Disease Severity In Idiopathic Pulmonary Fibrosis Research Articles

Analysis of tissue lipidomics and computed tomography pulmonary fat attenuation volume (CTPFAV ) in idiopathic pulmonary fibrosis.

There is increasing interest in the role of lipids in processes that modulate lung fibrosis with evidence of lipid deposition in idiopathic pulmonary fibrosis (IPF) histological specimens. The aim of this study was to identify measurable markers of pulmonary lipid that may have utility as IPF biomarkers. IPF and control lung biopsy specimens were analysed using a unbiased lipidomic approach. Pulmonary fat attenuation volume (PFAV) was assessed on chest CT images (CTPFAV ) with 3D semi-automated lung density software. Aerated lung was semi-automatically segmented and CTPFAV calculated using a Hounsfield-unit (-40 to -200HU) threshold range expressed as a percentage of total lung volume. CTPFAV was compared to pulmonary function, serum lipids and qualitative CT fibrosis scores. There was a significant increase in total lipid content on histological analysis of IPF lung tissue (23.16 nmol/mg) compared to controls (18.66 mol/mg, p = 0.0317). The median CTPFAV in IPF was higher than controls (1.34% vs. 0.72%, p < 0.001) and CTPFAV correlated significantly with DLCO% predicted (R2 = 0.356, p < 0.0001) and FVC% predicted (R2 = 0.407, p < 0.0001) in patients with IPF. CTPFAV correlated with CT features of fibrosis; higher CTPFAV was associated with >10% reticulation (1.6% vs. 0.94%, p = 0.0017) and >10% honeycombing (1.87% vs. 1.12%, p = 0.0003). CTPFAV showed no correlation with serum lipids. CTPFAV is an easily quantifiable non-invasive measure of pulmonary lipids. In this pilot study, CTPFAV correlates with pulmonary function and radiological features of IPF and could function as a potential biomarker for IPF disease severity assessment.

Disparities in Rural Populations With Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease (ILD) characterized by a progressive decline in lung function.1 Early diagnosis and treatment are essential to slow lung function decline.2,3 Rural populations experience socioeconomic disadvantage and fractured access to care, both of which contribute to worse health outcomes.4 The relationship between rurality, socioeconomic factors that may impair care access, and outcomes in IPF has not been previously explored. We investigated the association between rurality and IPF disease severity, measured by pulmonary function at presentation to ILD specialty care, and mortality rates.

DNA Methylome Alterations Are Associated with Airway Macrophage Differentiation and Phenotype during Lung Fibrosis.

Rationale: Airway macrophages (AMs) are key regulators of the lung environment and are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal respiratory disease with no cure. However, knowledge about the epigenetics of AMs in IPF is limited. Objectives: To assess the role of epigenetic regulation of AMs during lung fibrosis. Methods: We undertook DNA methylation (DNAm) profiling by using Illumina EPIC (850k) arrays in sorted AMs from healthy donors (n = 14) and donors with IPF (n = 30). Cell-type deconvolution was performed by using reference myeloid-cell DNA methylomes. Measurements and Main Results: Our analysis revealed thatepigenetic heterogeneity was a key characteristic of IPF AMs. DNAm "clock" analysis indicated that epigenetic alterations in IPF AMs were not associated with accelerated aging. In differential DNAm analysis, we identified numerous differentially methylated positions (n = 11) and differentially methylated regions (n = 49) between healthy and IPF AMs, respectively. Differentially methylated positions and differentially methylated regions encompassed genes involved in lipid (LPCAT1 [lysophosphatidylcholine acyltransferase 1]) and glucose (PFKFB3 [6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3]) metabolism, and importantly, the DNAm status was associated with disease severity in IPF. Conclusions: Collectively, our data identify that changes in the epigenome are associated with the development and function of AMs in the IPF lung.

Serum calprotectin as new biomarker for disease severity in idiopathic pulmonary fibrosis: a cross-sectional study in two independent cohorts

BackgroundNon-invasive biomarkers for the assessment of disease severity in idiopathic pulmonary fibrosis (IPF) are urgently needed. Calprotectin belongs to the S-100 proteins produced by neutrophils, which likely contribute to IPF...

