Research

11 pages, 680 KiB

Open AccessArticle

Baseline High-Resolution CT Findings Predict Acute Exacerbation of Idiopathic Pulmonary Fibrosis: German and Japanese Cohort Study

by Chihiro Hirano, Shinichiro Ohshimo, Yasushi Horimasu, Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Nobuoki Kohno, Daisuke Komoto, Kazuo Awai, Nobuaki Shime, Francesco Bonella, Josune Guzman, Hilmar Kühl, Ulrich Costabel and Noboru Hattori

J. Clin. Med. 2019, 8(12), 2069; https://doi.org/10.3390/jcm8122069 - 24 Nov 2019

Cited by 8 | Viewed by 3055

Abstract

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a major cause of morbidity and death in IPF. However, sensitive predictive factors of AE-IPF have not been well-investigated. To investigate whether high-resolution computed tomographic (HRCT) abnormalities predict AE-IPF in independent ethnic cohorts, this study [...] Read more.

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a major cause of morbidity and death in IPF. However, sensitive predictive factors of AE-IPF have not been well-investigated. To investigate whether high-resolution computed tomographic (HRCT) abnormalities predict AE-IPF in independent ethnic cohorts, this study included 121 patients with IPF (54 German and 67 Japanese; mean age, 68.5 ± 7.6 years). Two radiologists independently visually assessed the presence and extent of lung abnormalities in each patient. Twenty-two (18.2%) patients experienced AE-IPF during the follow-up. The incidence of AE-IPF was significantly higher in the Japanese patients (n = 18, 26.9%) than in the German patients (n = 4, 7.3%, p < 0.01). In the Kaplan–Meier analysis, patients with a larger extent of ground glass opacity (GGO), fibrosis, and traction bronchiectasis experienced an earlier onset of AE-IPF (p = 0.0033, 0.0088, and 0.049, respectively). In the multivariate analysis, a larger extent of GGO and fibrosis on HRCT were independent predictors of AE-IPF (p = 0.026 and 0.037, respectively). Additionally, Japanese ethnicity was independently associated with the incidence of AE-IPF after adjustment for HRCT findings (p = 0.0074). In conclusion, a larger extent of GGO and fibrosis on HRCT and Japanese ethnicity appear to be risk factors for AE-IPF. Full article

(This article belongs to the Special Issue The New Frontier in Pulmonary Fibrosis)

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13 pages, 2572 KiB

Open AccessArticle

Exploring the Ability of Electronic Nose Technology to Recognize Interstitial Lung Diseases (ILD) by Non-Invasive Breath Screening of Exhaled Volatile Compounds (VOC): A Pilot Study from the European IPF Registry (eurIPFreg) and Biobank

by Ekaterina Krauss, Jana Haberer, Olga Maurer, Guillermo Barreto, Fotios Drakopanagiotakis, Maria Degen, Werner Seeger and Andreas Guenther

J. Clin. Med. 2019, 8(10), 1698; https://doi.org/10.3390/jcm8101698 - 16 Oct 2019

Cited by 22 | Viewed by 3242

Abstract

Background: There is an increasing interest in employing electronic nose technology in the diagnosis and monitoring of lung diseases. Interstitial lung diseases (ILD) are challenging in regard to setting an accurate diagnosis in a timely manner. Thus, there is a high unmet need [...] Read more.

