scholarly journals Effect of Substrate Stiffness on Physicochemical Properties of Normal and Fibrotic Lung Fibroblasts

Materials ◽  
2020 ◽  
Vol 13 (20) ◽  
pp. 4495
Author(s):  
Joanna Raczkowska ◽  
Barbara Orzechowska ◽  
Sabina Patryas ◽  
Kamil Awsiuk ◽  
Andrzej Kubiak ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Physicochemical Properties ◽  
Chemical Properties ◽  
Principal Component ◽  
Lung Fibroblasts ◽  
Substrate Stiffness ◽  
Significant Difference ◽  
The Impact

The presented research aims to verify whether physicochemical properties of lung fibroblasts, modified by substrate stiffness, can be used to discriminate between normal and fibrotic cells from idiopathic pulmonary fibrosis (IPF). The impact of polydimethylsiloxane (PDMS) substrate stiffness on the physicochemical properties of normal (LL24) and IPF-derived lung fibroblasts (LL97A) was examined in detail. The growth and elasticity of cells were assessed using fluorescence microscopy and atomic force microscopy working in force spectroscopy mode, respectively. The number of fibroblasts, as well as their shape and the arrangement, strongly depends on the mechanical properties of the substrate. Moreover, normal fibroblasts remain more rigid as compared to their fibrotic counterparts, which may indicate the impairments of IPF-derived fibroblasts induced by the fibrosis process. The chemical properties of normal and IPF-derived lung fibroblasts inspected using time-of-flight secondary ion mass spectrometry, and analyzed complexly with principal component analysis (PCA), show a significant difference in the distribution of cholesterol and phospholipids. Based on the observed distinctions between healthy and fibrotic cells, the mechanical properties of cells may serve as prospective diagnostic biomarkers enabling fast and reliable identification of idiopathic pulmonary fibrosis (IPF).

The Impact of Smoking on Mechanical Properties of the Lungs in Idiopathic Pulmonary Fibrosis and Sarcoidosis

1991 ◽  
Vol 144 (5) ◽  
pp. 1102-1106 ◽  
Author(s):  
Michael E. Hanley ◽  
Talmadge E. King ◽  
Marvin I. Schwarz ◽  
Leslie C. Watters ◽  
Anthony S. Shen ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
The Impact

Coagulation Factor-XII induces interleukin-6 by primary lung fibroblasts: A role in idiopathic pulmonary fibrosis?

2021 ◽  
Author(s):  
Jade Jaffar ◽  
Laura McMillan ◽  
Nick Wilson ◽  
Con Panousis ◽  
Charles Hardy ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Tissue ◽  
Plasma Levels ◽  
Lung Fibroblasts ◽  
Factor Xii ◽  
Dependent Manner ◽  
Healthy Donors ◽  
Mechanistic Investigation ◽  
The Impact

Background The mechanisms driving idiopathic pulmonary fibrosis (IPF) remain undefined, however it is postulated that coagulation imbalances may play a role. The impact of blood-derived clotting factors, including factor XII (FXII) has not been investigated in the context of IPF. Methods Plasma levels of FXII were measured by ELISA in patients with IPF and age-matched healthy donors. Expression of FXII in human lung tissue was quantified using multiplex immunohistochemistry and western blotting. Mechanistic investigation of FXII activity was assessed in vitro on primary lung fibroblasts using qPCR and specific receptor/FXII inhibition. The functional outcome of FXII on fibroblast migration was examined by high-content image analysis. Findings Compared to 35 healthy donors, plasma levels of FXII were not higher in IPF (n=27, p>0·05). Tissue FXII was elevated in IPF (n=11) and increased numbers of FXII+ cells were found in IPF (n=8) lung tissue compared to non-diseased controls (n=6, p<0·0001). Activated FXII induced IL6 mRNA and IL-6 protein in fibroblasts that was blocked by anti-FXII antibody, CSL312. FXII-induced IL-6 production via PAR-1 and NF-kB. FXII induced migration of fibroblasts in a concentration-dependent manner. Interpretation FXII is normally confined to the circulation but leaks from damaged vessels into the lung interstitium in IPF where it 1) induces IL-6 production and 2) enhances migration of resident fibroblasts, critical events that drive chronic inflammation and therefore, contribute to fibrotic disease progression. Targeting FXII-induced fibroblastic processes in IPF may ameliorate pulmonary fibrosis. Funding National Health and Medical Research Council CRE in Lung Fibrosis and CSL Ltd.