Extracellular Vesicles from Fibroblasts Induce Epithelial-Cell Senescence in Pulmonary Fibrosis.

Aberrant epithelial-mesenchymal interactions have critical roles in regulating fibrosis development. The involvement of extracellular vesicles (EVs), including exosomes, remains to be elucidated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Here, we found that lung fibroblasts (LFs) from patients with IPF induce cellular senescence via EV-mediated transfer of pathogenic cargo to lung epithelial cells. Mechanistically, IPF LF-derived EVs increased mitochondrial reactive oxygen species and associated mitochondrial damage in lung epithelial cells, leading to activation of the DNA damage response and subsequent epithelial-cell senescence. We showed that IPF LF-derived EVs contain elevated levels of microRNA-23b-3p (miR-23b-3p) and miR-494-3p, which suppress SIRT3, resulting in the epithelial EV-induced phenotypic changes. Furthermore, the levels of miR-23b-3p and miR-494-3p found in IPF LF-derived EVs correlated positively with IPF disease severity. These findings reveal that the accelerated epithelial-cell mitochondrial damage and senescence observed during IPF pathogenesis are caused by a novel paracrine effect of IPF fibroblasts via microRNA-containing EVs.

Quantitative CT-derived vessel metrics in idiopathic pulmonary fibrosis: A structure-function study.

ABSTRACTBackground and objectiveThis study aimed to investigate whether quantitative lung vessel morphology determined by a new fully automated algorithm is associated with functional indices in idiopathic pulmonary fibrosis (IPF).MethodsA total of 152 IPF patients had vessel volume, density, tortuosity and heterogeneity quantified from computed tomography (CT) images by a fully automated algorithm. Separate quantitation of vessel metrics in pulmonary arteries and veins was performed in 106 patients. Results were evaluated against readouts from lung function tests.ResultsNormalized vessel volume expressed as a percentage of total lung volume was moderately correlated with functional indices on univariable linear regression analysis: forced vital capacity (R2 = 0.27, P < 1 × 10−6), diffusion capacity for carbon monoxide (DLCO; R2 = 0.12, P = 3 × 10−5), total lung capacity (TLC; R2 = 0.45, P < 1 × 10−6) and composite physiologic index (CPI; R2 = 0.28, P < 1 × 10−6). Normalized vessel volume was correlated with vessel density but not with vessel heterogeneity. Quantitatively derived vessel metrics (and artery and vein subdivision scores) were not significantly linked with the transfer factor for carbon monoxide (KCO), and only weakly with DLCO.On multivariable linear regression analysis, normalized vessel volume and vessel heterogeneity were independently linked with DLCO, TLC and CPI indicating that they capture different aspects of lung damage. Artery–vein separation provided no additional information beyond that captured in the whole vasculature.ConclusionOur study confirms previous observations of links between vessel volume and functional measures of disease severity in IPF using a new vessel quantitation tool. Additionally, the new tool shows independent linkages of normalized vessel volume and vessel heterogeneity with functional indices. Quantitative vessel metrics do not appear to reflect vasculopathic damage in IPF.

Airway Microstructure in Idiopathic Pulmonary Fibrosis: Assessment at Hyperpolarized 3He Diffusion-weighted MRI.