Background: There is an increasing interest in employing electronic nose technology in the diagnosis and monitoring of lung diseases. Interstitial lung diseases (ILD) are challenging in regard to setting an accurate diagnosis in a timely manner. Thus, there is a high unmet need in non-invasive diagnostic tests. This single-center explorative study aimed to evaluate the usefulness of electronic nose (Aeonose^®) in the diagnosis of ILDs. Methods: Exhaled volatile organic compound (VOC) signatures were obtained by Aeonose^® in 174 ILD patients, 23 patients with chronic obstructive pulmonary disease (COPD), and 33 healthy controls (HC). Results: By dichotomous comparison of VOC’s between ILD, COPD, and HC, a discriminating algorithm was established. In addition, direct analyses between the ILD subgroups, e.g., cryptogenic organizing pneumonia (COP, n = 28), idiopathic pulmonary fibrosis (IPF, n = 51), and connective tissue disease-associated ILD (CTD-ILD, n = 25) were performed. Area under the Curve (AUC) and Matthews’s correlation coefficient (MCC) were used to interpret the data. In direct comparison of the different ILD subgroups to HC, the algorithms developed on the basis of the Aeonose^® signatures allowed safe separation between IPF vs. HC (AUC of 0.95, MCC of 0.73), COP vs. HC (AUC 0.89, MCC 0.67), and CTD-ILD vs. HC (AUC 0.90, MCC 0.69). Additionally, to a case-control study design, the breath patterns of ILD subgroups were compared to each other. Following this approach, the sensitivity and specificity showed a relevant drop, which results in a poorer performance of the algorithm to separate the different ILD subgroups (IPF vs. COP with MCC 0.49, IPF vs. CTD-ILD with MCC 0.55, and COP vs. CT-ILD with MCC 0.40). Conclusions: The Aeonose^® showed some potential in separating ILD subgroups from HC. Unfortunately, when applying the algorithm to distinguish ILD subgroups from each other, the device showed low specificity. We suggest that artificial intelligence or principle compound analysis-based studies of a much broader data set of patients with ILDs may be much better suited to train these devices. Full article

(This article belongs to the Special Issue The New Frontier in Pulmonary Fibrosis)

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21 pages, 1615 KiB

Open AccessArticle

Epithelial Alarmins in Serum and Exhaled Breath in Patients with Idiopathic Pulmonary Fibrosis: A Prospective One-Year Follow-Up Cohort Study

by Sebastian Majewski, Karolina Szewczyk, Adam J. Białas, Joanna Miłkowska-Dymanowska, Paweł Górski and Wojciech J. Piotrowski

J. Clin. Med. 2019, 8(10), 1590; https://doi.org/10.3390/jcm8101590 - 02 Oct 2019

Cited by 9 | Viewed by 2870

Abstract

Background: Recently, epithelial alarmins have been shown to play important roles in non-allergen driven respiratory diseases like idiopathic pulmonary fibrosis (IPF). Little is known about the expression of the epithelial alarmins in IPF. Methods: This study aimed to prospectively examine interleukin (IL)-25, IL-33, [...] Read more.

Background: Recently, epithelial alarmins have been shown to play important roles in non-allergen driven respiratory diseases like idiopathic pulmonary fibrosis (IPF). Little is known about the expression of the epithelial alarmins in IPF. Methods: This study aimed to prospectively examine interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP) levels in the serum and exhaled breath condensate (EBC) in patients with IPF before and after one-year of antifibrotic treatment. A total of 82 volunteers, including 52 patients diagnosed with IPF that qualified for antifibrotic therapy as well as 30 controls, were examined. All study participants underwent baseline peripheral blood and EBC sampling. In 35 out of 52 IPF subjects, a follow-up sampling was performed after 12 months of antifibrotic treatment. Concentrations of alarmins in the serum and EBC were evaluated by means of ELISA. Results: Baseline TSLP concentrations were significantly elevated in patients with IPF compared to controls both in the serum (p < 0.05) and EBC (p < 0.0001). Baseline IL-25 and IL-33 serum and EBC levels did not differ significantly between IPF subjects and controls. Prospective analysis of changes in the epithelial alarmin levels showed significantly decreased IL-25 and TSLP EBC concentrations after 12 months of antifibrotic treatment (p < 0.05), which was observed in the subgroup of IPF patients treated with pirfenidone, but not in those treated with nintedanib. In stable patients with IPF over a study period (absolute forced vital capacity (FVC) % of predicted decline/year ≤ 5%, n = 25), a significant decrease in the EBC levels of both IL-25 and TSLP after 12 months of antifibrotic treatment was noted (p < 0.05), whereas, in progressor IPF patients (absolute FVC % of predicted decline/year > 5%, n = 10), a significant decrease was noted in the IL-25 EBC levels only (p < 0.05). Conclusions: Elevated TSLP levels in patients with IPF and their significant decrease in the lung compartment during antifibrotic therapy in stable patients with IPF, but not in progressors, support its significant contribution to pro-fibrotic type 2 immune responses in IPF. Noted changes in the epithelial alarmins concentration in the lung compartment during pirfenidone therapy may suggest its possible interaction with epithelial alarmins pathways in IPF. Full article

