scholarly journals Distal Lung Microenvironment Triggers Release of Mediators Recognized as Potential Systemic Biomarkers for Idiopathic Pulmonary Fibrosis

2021 ◽  
Vol 22 (24) ◽  
pp. 13421
Author(s):  
Dimitrios Kalafatis ◽  
Anna Löfdahl ◽  
Per Näsman ◽  
Göran Dellgren ◽  
Åsa M. Wheelock ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Serum Proteins ◽  
Ex Vivo ◽  
Unmet Need ◽  
Response To Treatment ◽  
Serum Samples ◽  
Ex Vivo Model ◽  
Prognostic Assessment ◽  
New Biomarkers

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with an unmet need of biomarkers that can aid in the diagnostic and prognostic assessment of the disease and response to treatment. In this two-part explorative proteomic study, we demonstrate how proteins associated with tissue remodeling, inflammation and chemotaxis such as MMP7, CXCL13 and CCL19 are released in response to aberrant extracellular matrix (ECM) in IPF lung. We used a novel ex vivo model where decellularized lung tissue from IPF patients and healthy donors were repopulated with healthy fibroblasts to monitor locally released mediators. Results were validated in longitudinally collected serum samples from 38 IPF patients and from 77 healthy controls. We demonstrate how proteins elevated in the ex vivo model (e.g., MMP7), and other serum proteins found elevated in IPF patients such as HGF, VEGFA, MCP-3, IL-6 and TNFRSF12A, are associated with disease severity and progression and their response to antifibrotic treatment. Our study supports the model’s applicability in studying mechanisms involved in IPF and provides additional evidence for both established and potentially new biomarkers in IPF.

scholarly journals Changes in Neutrophil–Lymphocyte or Platelet–Lymphocyte Ratios and Their Associations with Clinical Outcomes in Idiopathic Pulmonary Fibrosis

2021 ◽  
Vol 10 (7) ◽  
pp. 1427
Author(s):  
Steven D. Nathan ◽  
Jayesh Mehta ◽  
John Stauffer ◽  
Elizabeth Morgenthien ◽  
Ming Yang ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Clinical Outcomes ◽  
Predictive Biomarkers ◽  
Phase Iii ◽  
Response To Treatment ◽  
Reference Ranges ◽  
Neutrophil Lymphocyte Ratio ◽  
Lymphocyte Ratio ◽  
The Relationship

Identification of prognostic and predictive biomarkers in idiopathic pulmonary fibrosis (IPF) could aid assessment of disease severity and prediction of progression and response to treatment. This analysis examined reference ranges for neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) in IPF, and the relationship between NLR or PLR changes and clinical outcomes over 12 months. This post hoc analysis included patients with IPF from the Phase III, double-blind trials of pirfenidone, ASCEND (NCT01366209) and CAPACITY (NCT00287716 and NCT00287729). The relationship between change from baseline to Month 12 in NLR or PLR (divided into quartiles (Q1–Q4)) and outcomes (mortality, respiratory hospitalization, declines in lung function, exercise capacity and quality of life) was assessed. Estimated reference ranges at baseline for all patients analyzed (n = 1334) were 1.1–6.4 for NLR and 56.8–250.5 for PLR. Significant trends were observed across NLR and PLR quartiles for all outcomes in placebo-treated patients, with patients manifesting the greatest NLR or PLR changes experiencing the worst outcomes. These results suggest that the greatest NLR or PLR changes over 12 months were associated with worse clinical outcomes. Further research is needed to determine the utility of NLR and PLR as prognostic biomarkers in IPF.

Adherence, Persistence, and Effectiveness in Real Life. Multicenter Long-Term Study on the Use of Pirfenidone and Nintedanib in the Treatment of Idiopathic Pulmonary Fibrosis

2021 ◽  
pp. 089719002110086
Author(s):  
Fiorenzo Santoleri ◽  
Luigia Auriemma ◽  
Antonella Spacone ◽  
Stefano Marinari ◽  
Fabio Esposito ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Pharmacological Study ◽  
Functional Decline ◽  
Real Life ◽  
Point Of View ◽  
Response To Treatment ◽  
First Year ◽  
Long Term Study ◽  
Second Year

Background: In the treatment of idiopathic pulmonary fibrosis (IPF), nintedanib and pirfenidone, with their different mechanisms of action, lead to a reduction in the rate of progression of the fibrosis process measured by the reduction of functional decline, and, in particular, the decrease in forced vital capacity (FVC) and of the diffusion capacity of the lungs for carbon monoxide (DLCO). The objective of this study was to analyze real-life adherence, persistence and efficacy in the use of pirfenidone and nintedanib in the treatment of IPF. Methods: A non-interventional multicenter retrospective observational pharmacological study in real-life treat-ment at 1 and 2 years was conducted. Furthermore, we analyzed the levels of FVC and DLCO at 6 and 12 months, respectively, from the start of treatment. Results: We identified 144 patients in the period between January 2013 and April 2019. From the point of view of adherence, there is no difference between the two drugs, even though patients who used pirfenidone had increasingly higher values: 0.90 vs 0.89, in the first year, and 0.91 vs 0.84, in the second year. In the first year of treatment, the percentage of persistent patients was 67% and 76%, while in the second year, it dropped to 47% and 53% for pirfenidone and nintedanib, respectively. Conclusion: The stratification of the adherence values as a function of the response to treatment in terms of FVC at 12 months for both study drugs showed that patients with optimal response scored adherence of more than 90%.

