J Korean Med Sci. 2021 Oct 25;36(41):e257. doi: 10.3346/jkms.2021.36.e257.

ABSTRACT

BACKGROUND: Several parameters are useful for assessing disease severity in idiopathic pulmonary fibrosis (IPF); however, the role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is not well-defined. We aimed to evaluate the value of 18F-FDG PET/CT for assessing disease severity and prognosis in IPF patients.

METHODS: Clinical data of 89 IPF patients (mean age: 68.1 years, male: 94%) who underwent 18F-FDG PET/CT for evaluation of lung nodules or cancer staging were retrospectively reviewed. Mean and maximal standardized uptake values (SUVmean, SUVmax, respectively) were measured in the fibrotic area. Adjusted SUV, including SUV ratio (SUVR, defined as SUVmax-to-liver SUVmean ratio), tissue fraction-corrected SUVmean (SUVmeanTF), and SUVR (SUVRTF), and tissue-to-blood ratio (SUVmax/SUVmean venous; TBRblood) were obtained. Death was defined as the primary outcome, and associations between other clinical parameters (lung function, exercise capacity, C-reactive protein [CRP] level) were also investigated.

RESULTS: All SUV parameters were inversely correlated with the forced vital capacity, diffusing capacity for carbon monoxide, and positively correlated with CRP level and the gender-age-physiology index. The SUVmean, SUVmax, and SUVmeanTF were associated with changes in lung function at six months. The SUVR (hazard ratio [HR], 1.738; 95% confidence interval [CI], 1.011-2.991), SUVRTF (HR, 1.441; 95% CI, 1.000-2.098), and TBRblood (HR, 1.377; 95% CI, 1.038-1.827) were significant predictors for mortality in patients with IPF in the univariate analysis, but not in the multivariate analysis.

CONCLUSION: 18F-FDG PET/CT may provide additional information on the disease severity and prognosis in IPF patients, and the SUVR may be superior to other SUV parameters.

PMID:34697928 | DOI:10.3346/jkms.2021.36.e257

Bioorg Chem. 2021 Oct 4;117:105386. doi: 10.1016/j.bioorg.2021.105386. Online ahead of print.

ABSTRACT

Lysophosphatidic acids (LPAs) are bioactive phospholipids implicated in a wide range of cellular activities that regulate a diverse array of biological functions. They recognize two types of G protein-coupled receptors (LPARs): LPA1-3 receptors and LPA4-6 receptors that belong to the endothelial gene (EDG) family and non-endothelial gene family, respectively. In recent years, the LPA signaling pathway has captured an increasing amount of attention because of its involvement in various diseases, such as idiopathic pulmonary fibrosis, cancers, cardiovascular diseases and neuropathic pain, making it a promising target for drug development. While no drugs targeting LPARs have been approved by the FDA thus far, at least three antagonists have entered phase Ⅱ clinical trials for idiopathic pulmonary fibrosis (BMS-986020 and BMS-986278) and systemic sclerosis (SAR100842), and one radioligand (BMT-136088/18F-BMS-986327) has entered phase Ⅰ clinical trials for positron emission tomography (PET) imaging of idiopathic pulmonary fibrosis. This article provides an extensive review on the current status of ligand development targeting LPA receptors to modulate LPA signaling and their therapeutic potential in various diseases.

PMID:34695732 | DOI:10.1016/j.bioorg.2021.105386

Front Mol Biosci. 2021 Oct 7;8:645846. doi: 10.3389/fmolb.2021.645846. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a distressing lung disorder with poor prognosis and high mortality rates. Limited therapeutic options for IPF is a major clinical challenge. Well-known for its anti-apoptotic properties, B-cell lymphoma 2 (Bcl-2) plays a critical role in the pathology of malignancies and inflammatory diseases, including IPF. In this study, we aimed to investigate the therapeutic effect of a Bcl-2 homology domain 3 mimetic inhibitor, ABT-199, on bleomycin (BLM)-induced pulmonary fibrosis in mice, and explore possible underlying mechanism. The lung inflammation and fibrosis model was established by intratracheal instillation of a single dose of BLM. We observed elevated Bcl-2 in the alveolar macrophages and fibroblasts derived from BLM-instilled mice from day 7. Further, we obtained in vivo evidence that early therapeutic treatment with Bcl-2 inhibitor ABT-199 from day 3, and late treatment from day 10, both alleviated airway inflammation and lung fibrosis induced by BLM. Our data suggest that ABT-199 might be an effective antifibrotic agent that interferes with profibrogenic cells, which may be a promising therapy in the treatment of clinical IPF patients.