(This article belongs to the Special Issue The New Frontier in Pulmonary Fibrosis)

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12 pages, 1577 KiB

Open AccessArticle

High-Resolution CT Change over Time in Patients with Idiopathic Pulmonary Fibrosis on Antifibrotic Treatment

by Elisabetta Balestro, Elisabetta Cocconcelli, Chiara Giraudo, Roberta Polverosi, Davide Biondini, Donato Lacedonia, Erica Bazzan, Linda Mazzai, Giulia Rizzon, Sara Lococo, Graziella Turato, Mariaenrica Tinè, Manuel G. Cosio, Marina Saetta and Paolo Spagnolo

J. Clin. Med. 2019, 8(9), 1469; https://doi.org/10.3390/jcm8091469 - 15 Sep 2019

Cited by 17 | Viewed by 2749

Abstract

Antifibrotic treatment slows down functional decline and disease progression in idiopathic pulmonary fibrosis (IPF). High-resolution computed tomography (HRCT) is useful to diagnose IPF; however, little is known about whether and to what extent HRCT changes reflect functional changes during antifibrotic therapy. The aim [...] Read more.

Antifibrotic treatment slows down functional decline and disease progression in idiopathic pulmonary fibrosis (IPF). High-resolution computed tomography (HRCT) is useful to diagnose IPF; however, little is known about whether and to what extent HRCT changes reflect functional changes during antifibrotic therapy. The aim of this study was, therefore, to assess HRCT change over time after 1 year of treatment and to evaluate whether these changes correlate with functional decline over the same period of time. Sixty-eight IPF patients on antifibrotic treatment (i.e., pirfenidone or nintedanib) were functionally categorized as stable or progressors based on whether (or not) they had a decline in forced vital capacity (FVC) >5% predicted/year, and their HRCT were scored blindly and independently by two expert thoracic radiologists at treatment initiation (HRCT1) and after 1 year of treatment (HRCT2). Ground glass opacities (Alveolar Score, AS), reticulations (Interstitial Score, IS) and honeycombing (HC) were quantified and correlated with FVC decline between HRCT1 and HRCT2. At treatment initiation, HRCT scores were similar in both stable patients and progressors. After one year of treatment, in the entire population, AS and HC increased significantly, while IS did not. However, when stratified by the rate of functional decline, in stable patients, HC increased significantly while AS and IS did not. On the other hand, among progressors AS and HC increased significantly whereas IS did not. In the entire population, the combined score of fibrosis (IS + HC) correlated significantly with FVC decline. In conclusion, IPF patients on antifibrotic treatment exhibit different patterns of HRCT change over time based on their rate of functional decline. HRCT data should be integrated to lung function data when assessing response to antifibrotic treatment in patients with IPF. Full article

(This article belongs to the Special Issue The New Frontier in Pulmonary Fibrosis)

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13 pages, 2611 KiB

Open AccessArticle

Correlation between Transthoracic Lung Ultrasound Score and HRCT Features in Patients with Interstitial Lung Diseases

by Milena Adina Man, Elena Dantes, Bianca Domokos Hancu, Cosmina Ioana Bondor, Alina Ruscovan, Adriana Parau, Nicoleta Stefania Motoc and Monica Marc

J. Clin. Med. 2019, 8(8), 1199; https://doi.org/10.3390/jcm8081199 - 11 Aug 2019

Cited by 33 | Viewed by 5106

Abstract

Chest high-resolution computed tomography (HRCT) is considered the “gold” standard radiological method in interstitial lung disease (ILD) patients. The objectives of our study were to evaluate the correlation between two transthoracic lung ultrasound (LUS) scores (total number of B-lines score = the total [...] Read more.