Background MRI with inhaled hyperpolarized helium 3 (3He) allows for functional and structural imaging of the lungs. Hyperpolarized gas diffusion-weighted (DW) MRI provides noninvasive and quantitative assessment of microstructural acinar changes in the lungs. Purpose To investigate whether microstructural imaging metrics from in-vivo hyperpolarized 3He DW MRI are sensitive to longitudinal changes in a cohort of participants with idiopathic pulmonary fibrosis (IPF) and to evaluate the reproducibility of these metrics and their correlation with existing clinical measures of IPF disease severity. Materials and Methods In this prospective study, 18 participants with IPF underwent 3He DW MRI at 1.5 T and 11 participants underwent an identical same-day examination for reproducibility assessment. Thirteen participants returned for 6- and 12-month follow-up examinations. Pulmonary function tests, including diffusing capacity of the lungs for carbon monoxide and forced vital capacity, were performed at each examination. The apparent diffusion coefficient (ADC) and stretched exponential model-derived mean diffusive length scale (LmD) from DW MRI was compared with baseline CT fibrosis scores and pulmonary function tests by using Spearman rank correlation coefficient. Longitudinal changes in DW MRI and pulmonary function test measurements were assessed with Friedman tests and post hoc Dunn test. Results 3He ADC and LmD were reproducible (mean Bland-Altman analysis bias, 0.002 cm2 · sec-1 and -1.5 μm, respectively). Elevated ADC and LmD regions qualitatively corresponded to fibrotic regions at CT. ADC and LmD correlated with diffusing capacity of the lungs for carbon monoxide (respectively: r = -0.56, P = .017; and r = -0.54, P = .02) and CT fibrosis score (respectively: r = 0.71, P = .001; and r = 0.65, P = .003). LmD increased by 12 μm after 12 months (P = .001) whereas mean ADC (P = .17), forced vital capacity (P = .12), and diffusing capacity of the lungs for carbon monoxide (P > .99) were not statistically different between examinations. Conclusion Helium 3 diffusion-weighted MRI-derived mean diffusive length scale demonstrates longitudinal changes in lungs affected by idiopathic pulmonary fibrosis. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Altes and Flors in this issue.

A Multimodal Imaging Approach Based on Micro-CT and Fluorescence Molecular Tomography for Longitudinal Assessment of Bleomycin-Induced Lung Fibrosis in Mice.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by the progressive and irreversible destruction of lung architecture, which causes significant deterioration in lung function and subsequent death from respiratory failure. The pathogenesis of IPF in experimental animal models has been induced by bleomycin administration. In this study, we investigate an IPF-like mouse model induced by a double intratracheal bleomycin instillation. Standard histological assessments used for studying lung fibrosis are invasive terminal procedures. The goal of this work is to monitor lung fibrosis through noninvasive imaging techniques such as Fluorescent Molecular Tomography (FMT) and Micro-CT. These two technologies validated with histology findings could represent a revolutionary functional approach for real time non-invasive monitoring of IPF disease severity and progression. The fusion of different approaches represents a step further for understanding the IPF disease, where the molecular events occurring in a pathological condition can be observed with FMT and the subsequent anatomical changes can be monitored by Micro-CT.

Evaluating disease severity in idiopathic pulmonary fibrosis.

Accurate assessment of idiopathic pulmonary fibrosis (IPF) disease severity is integral to the care provided to patients with IPF. However, to date, there are no generally accepted or validated staging systems. There is an abundance of data on using information acquired from physiological, radiological and pathological parameters, in isolation or in combination, to assess disease severity in IPF. Recently, there has been interest in using serum biomarkers and computed tomography-derived quantitative lung fibrosis measures to stage disease severity in IPF. This review will focus on the suggested methods for staging IPF, at baseline and on serial assessment, their strengths and limitations, as well as future developments.

Plasma Soluble Receptor for Advanced Glycation End Products in Idiopathic Pulmonary Fibrosis.

The receptor for advanced glycation end products (RAGE) is underexpressed in idiopathic pulmonary fibrosis (IPF) lung, but the role of RAGE in human lung fibrosis remains uncertain. To examine (1) the association between IPF risk and variation at rs2070600, a functional missense variant in AGER (the gene that codes for RAGE), and (2) the associations between plasma-soluble RAGE (sRAGE) levels with disease severity and time to death or lung transplant in IPF. We genotyped the rs2070600 single-nucleotide polymorphism in 108 adults with IPF and 324 race-/ethnicity-matched control subjects. We measured plasma sRAGE by ELISA in 103 adults with IPF. We used generalized linear and additive models as well as Cox models to control for potential confounders. We repeated our analyses in 168 (genetic analyses) and 177 (sRAGE analyses) adults with other forms of interstitial lung disease (ILD). There was no association between rs2070600 variation among adults with IPF (P = 0.31). Plasma sRAGE levels were lower among adults with IPF and other forms of ILD than in control subjects (P < 0.001). The rs2070600 allele A was associated with a 49% lower sRAGE level (95% confidence interval [CI], 11 to 71%; P = 0.02) among adults with IPF. In adjusted analyses, lower sRAGE levels were associated with greater disease severity (14% sRAGE decrement per 10% FVC decrement; 95% CI, 5 to 22%) and a higher rate of death or lung transplant at 1 year (adjusted hazard ratio, 1.9 per logarithmic unit of sRAGE decrement; 95% CI, 1.2-3.3) in IPF. Similar findings were observed in a heterogeneous group of adults with other forms of ILD. Lower plasma sRAGE levels may be a biological measure of disease severity in IPF. Variation at the rs2070600 single-nucleotide polymorphism was not associated with IPF risk.