Intraindividual Response to Treatment with Pirfenidone in Idiopathic Pulmonary Fibrosis

2015 ◽  
Vol 191 (1) ◽  
pp. 110-113 ◽  
Author(s):  
Benjamin Loeh ◽  
Fotios Drakopanagiotakis ◽  
Gian Piero Bandelli ◽  
Daniel von der Beck ◽  
Silke Tello ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Response To Treatment

scholarly journals Comorbidity in idiopathic pulmonary fibrosis - what can biomarkers tell us?

2020 ◽  
Vol 14 ◽  
pp. 175346662091009 ◽  
Author(s):  
Tiago M. Alfaro ◽  
Carlos Robalo Cordeiro
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Clinical Manifestations ◽  
Premature Death ◽  
Sleep Apnoea ◽  
Significant Loss ◽  
Diagnostic Methods ◽  
Response To Treatment ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive parenchymal scarring, leading to dyspnoea, respiratory failure and premature death. Although IPF is confined to the lungs, the importance of IPF comorbidities such as pulmonary hypertension and ischaemic heart disease, lung cancer, emphysema/chronic obstructive pulmonary disease, gastroesophageal reflux, sleep apnoea and depression has been increasingly recognized. These comorbidities may be associated with increased mortality and significant loss of quality of life, so their identification and management are vital. The development of good-quality biomarkers could lead to numerous gains in the management of these patients. Biomarkers can be used for the identification of predisposed individuals, early diagnosis, assessment of prognosis, selection of best treatment and assessment of response to treatment. However, the role of biomarkers for IPF comorbidities is still quite limited, and mostly based on evidence coming from populations without IPF. The future development of new biomarker studies could be informed by those that have been studied independently for each of these conditions. For now, clinicians should be mostly attentive to clinical manifestations of IPF comorbidities, and use validated diagnostic methods for diagnosis. As research on biomarkers of most common diseases continues, it is expected that useful biomarkers are developed for these diseases and then validated for IPF populations. The reviews of this paper are available via the supplemental material section.

scholarly journals Type-1 IFN primed monocytes in pathogenesis of idiopathic pulmonary fibrosis

2020 ◽  
Author(s):  
Emily Fraser ◽  
Laura Denney ◽  
Karl Blirando ◽  
Chaitanya Vuppusetty ◽  
Agne Antanaviciute ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Immune Cells ◽  
Therapeutic Target ◽  
Lung Fibrosis ◽  
Ex Vivo ◽  
Treatment Options ◽  
Gene Expression Signature ◽  
Severe Form

ABSTRACTIdiopathic pulmonary fibrosis (IPF) is the most severe form of lung fibrosis. It is progressive, and has an extremely poor outcome and limited treatment options. The disease exclusively affects the lungs, and thus less attention has been focused on blood-borne immune cells. which could be a more effective therapeutic target than lung-based cells. Here, we questioned if circulating monocytes, which has been shown to be increased in IPF, bore abnormalities that might contribute to its pathogenesis. We found that levels of circulating monocytes correlated directly with the extent of fibrosis in the lungs, and increased further during acute clinical deterioration. Monocytes in IPF were phenotypically distinct, displaying increased expression of CD64, a type 1 IFN gene expression signature and a greater magnitude of type 1 IFN response when stimulated. These abnormalities were accompanied by markedly raised CSF-1 levels in the serum, prolonged survival of monocytes ex vivo, and increased numbers of monocytes in lung tissue. Our study defines the key monocytic abnormalities in IPF, proposing type 1 IFN-primed monocytes as a potential driver of an aberrant repair response and fibrosis. It provides a rationale for targeting monocytes and identifies monocytic CD64 as a potential specific therapeutic target for IPF.

scholarly journals Circulating argonaute-bound microRNA-126 reports vascular dysfunction & response to treatment in acute & chronic kidney disease

2020 ◽  
Author(s):  
Kathleen M Scullion ◽  
A D Bastiaan Vliegenthart ◽  
Laura Rivoli ◽  
Wilna Oosthuyzen ◽  
Tariq E Farrah ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Vascular Function ◽  
Clinical Decision Making ◽  
Vascular Dysfunction ◽  
Unmet Need ◽  
Post Treatment ◽  
Response To Treatment ◽  
Serum Samples ◽  
Anca Vasculitis