Chest high-resolution computed tomography (HRCT) is considered the “gold” standard radiological method in interstitial lung disease (ILD) patients. The objectives of our study were to evaluate the correlation between two transthoracic lung ultrasound (LUS) scores (total number of B-lines score = the total sum of B-lines in 10 predefined scanning sites and total number of positive chest areas score = intercostal spaces with ≥3 B-lines) and the features in HRCT simplified scores, in different interstitial disorders, between LUS scores and symptoms, as well as between LUS scores and pulmonary function impairment. We have evaluated 58 consecutive patients diagnosed with ILD. We demonstrated that there was a good correlation between the total number of B-lines score and the HRCT simplified score (r = 0.784, p < 0.001), and also a good correlation between the total number of positive chest areas score and the HRCT score (r = 0.805, p < 0.005). The results confirmed the value of using LUS as a diagnostic tool for the assessment of ILD compared to HRCT. The use of LUS in ILD patients can be a useful, cheap, accessible and radiation-free investigation and can play a complementary role in the diagnosis and monitoring of these patients. Full article

(This article belongs to the Special Issue The New Frontier in Pulmonary Fibrosis)

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16 pages, 2031 KiB

Open AccessArticle

Exhalative Breath Markers Do Not Offer for Diagnosis of Interstitial Lung Diseases: Data from the European IPF Registry (eurIPFreg) and Biobank

by Ekaterina Krauss, Maike Froehler, Maria Degen, Poornima Mahavadi, Ruth C. Dartsch, Martina Korfei, Clemens Ruppert, Werner Seeger and Andreas Guenther

J. Clin. Med. 2019, 8(5), 643; https://doi.org/10.3390/jcm8050643 - 09 May 2019

Cited by 8 | Viewed by 3627

Abstract

Background: New biomarkers are urgently needed to facilitate diagnosis in Interstitial Lung Diseases (ILD), thus reducing the need for invasive procedures, and to enable tailoring and monitoring of medical treatment. Methods: In this study we investigated if patients with idiopathic pulmonary [...] Read more.

Background: New biomarkers are urgently needed to facilitate diagnosis in Interstitial Lung Diseases (ILD), thus reducing the need for invasive procedures, and to enable tailoring and monitoring of medical treatment. Methods: In this study we investigated if patients with idiopathic pulmonary fibrosis (IPF; n = 21), non-IPF ILDs (n = 57) and other lung diseases (chronic obstructive pulmonary disease (COPD) n = 24, lung cancer (LC) n = 16) as well as healthy subjects (n = 20) show relevant differences in exhaled NO (FeNO; Niox MINO), or in eicosanoid (PGE2, 8-isoprostane; enzyme-linked immunosorbent assay (ELISA)) levels as measured in exhaled breath condensates (EBC) and bronchoalveolar lavage fluids (BALF). Results: There was no significant difference in FeNO values between IPF, non-IPF ILDs and healthy subjects, although some individual patients showed highly elevated FeNO. On the basis of the FeNO signal, it was neither possible to differentiate between the kind of disease nor to detect exacerbations. In addition, there was no correlation between FeNO values and lung function. The investigation of the eicosanoids in EBCs was challenging (PGE2) or unreliable (8-isoprostane), but worked out well in BALF. A significant increase of free 8-isoprostane was observed in BALF, but not in EBCs, of patients with IPF, hypersensitivity pneumonitis (HP) and sarcoidosis, possibly indicating severity of oxidative stress. Conclusions: FeNO-measurements are not of diagnostic benefit in different ILDs including IPF. The same holds true for PGE2 and 8-isoprostane in EBC by ELISA. Full article

(This article belongs to the Special Issue The New Frontier in Pulmonary Fibrosis)

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12 pages, 1821 KiB

Open AccessArticle

High-Resolution Computed Tomography (HRCT) Reflects Disease Progression in Patients with Idiopathic Pulmonary Fibrosis (IPF): Relationship with Lung Pathology

by Elisabetta Cocconcelli, Elisabetta Balestro, Davide Biondini, Giulio Barbiero, Roberta Polverosi, Fiorella Calabrese, Federica Pezzuto, Donato Lacedonia, Federico Rea, Marco Schiavon, Erica Bazzan, Maria Pia Foschino Barbaro, Graziella Turato, Paolo Spagnolo, Manuel G. Cosio and Marina Saetta