NFATc3 and VIP in Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease.

Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are both debilitating lung diseases which can lead to hypoxemia and pulmonary hypertension (PH). Nuclear Factor of Activated T-cells (NFAT) is a transcription factor implicated in the etiology of vascular remodeling in hypoxic PH. We have previously shown that mice lacking the ability to generate Vasoactive Intestinal Peptide (VIP) develop spontaneous PH, pulmonary arterial remodeling and lung inflammation. Inhibition of NFAT attenuated PH in these mice suggesting a connection between NFAT and VIP. To test the hypotheses that: 1) VIP inhibits NFAT isoform c3 (NFATc3) activity in pulmonary vascular smooth muscle cells; 2) lung NFATc3 activation is associated with disease severity in IPF and COPD patients, and 3) VIP and NFATc3 expression correlate in lung tissue from IPF and COPD patients. NFAT activity was determined in isolated pulmonary arteries from NFAT-luciferase reporter mice. The % of nuclei with NFAT nuclear accumulation was determined in primary human pulmonary artery smooth muscle cell (PASMC) cultures; in lung airway epithelia and smooth muscle and pulmonary endothelia and smooth muscle from IPF and COPD patients; and in PASMC from mouse lung sections by fluorescence microscopy. Both NFAT and VIP mRNA levels were measured in lungs from IPF and COPD patients. Empirical strategies applied to test hypotheses regarding VIP, NFATc3 expression and activity, and disease type and severity. This study shows a significant negative correlation between NFAT isoform c3 protein expression levels in PASMC, activity of NFATc3 in pulmonary endothelial cells, expression and activity of NFATc3 in bronchial epithelial cells and lung function in IPF patients, supporting the concept that NFATc3 is activated in the early stages of IPF. We further show that there is a significant positive correlation between NFATc3 mRNA expression and VIP RNA expression only in lungs from IPF patients. In addition, we found that VIP inhibits NFAT nuclear translocation in primary human pulmonary artery smooth muscle cells (PASMC). Early activation of NFATc3 in IPF patients may contribute to disease progression and the increase in VIP expression could be a protective compensatory mechanism.

Non-invasive Imaging of Idiopathic Pulmonary Fibrosis Using Cathepsin Protease Probes.

Idiopathic pulmonary fibrosis (IPF) is a lethal, chronic, progressive disease characterized by formation of scar tissue within the lungs. Because it is a disease of unknown etiology, it is difficult to diagnose, to predict disease course and to devise treatment strategies. Recent evidence suggests that activated macrophages play key roles in the pathology of IPF. Therefore, imaging probes that specifically recognize these pools of activated immune cells could provide valuable information about how these cells contribute to the pathobiology of the disease. Here we demonstrate that cysteine cathepsin-targeted imaging probes can be used to monitor the contribution of macrophages to fibrotic disease progression in the bleomycin-induced murine model of pulmonary fibrosis. Furthermore, we show that the probes highlight regions of macrophage involvement in fibrosis in human biopsy tissues from IPF patients. Finally, we present first-in-human results demonstrating non-invasive imaging of active cathepsins in fibrotic lesions of patients with IPF. Together, our findings validate small molecule cysteine cathepsin probes for clinical PET imaging and suggest that they have the potential to be used to generate mechanistically-informative molecular information regarding cellular drivers of IPF disease severity and progression.