Background: Vascular and kidney dysfunction commonly co-exist. There is an unmet need for biomarkers of vascular health. Circulating microRNAs (miRs) are disease biomarkers; miR-126 is endothelial cell-enriched. We measured circulating miR-126 in rats with nephrotoxic nephritis (NTN) and humans with acute endothelial and renal injury (vasculitis associated with autoantibodies to neutrophil cytoplasm antigens (ANCA)). We then compared these findings to those from patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD), and explored the relationship between miR-126 and markers of vascular dysfunction. Methods: In rats, NTN was induced with nephrotoxic serum. Samples were prospectively collected from 70 patients with ANCA vasculitis (at presentation and once in treatment-induced remission), healthy subjects (n=60), patients with CKD (n=30) and ESRD before and after dialysis (n=15). In humans and rats, miR-126 and miR-122 (liver-specific control) were measured and correlated with vascular function. Results: In NTN rats, miR-126 was selectively reduced. In ANCA vasculitis, pre-treatment circulating miR-126 was reduced compared to health (88-fold reduction, ROC-AUC 0.87 (0.80-0.94)). miR-126 increased 3.4-fold post-treatment but remained lower than in health (~26-fold). There was no change in miR-122. Plasma fractionation demonstrated that argonaute 2-bound miR-126 increased with treatment of ANCA vasculitis. Urinary miR-126 decreased post-treatment. miR-126 did not differ between CKD and health but its concentration significantly correlated with measures of endothelial dysfunction. miR-126 was substantially reduced in ESRD (~350 fold compared to health and CKD). Conclusions: miR-126 may be a marker of vascular inflammation and has the potential to aid in clinical decision-making.

scholarly journals Molecular characterization of a precision-cut rat lung slice model for the evaluation of antifibrotic drugs

2019 ◽  
Vol 316 (2) ◽  
pp. L348-L357 ◽  
Author(s):  
Xinqiang Huang ◽  
Li Li ◽  
Ron Ammar ◽  
Yan Zhang ◽  
Yihe Wang ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Attrition Rate ◽  
Molecular Signature ◽  
Matrix Remodeling ◽  
Preclinical Models ◽  
Ex Vivo Model ◽  
Mesenchymal Transition

The translation of novel pulmonary fibrosis therapies from preclinical models into the clinic represents a major challenge demonstrated by the high attrition rate of compounds that showed efficacy in preclinical models but demonstrated no significant beneficial effects in clinical trials. A precision-cut lung tissue slice (PCLS) contains all major cell types of the lung and preserves the original cell-cell and cell-matrix contacts. It represents a promising ex vivo model to study pulmonary fibrosis. In this study, using RNA sequencing, we demonstrated that transforming growth factor-β1 (TGFβ1) induced robust fibrotic responses in the rat PCLS model, as it changed the expression of genes functionally related to extracellular matrix remodeling, cell adhesion, epithelial-to-mesenchymal transition, and various immune responses. Nintedanib, pirfenidone, and sorafenib each reversed a subset of genes modulated by TGFβ1, and of those genes we identified 229 whose expression was reversed by all three drugs. These genes define a molecular signature characterizing many aspects of pulmonary fibrosis pathology and its attenuation in the rat PCLS fibrosis model. A panel of 12 genes and three secreted biomarkers, including procollagen I, hyaluronic acid, and WNT1-inducible signaling pathway protein 1 were validated as efficacy end points for the evaluation of antifibrotic activity of experimental compounds. Finally, we showed that blockade of αV-integrins suppressed TGFβ1-induced fibrotic responses in the rat PCLS fibrosis model. Overall, our results suggest that the TGFβ1-induced rat PCLS fibrosis model may represent a valuable system for target validation and to determine the efficacy of experimental compounds.

scholarly journals Identification of a novel missense variant in SPDL1 associated with idiopathic pulmonary fibrosis

2020 ◽  
Author(s):  
Ryan S. Dhindsa ◽  
Johan Mattsson ◽  
Abhishek Nag ◽  
Quanli Wang ◽  
Louise V. Wain ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Unmet Need ◽  
Missense Variant ◽  
Mitotic Checkpoint ◽  
Next Generation Sequencing Data ◽  
Sequencing Data ◽  
Genetic Determinants ◽  
Gene Level ◽  
Generation Sequencing

AbstractIdiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Despite significant progress, the genetic determinants of this disease remain incompletely defined. Using next generation sequencing data from 752 individuals with sporadic IPF and 119,055 controls, we performed both variant- and gene-level analyses to identify novel IPF genetic risk factors. Our variant-level analysis revealed a novel rare missense variant in SPDL1 (NM_017785.5 p.Arg20Gln; p = 2.4 × 10−7, odds ratio = 2.87). This signal was independently replicated in the FinnGen cohort (combined p = 2.2 × 10−20), firmly associating this variant as a novel IPF risk allele. SPDL1 encodes Spindly, a protein involved in mitotic checkpoint signalling during cell division that has not been previously described in fibrosis. Our results highlight a novel mechanism underlying IPF, providing the potential for new therapeutic discoveries in a disease of great unmet need.

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