scholarly journals Prognostic significance of forced vital capacity decline prior to and following antifibrotic therapy in idiopathic pulmonary fibrosis

2020 ◽  
Vol 14 ◽  
pp. 175346662095378
Author(s):  
Yuya Aono ◽  
Yutaro Nakamura ◽  
Masato Kono ◽  
Hidenori Nakamura ◽  
Koshi Yokomura ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Forced Vital Capacity ◽  
Slow Rate ◽  
Vital Capacity ◽  
Survival Outcome ◽  
Antifibrotic Therapy ◽  
Significant Difference ◽  
The Impact ◽  
Antifibrotic Drugs

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease (ILD). Currently, two antifibrotic drugs are available for reducing forced vital capacity (FVC) decline in IPF. However, many pulmonologists wait before initiating treatment, especially when IPF patients have stable disease. This study aimed to investigate the impact on survival outcome of FVC decline and a slow rate of FVC decline prior to and following treatment with these two antifibrotic drugs. Methods: Out of the 235 IPF patients treated with antifibrotic therapy that were screened, 105 cases were eligible, who then underwent physiological evaluation at 6 months prior to and following antifibrotic therapy. Clinical characteristics and prognostic outcomes were compared among groups, and prognostic factors were evaluated using a Cox proportional hazards analysis. Results: In terms of %FVC decline prior to the therapy and a slow rate of FVC decline, there was no significant difference between stable and worsened groups and responder and non-responder groups, respectively. On the other hand, in terms of %FVC decline (decline >5%) following antifibrotic therapy, the stable/improved group had significantly better prognosis than the worsened group. Prognostic analysis revealed that a stable/improved status following antifibrotic therapy [HR: 0.35 (0.15–0.87)] was significantly associated with a better prognosis. Conclusions: Concerning the FVC decline prior to and following antifibrotic therapy and a slow rate of FVC decline, only the FVC decline following the therapy is associated with a greater survival outcome. An early treatment decision may thus be beneficial for IPF. The reviews of this paper are available via the supplemental material section.

scholarly journals Efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis who are elderly or have comorbidities

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Ian Glaspole ◽  
Francesco Bonella ◽  
Elena Bargagli ◽  
Marilyn K. Glassberg ◽  
Fabian Caro ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Adverse Events ◽  
Treatment Discontinuation ◽  
Efficacy And Safety ◽  
Data Set ◽  
Proactive Management ◽  
Comorbidity Burden ◽  
Rate Of Decline ◽  
The Impact

Abstract Background Idiopathic pulmonary fibrosis (IPF) predominantly affects individuals aged > 60 years who have several comorbidities. Nintedanib is an approved treatment for IPF, which reduces the rate of decline in forced vital capacity (FVC). We assessed the efficacy and safety of nintedanib in patients with IPF who were elderly and who had multiple comorbidities. Methods Data were pooled from five clinical trials in which patients were randomised to receive nintedanib 150 mg twice daily or placebo. We assessed outcomes in subgroups by age < 75 versus ≥ 75 years, by < 5 and ≥ 5 comorbidities, and by Charlson Comorbidity Index (CCI) ≤ 3 and > 3 at baseline. Results The data set comprised 1690 patients. Nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks versus placebo in patients aged ≥ 75 years (difference: 105.3 [95% CI 39.3, 171.2]) (n = 326) and < 75 years (difference 125.2 [90.1, 160.4]) (n = 1364) (p = 0.60 for treatment-by-time-by-subgroup interaction), in patients with < 5 comorbidities (difference: 107.9 [95% CI 65.0, 150.9]) (n = 843) and ≥ 5 comorbidities (difference 139.3 [93.8, 184.8]) (n = 847) (p = 0.41 for treatment-by-time-by-subgroup interaction) and in patients with CCI score ≤ 3 (difference: 106.4 [95% CI 70.4, 142.4]) (n = 1330) and CCI score > 3 (difference: 129.5 [57.6, 201.4]) (n = 360) (p = 0.57 for treatment-by-time-by-subgroup interaction). The adverse event profile of nintedanib was generally similar across subgroups. The proportion of patients with adverse events leading to treatment discontinuation was greater in patients aged ≥ 75 years than < 75 years in both the nintedanib (26.4% versus 16.0%) and placebo (12.2% versus 10.8%) groups. Similarly the proportion of patients with adverse events leading to treatment discontinuation was greater in patients with ≥ 5 than < 5 comorbidities (nintedanib: 20.5% versus 15.7%; placebo: 12.1% versus 10.0%). Conclusions Our findings suggest that the effect of nintedanib on reducing the rate of FVC decline is consistent across subgroups based on age and comorbidity burden. Proactive management of adverse events is important to reduce the impact of adverse events and help patients remain on therapy. Trial registration: ClinicalTrials.gov NCT00514683, NCT01335464, NCT01335477, NCT02788474, NCT01979952.