Acute exacerbation of idiopathic pulmonary fibrosis: a clinical review.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic disease limited to the lung, with high variability in the course of disease from one patient to another. Patients with IPF may experience acute respiratory deteriorations; many of these acute declines are idiopathic and are termed acute exacerbations (AE) of IPF. In these cases, the exclusion of alternative causes of rapid deterioration, including heart failure, bilateral pneumonia or pulmonary embolism, is a challenging goal. AE may occur at any time during the course of IPF, although they are more common in patients with more progressive disease and gastroesophageal reflux. Surgical lung biopsy or even surgical procedures in organs other than the lungs may also trigger AE, mainly in rapidly progressive or advanced IPF. Current diagnostic criteria include the presence of new-onset ground glass opacities or airspace consolidation superimposed on an underlying usual interstitial pneumonia pattern seen on high-resolution computed tomography. The outcome is poor with a short-term mortality in excess of 50 % despite therapy. Currently, there is no treatment with demonstrated efficacy for AE-IPF: empirical high-dose corticosteroid therapy is generally used, with or without immunosuppressive agents, with limited evidence. On the other hand, there is hope that new treatments to slow down progression of IPF will translate into a reduction of AE-IPF’s occurrence. In conclusion, although significant progress in assessing disease severity in IPF has been made, AEs remain unpredictable and are associated with a high risk of death. Improvements in our understanding of the etiology, risk factors, clinical predictors and epidemiology are needed. It is the goal of clinical researchers in the field to provide respiratory physicians with evidence-based guidance to identify patients who may benefit from therapy for preventing or treating AE-IPF.

A cohort study of interstitial lung diseases in central Denmark

Interstitial lung diseases (ILDs) form a heterogeneous group of diseases with varying degrees of inflammation and fibrosis. Epidemiological data based on the current diagnostic criteria are sparse. To characterize the incidence rate of ILDs and idiopathic pulmonary fibrosis (IPF) in Danish patients diagnosed at a referral hospital, to evaluate disease severity and survival in these ILD patients and to compare the use of the 2001 and 2011 guidelines to diagnosis of IPF. Single-centre, retrospective, observational cohort study including incident patients diagnosed with ILD at Aarhus University Hospital between 2003 and 2009. All diagnoses were re-evaluated according to current diagnostic criteria. Disease severity in IPF was assessed using the GAP index. The ILD incidence was 4.1 per 100,000 inhabitants/year. IPF was the most common diagnosis (28%) followed by connective tissue disease-related ILD (14%), hypersensitivity pneumonitis (7%) and non-specific interstitial pneumonia (NSIP) (7%). The GAP index was a strong predictor of survival in IPF. Twenty-three patients who had IPF based on the 2001 criteria had a "possible UIP" HRCT pattern but no lung biopsy, and IPF could therefore not be diagnosed based on the 2011 criteria. ILD and IPF incidence was 4.1 and 1.3 per 100,000 inhabitants/year. The diagnostic re-evaluation raised the number of IPF diagnoses, but a diagnostic "grey zone" was still evident in patients with UIP features not qualifying the patients to be diagnosed with IPF. The GAP index was valuable as a measure of IPF severity in this cohort.

The Significance of Elevated Tumor Markers Among Patients With Idiopathic Pulmonary Fibrosis Before and After Lung Transplantation

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a 3-year median survival. Lung volume and diffusion capacity at rest are usually used to monitor the clinical course. Because of high mortality, identification of patients at high risk is crucial for treatment strategies such as lung transplantation (LTX). This study was designed to determine if tumor markers could accurately characterize disease severity and survival in patients with IPF. The study population consisted of 61 patients with progressive IPF referred for LTX. Pulmonary function tests, cardiopulmonary exercise test, 6-min walk distance test, and Doppler echocardiogram were assessed at baseline and compared with tumor marker levels. Participants were prospectively followed for at least 25 months to determine the relationship between test parameters and survival. Tumor marker levels were reassessed in patients who underwent LTX. Forty-one age- and sex-matched patients (21 LTX recipients) with COPD served as control subjects. In the IPF group, nine patients (14.7%) died during follow-up and 20 (32.8%) underwent LTX. Univariate analysis showed correlations between carbohydrate antigen (CA) 125 and FEV(1) % (P = .0001). CA 19-9 yielded the best correlations with exercise parameters and PAP. Significant correlation with survival was noted with CA 15-3 (P = .04) only. All tumor marker levels decreased significantly following LTX, except CA 125. CA 15-3 had the largest decrease (P = .001). Among the COPD group, tumor marker levels before LTX were significantly lower compared with the IPF and did not decrease following LTX. No patient in either group developed malignancy. CA 15-3 levels may predict disease severity in IPF. Levels decreased in patients with IPF but not with COPD following LTX and were not associated with malignancy. This preliminary observation suggests that mucin has a role in the pathogenesis of IPF and possibly is a marker for disease activity.