J. Clin. Med. 2019, 8(3), 399; https://doi.org/10.3390/jcm8030399 - 22 Mar 2019

Cited by 16 | Viewed by 4490

Abstract

High-Resolution Computed Tomography (HRCT) plays a central role in diagnosing Idiopathic Pulmonary Fibrosis (IPF) while its role in monitoring disease progression is not clearly defined. Given the variable clinical course of the disease, we evaluated whether HRCT abnormalities predict disease behavior and correlate [...] Read more.

High-Resolution Computed Tomography (HRCT) plays a central role in diagnosing Idiopathic Pulmonary Fibrosis (IPF) while its role in monitoring disease progression is not clearly defined. Given the variable clinical course of the disease, we evaluated whether HRCT abnormalities predict disease behavior and correlate with functional decline in untreated IPF patients. Forty-nine patients (with HRCT₁) were functionally categorized as rapid or slow progressors. Twenty-one had a second HRCT₂. Thirteen patients underwent lung transplantation and pathology was quantified. HRCT Alveolar (AS) and Interstitial Scores (IS) were assessed and correlated with Forced Vital Capacity (FVC) decline between HRCT₁ and HRCT₂. At baseline, AS was greater in rapids than in slows, while IS was similar in the two groups. In the 21 subjects with HRCT₂, IS increased over time in both slows and rapids, while AS increased only in rapids. The IS change from HRCT₁ to HRCT₂ normalized per month correlated with FVC decline/month in the whole population, but the change in AS did not. In the 13 patients with pathology, the number of total lymphocytes was higher in rapids than in slows and correlated with AS. Quantitative estimation of HRCTs AS and IS reflects the distinct clinical and pathological behavior of slow and rapid decliners. Furthermore, AS, which reflects the immune/inflammatory infiltrate in lung tissue, could be a useful tool to differentiate rapid from slow progressors at presentation. Full article

(This article belongs to the Special Issue The New Frontier in Pulmonary Fibrosis)

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20 pages, 10704 KiB

Open AccessArticle

Inhibition of NADPH Oxidase 4 (NOX4) Signaling Attenuates Tuberculous Pleural Fibrosis

by Youngmi Kim, So Yeong Park, Harry Jung, You Sun Noh, Jae Jun Lee and Ji Young Hong

J. Clin. Med. 2019, 8(1), 116; https://doi.org/10.3390/jcm8010116 - 18 Jan 2019

Cited by 6 | Viewed by 5595

Abstract

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [NOX] enzymes serve several hemostatic and host defense functions in various lung diseases, but the role of NOX4 signaling in tuberculous pleurisy is not well understood. The role of NOX4 signaling in tuberculous pleural fibrosis was studied [...] Read more.

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [NOX] enzymes serve several hemostatic and host defense functions in various lung diseases, but the role of NOX4 signaling in tuberculous pleurisy is not well understood. The role of NOX4 signaling in tuberculous pleural fibrosis was studied using invitro pleural mesothelial cell (PMC) experiments and a murine model of Mycobacterium bovis bacillus Calmette–Guérin (BCG) pleural infection. The production of NOX4 reactive oxygen species (NOX4–ROS) and the epithelial mesenchymal transition (EMT) in PMCs were both induced by heat-killed mycobacterium tuberculosis (HKMT). In cultured PMCs, HKMT-induced collagen-1 synthesis and EMT were blocked by pretreatment with small interfering RNA (siRNA) NOX4. Moreover, NOX4–ROS production and subsequent fibrosis were reduced by treatment with losartan and the toll-like receptor 4 (TLR4) inhibitor TAK-242. The HKMT-induced EMT and intracellular ROS production were mediated by NOX4 via the activation of extracellular signal-regulated kinase (ERK) signaling. Finally, in a BCG-induced pleurisy model, recruitment of inflammatory pleural cells, release of inflammatory cytokines, and thickened mesothelial fibrosis were attenuated by SiNOX4 compared to SiCon. Our study identified that HKMT-induced pleural fibrosis is mediated by NOX4–ERK–ROS via TLR4 and Angiotensin II receptor type1 (AT1R). There results suggest that NOX4 may be a novel therapeutic target for intervention in tuberculous pleural fibrosis. Full article