scholarly journals Mortality Associated with Idiopathic Pulmonary Fibrosis in Northeastern Italy, 2008–2020: A Multiple Cause of Death Analysis

2021 ◽  
Vol 18 (14) ◽  
pp. 7249
Author(s):  
Alessandro Marcon ◽  
Elena Schievano ◽  
Ugo Fedeli
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Cause Of Death ◽  
Age Groups ◽  
Mortality Rates ◽  
Annual Percent Change ◽  
Northeastern Italy ◽  
Mortality Ratio ◽  
The Impact ◽  
Related Mortality

Mortality from idiopathic pulmonary fibrosis (IPF) is increasing in most European countries, but there are no data for Italy. We analysed the registry data from a region in northeastern Italy to assess the trends in IPF-related mortality during 2008–2019, to compare results of underlying vs. multiple cause of death analyses, and to describe the impact of the COVID-19 epidemic in 2020. We identified IPF (ICD-10 code J84.1) among the causes of death registered in 557,932 certificates in the Veneto region. We assessed time trends in annual age-standardized mortality rates by gender and age (40–74, 75–84, and ≥85 years). IPF was the underlying cause of 1310 deaths in the 2251 certificates mentioning IPF. For all age groups combined, the age-standardized mortality rate from IPF identified as the underlying cause of death was close to the European median (males and females: 3.1 and 1.3 per 100,000/year, respectively). During 2008–2019, mortality rates increased in men aged ≥85 years (annual percent change of 6.5%, 95% CI: 2.0, 11.2%), but not among women or for the younger age groups. A 72% excess of IPF-related deaths was registered in March–April 2020 (mortality ratio 1.72, 95% CI: 1.29, 2.24). IPF mortality was increasing among older men in northeastern Italy. The burden of IPF was heavier than assessed by routine statistics, since less than two out of three IPF-related deaths were directly attributed to this condition. COVID-19 was accompanied by a remarkable increase in IPF-related mortality.

scholarly journals Reconstruction of the miR-506-Quaking axis in Idiopathic Pulmonary Fibrosis using integrative multi-source bioinformatics

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Stevan D. Stojanović ◽  
Maximilian Fuchs ◽  
Chunguang Liang ◽  
Kevin Schmidt ◽  
Ke Xiao ◽  
...  
Keyword(s):  
Data Mining ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Rna Sequencing ◽  
In Silico ◽  
Rna Binding ◽  
Human Lung ◽  
Model Systems ◽  
Lung Fibroblasts ◽  
Sequencing Analysis

AbstractThe family of RNA-binding proteins (RBP) functions as a crucial regulator of multiple biological processes and diseases. However, RBP function in the clinical setting of idiopathic pulmonary fibrosis (IPF) is still unknown. We developed a practical in silico screening approach for the characterization of RBPs using multi-sources data information and comparative molecular network bioinformatics followed by wet-lab validation studies. Data mining of bulk RNA-Sequencing data of tissues of patients with IPF identified Quaking (QKI) as a significant downregulated RBP. Cell-type specific expression was confirmed by single-cell RNA-Sequencing analysis of IPF patient data. We systematically analyzed the molecular interaction network around QKI and its functional interplay with microRNAs (miRs) in human lung fibroblasts and discovered a novel regulatory miR-506-QKI axis contributing to the pathogenesis of IPF. The in silico results were validated by in-house experiments applying model systems of miR and lung biology. This study supports an understanding of the intrinsic molecular mechanisms of IPF regulated by the miR-506-QKI axis. Initially applied to human lung disease, the herein presented integrative in silico data mining approach can be adapted to other disease entities, underlining its practical relevance in RBP research.

scholarly journals S19 The impact of clotting abnormalities on the natural history of idiopathic pulmonary fibrosis: an extended follow up of a population based cohort

Thorax ◽  
2016 ◽  
Vol 71 (Suppl 3) ◽  
pp. A13.1-A13
Author(s):  
V Navaratnam ◽  
AW Fogarty ◽  
T McKeever ◽  
N Thompson ◽  
G Jenkins ◽  
...  
Keyword(s):  
Natural History ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Population Based ◽  
History Of ◽  
The Impact
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