Clinical trials in idiopathic pulmonary fibrosis: a word of caution concerning choice of outcome measures

Idiopathic pulmonary fibrosis (IPF) is a challenging and frustrating disease for clinicians and patients confronted with this clinical entity, since it is associated with a dismal ∼3-yr median survival from the time of diagnosis 1 and an effective treatment regimen is yet to be determined. The lack of an effective treatment option has encouraged investigation of new treatment regimens, and promising agents are being investigated in several clinical trials worldwide. Despite aggressive, worldwide collaborations in pursuit of an effective regimen, significant progress is still needed to recommend a specific treatment regimen for IPF 2. While recent publications have provided insights regarding appropriate outcome measures chosen as end points for IPF clinical trials, results from these studies have either (unfortunately) been negative or merely provided positive signals and generated hypotheses that deserve to be investigated further in well-designed studies 3–6. Investigators who are involved in planning IPF studies face daunting challenges in selecting outcome measures that will appropriately allow statistical assessment of clinically meaningful effects or outcomes. Clinicians reviewing the IPF literature are confronted with equally daunting challenges in interpreting the clinical and statistical importance of these findings and applying this knowledge in the clinical care of their patients. Both the investigator and the clinician interpreting the results need to understand how IPF disease severity and progression are best measured in order to provide the most convincing and interpretable study evidence. The 2000 International Consensus statement for IPF diagnosis and treatment suggests measures with promise for measuring IPF disease extent and potential for measuring change, but it is clear that validated outcome measures were not known when the document was drafted 1. Investigators involved in the largest IPF trial conducted to date recently reported an apparent lack of appropriate IPF outcome measures 6. They reported …

IL-4-induced macrophage-derived IGF-I protects myofibroblasts from apoptosis following growth factor withdrawal.

The development of idiopathic pulmonary fibrosis (IPF) is associated with myofibroblast accumulation and collagen deposition in the lung parenchyma. Recent studies have suggested that the fibroproliferative response is associated with immune deviation toward a T helper cell type 2 (Th2) cytokine profile. In addition, myofibroblast accumulation may be the result of resistance to physiologic apoptosis. If and how these events are linked remain largely unknown. Insulin-like growth factor-I (IGF-I) is a fibroblast growth and survival factor that has long been implicated in the pathogenesis of IPF. We have previously shown that interstitial macrophage-derived IGF-I correlates with disease severity in IPF, and the Th2 cytokines interleukin (IL)-4 and IL-13 stimulate the expression and secretion of IGF-I by macrophages. In the present study, we tested the hypothesis that IL-4-induced, macrophage-derived IGF-I protects myofibroblasts from apoptosis. Using a growth factor withdrawal model of apoptosis in the myofibroblast cell line, CCL39, we demonstrate that conditioned media from IL-4-stimulated macrophages protect myofibroblasts from apoptosis. The survival effect is lost when IGF-I is immunodepleted from macrophage-conditioned media with IGF-I-specific antibodies. We also show that the protection of myofibroblasts by macrophage-derived IGF-I correlates with and is dependent on the activation of the prosurvival kinases Akt and extracellular signal-regulated kinase. These findings support the view that IL-4-stimulated, macrophage-derived IGF-I may contribute to the persistence of myofibroblasts in pulmonary fibrosis in the Th2-deviated environment of the fibrotic lung.