(This article belongs to the Special Issue The New Frontier in Pulmonary Fibrosis)

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Review

Jump to: Research, Other

21 pages, 1136 KiB

Open AccessReview

Interstitial Lung Disease in Rheumatoid Arthritis Remains a Challenge for Clinicians

by Elisabeth Bendstrup, Janne Møller, Sissel Kronborg-White, Thomas Skovhus Prior and Charlotte Hyldgaard

J. Clin. Med. 2019, 8(12), 2038; https://doi.org/10.3390/jcm8122038 - 21 Nov 2019

Cited by 48 | Viewed by 7441

Abstract

Interstitial lung disease (ILD) is a serious complication of rheumatoid arthritis (RA) contributing to significantly increased morbidity and mortality. Other respiratory complications, such as chronic obstructive pulmonary disease and bronchiectasis, are frequent in RA. Infections and drug toxicity are important differential diagnoses and [...] Read more.

Interstitial lung disease (ILD) is a serious complication of rheumatoid arthritis (RA) contributing to significantly increased morbidity and mortality. Other respiratory complications, such as chronic obstructive pulmonary disease and bronchiectasis, are frequent in RA. Infections and drug toxicity are important differential diagnoses and should be considered in the diagnostic work-up of patients with RA presenting with respiratory symptoms. This review provides an overview of the epidemiology and pathogenesis of RA-ILD, the radiological and histopathological characteristics of the disease as well as the current and future treatment options. Currently, there is no available evidence-based therapy for RA-ILD, and immunosuppressants are the mainstay of therapy. Ongoing studies are exploring the role of antifibrotic therapy in patients with progressive fibrotic ILD, which may lead to a new treatment approach for subgroups of patients with RA-ILD. Full article

(This article belongs to the Special Issue The New Frontier in Pulmonary Fibrosis)

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13 pages, 765 KiB

Open AccessReview

Immune Checkpoints as Promising Targets for the Treatment of Idiopathic Pulmonary Fibrosis?

by JanWillem Duitman, Tom van den Ende and C. Arnold Spek

J. Clin. Med. 2019, 8(10), 1547; https://doi.org/10.3390/jcm8101547 - 26 Sep 2019

Cited by 26 | Viewed by 4970

Abstract

Idiopathic pulmonary fibrosis is a rare, progressive and fatal lung disease which affects approximately 5 million persons worldwide. Although pirfenidone and/or nintedanib treatment improves patients’ wellbeing, the prognosis of IPF remains poor with 5-year mortality rates still ranging from 70 to 80%. The [...] Read more.

Idiopathic pulmonary fibrosis is a rare, progressive and fatal lung disease which affects approximately 5 million persons worldwide. Although pirfenidone and/or nintedanib treatment improves patients’ wellbeing, the prognosis of IPF remains poor with 5-year mortality rates still ranging from 70 to 80%. The promise of the anti-cancer agent nintedanib in IPF, in combination with the recent notion that IPF shares several pathogenic pathways with cancer, raised hope that immune checkpoint inhibitors, the novel revolutionary anticancer agents, could also be the eagerly awaited ground-breaking and unconventional novel treatment modality limiting IPF-related morbidity/mortality. In the current review, we analyse the available literature on immune checkpoint proteins in IPF to explore whether immune checkpoint inhibition may be as promising in IPF as it is in cancer. We conclude that despite several promising papers showing that inhibiting specific immune checkpoint proteins limits pulmonary fibrosis, overall the data seem to argue against a general role of immune checkpoint inhibition in IPF and suggest that only PD-1/PD-L1 inhibition may be beneficial. Full article

