0.0471, p = 0.0082, and p = 0.0143, respectively). CD42a was lower in IPF subjects than in controls (p = 0.0153), while CD209, Cd133/1, MCSP, and ROR1 were higher in IPF patients than in controls (p = 0.0007, p = 0.0050, p = 0.0139, and p = 0.0335, respectively). Kaplan–Meier survival analysis for IPF patients: for median values and a cut-off of 0.48 for CD25, the two subgroups showed a significant difference in survival rate (p = 0.0243, hazard ratio: 0.52 (95%CI 0.29–0.92); the same was true for CD8 (cut-off 1.53, p = 0.0309, hazard ratio: 1.39 (95%CI 0.75–2.53). Conclusion: Our multicenter study showed for the first time the expression of surface epitopes on EVs from IPF patients, providing interesting data on the communication signatures/exosomal profile in serum from IPF patients and new insights into the pathogenesis of the disease and a promising reliability in predicting mid-term survival of IPF patients.

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Antithrombin III as predictive indicator of survival in idiopathic pulmonary fibrosis (IPF) patients treated with nintedanib: a preliminary study

Cited by 12 publications

References 23 publications

Metabolic Dysregulation in Idiopathic Pulmonary Fibrosis

Metabolic Dysregulation in Idiopathic Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis Serum proteomic analysis before and after nintedanib therapy

Extracellular Vesicle Surface Signatures in IPF Patients: A Multiplex Bead-Based Flow Cytometry Approach

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