(This article belongs to the Special Issue The New Frontier in Pulmonary Fibrosis)

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29 pages, 4710 KiB

Open AccessReview

Mucins as a New Frontier in Pulmonary Fibrosis

by Beatriz Ballester, Javier Milara and Julio Cortijo

J. Clin. Med. 2019, 8(9), 1447; https://doi.org/10.3390/jcm8091447 - 11 Sep 2019

Cited by 30 | Viewed by 5895

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue The New Frontier in Pulmonary Fibrosis)

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17 pages, 2126 KiB

Open AccessReview

Exosomal miRNAs in Lung Diseases: From Biologic Function to Therapeutic Targets

by Julien Guiot, Ingrid Struman, Edouard Louis, Renaud Louis, Michel Malaise and Makon-Sébastien Njock

J. Clin. Med. 2019, 8(9), 1345; https://doi.org/10.3390/jcm8091345 - 29 Aug 2019

Cited by 63 | Viewed by 6070

Abstract

Increasing evidence suggests the potential role of extracellular vesicles (EVs) in many lung diseases. According to their subcellular origin, secretion mechanism, and size, EVs are currently classified into three subpopulations: exosomes, microvesicles, and apoptotic bodies. Exosomes are released in most biofluids, including airway [...] Read more.

Increasing evidence suggests the potential role of extracellular vesicles (EVs) in many lung diseases. According to their subcellular origin, secretion mechanism, and size, EVs are currently classified into three subpopulations: exosomes, microvesicles, and apoptotic bodies. Exosomes are released in most biofluids, including airway fluids, and play a key role in intercellular communication via the delivery of their cargo (e.g., microRNAs (miRNAs)) to target cell. In a physiological context, lung exosomes present protective effects against stress signals which allow them to participate in the maintenance of lung homeostasis. The presence of air pollution alters the composition of lung exosomes (dysregulation of exosomal miRNAs) and their homeostatic property. Indeed, besides their potential as diagnostic biomarkers for lung diseases, lung exosomes are functional units capable of dysregulating numerous pathophysiological processes (including inflammation or fibrosis), resulting in the promotion of lung disease progression. Here, we review recent studies on the known and potential role of lung exosomes/exosomal miRNAs, in the maintaining of lung homeostasis on one hand, and in promoting lung disease progression on the other. We will also discuss using exosomes as prognostic/diagnostic biomarkers as well as therapeutic tools for lung diseases. Full article

(This article belongs to the Special Issue The New Frontier in Pulmonary Fibrosis)

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15 pages, 1094 KiB

Open AccessReview

Pulmonary Fibrosis in Children

by Nadia Nathan, Chiara Sileo, Guillaume Thouvenin, Laura Berdah, Céline Delestrain, Effrosyne Manali, Spyros Papiris, Pierre-Louis Léger, Hubert Ducou le Pointe, Aurore Coulomb l’Hermine and Annick Clement

J. Clin. Med. 2019, 8(9), 1312; https://doi.org/10.3390/jcm8091312 - 26 Aug 2019

Cited by 18 | Viewed by 6679

Abstract

Pulmonary fibrosis (PF) is a very rare condition in children, which may be observed in specific forms of interstitial lung disease. None of the clinical, radiological, or histological descriptions used for PF diagnosis in adult patients, especially in situations of idiopathic PF, can [...] Read more.

Pulmonary fibrosis (PF) is a very rare condition in children, which may be observed in specific forms of interstitial lung disease. None of the clinical, radiological, or histological descriptions used for PF diagnosis in adult patients, especially in situations of idiopathic PF, can apply to pediatric situations. This observation supports the view that PF expression may differ with age and, most likely, may cover distinct entities. The present review aims at summarizing the current understanding of PF pathophysiology in children and identifying suitable diagnostic criteria. Full article

(This article belongs to the Special Issue The New Frontier in Pulmonary Fibrosis)

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12 pages, 260 KiB

Open AccessReview

Telomere Abnormalities in the Pathobiology of Idiopathic Pulmonary Fibrosis

by Hasancan Bilgili, Adam J. Białas, Paweł Górski and Wojciech J. Piotrowski

J. Clin. Med. 2019, 8(8), 1232; https://doi.org/10.3390/jcm8081232 - 16 Aug 2019

Cited by 22 | Viewed by 4633

Abstract

Idiopathic pulmonary fibrosis (IPF) occurs primarily in older adults and the incidence is clearly associated with aging. This disease seems to be associated with several hallmarks of aging, including telomere attrition and cellular senescence. Increasing evidence suggests that abnormalities involving telomeres and their [...] Read more.

Idiopathic pulmonary fibrosis (IPF) occurs primarily in older adults and the incidence is clearly associated with aging. This disease seems to be associated with several hallmarks of aging, including telomere attrition and cellular senescence. Increasing evidence suggests that abnormalities involving telomeres and their proteome play a significant role in the pathobiology of IPF. The aim of this study is to summarize present knowledge in the field, as well as to discuss its possible clinical implications. Numerous mutations in genes associated with telomere functioning were studied in the context of IPF, mainly for Telomerase Reverse Transcriptase (TERT) and Telomerase RNA Component (TERC). Such mutations may lead to telomere shortening, which seems to increase the risk of IPF, negatively influence disease progression, and contribute to worse prognosis after lung transplantation. Some evidence indicates the possibility for the use of telomerase activators as potential therapeutic agents in pulmonary fibrosis. To sum up, increasing evidence suggests the role of telomere abnormalities in the pathobiology of IPF, natural history and prognosis of the disease. There are also possibilities for telomerase targeting in the potential development of new treatment agents. However, all these aspects require further research. Full article

(This article belongs to the Special Issue The New Frontier in Pulmonary Fibrosis)

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Other

Jump to: Research, Review

8 pages, 378 KiB

Open AccessBrief Report

Nintedanib Treatment for Idiopathic Pulmonary Fibrosis Patients Who Have Been Switched from Pirfenidone Therapy: A Retrospective Case Series Study

by Andrea Vianello, Francesco Salton, Beatrice Molena, Cristian Turato, Maria Laura Graziani, Fausto Braccioni, Valeria Frassani, Dino Sella, Paolo Pretto, Luciana Paladini, Andi Sukthi and Marco Confalonieri

J. Clin. Med. 2020, 9(2), 422; https://doi.org/10.3390/jcm9020422 - 04 Feb 2020

Cited by 13 | Viewed by 4273

Abstract

Background: The efficacy and effectiveness of nintedanib as a first-line therapy in idiopathic pulmonary fibrosis (IPF) patients have been demonstrated by clinical trials and real-life studies. Our aim was to examine the safety profile and effectiveness of nintedanib when it is utilized as [...] Read more.

Background: The efficacy and effectiveness of nintedanib as a first-line therapy in idiopathic pulmonary fibrosis (IPF) patients have been demonstrated by clinical trials and real-life studies. Our aim was to examine the safety profile and effectiveness of nintedanib when it is utilized as a second-line treatment in subjects who have discontinued pirfenidone. Methods: The medical charts of 12 patients who were switched from pirfenidone to nintedanib were examined retrospectively. The drug’s safety was defined by the number of adverse events (AEs) that were reported; disease progression was evaluated based on the patient’s vital status and changes in forced vital capacity (FVC) at 12-month follow-up. Results: The numbers of patients experiencing AEs and of the AEs per patient in our study group didn’t significantly differ with respect to a group of 56 individuals who were taking nintedanib as a first-line therapy during the study period (5/12 vs. 22/56; p = 0.9999, and 0.00 (0.00–1.00) vs. 0.00 (0.00–3.00); p = 0.517, respectively). Two out of the 3 patients who had been switched to nintedanib due to a rapid disease progression showed stabilized FVC values. Conclusions: Nintedanib was found to have an acceptable safety profile in the majority of the IPF patients switched from pirfenidone. Prospective studies are warranted to determine if the drug can effectively delay disease progression in these patients. Full article

(This article belongs to the Special Issue The New Frontier in Pulmonary Fibrosis)

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