PMID:34692765 | PMC:PMC8529052 | DOI:10.3389/fmolb.2021.645846

Int J Inflam. 2021 Oct 13;2021:3963659. doi: 10.1155/2021/3963659. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a disease with an unknown etiology mainly characterized by a progressive decline of lung function due to the scarring of the tissue deep in the lungs. The overall survival after diagnosis remains low between 3 and 5 years. IPF is a heterogeneous disease and much progress has been made in the past decade in understanding the disease mechanisms that contributed to the development of two new drugs, pirfenidone and nintedanib, which improved the therapeutic management of the disease. The understanding of the cofactors and comorbidities of IPF also contributed to improved management of the disease outcome. In the present review, we evaluate scientific evidence which indicates IPF as a risk factor for other diseases based on the complexity of molecular and cellular mechanisms involved in the disease development and of comorbidities. We conclude from the existing literature that while much progress has been made in understating the mechanisms involved in IPF development, further studies are still necessary to fully understand IPF pathogenesis which will contribute to the identification of novel therapeutic targets for IPF management as well as other diseases for which IPF is a major risk factor.

PMID:34691383 | PMC:PMC8528608 | DOI:10.1155/2021/3963659

Respir Res. 2021 Oct 24;22(1):273. doi: 10.1186/s12931-021-01860-3.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with a significant unmet medical need. Development of transformational therapies for IPF is challenging in part to due to lack of robust predictive biomarkers of prognosis and treatment response. Importantly, circulating biomarkers of IPF are limited and none are in clinical use.

METHODS: We previously reported dysregulated pathways and new disease biomarkers in advanced IPF through RNA sequencing of lung tissues from a cohort of transplant-stage IPF patients (n = 36) in comparison to normal healthy donors (n = 19) and patients with acute lung injury (n = 11). Here we performed proteomic profiling of matching plasma samples from these cohorts through the Somascan-1300 SomaLogics platform.

RESULTS: Comparative analyses of lung transcriptomic and plasma proteomic signatures identified a set of 34 differentially expressed analytes (fold change (FC) ≥ ± 1.5, false discovery ratio (FDR) ≤ 0.1) in IPF samples compared to healthy controls. IPF samples showed strong enrichment of chemotaxis, tumor infiltration and mast cell migration pathways and downregulated extracellular matrix (ECM) degradation. Mucosal (CCL25 and CCL28) and Th2 (CCL17 and CCL22) chemokines were markedly upregulated in IPF and highly correlated within the subjects. The mast cell maturation chemokine, CXCL12, was also upregulated in IPF plasma (fold change 1.92, FDR 0.006) and significantly correlated (Pearson r = - 0.38, p = 0.022) to lung function (%predicted FVC), with a concomitant increase in the mast cell Tryptase, TPSB2. Markers of collagen III and VI degradation (C3M and C6M) were significantly downregulated (C3M p < 0.001 and C6M p < 0.0001 IPF vs control) and correlated, Pearson r = 0.77) in advanced IPF consistent with altered ECM homeostasis.

CONCLUSIONS: Our study identifies a panel of tissue and circulating biomarkers with clinical utility in IPF that can be validated in future studies across larger cohorts.

PMID:34689792 | DOI:10.1186/s12931-021-01860-3

Inflammation. 2021 Oct 22. doi: 10.1007/s10753-021-01582-0. Online ahead of print.

ABSTRACT

Mast cells (MCs) are known to be involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF), although their role in acute exacerbations of IPF has not been investigated. The aims of the study were to evaluate the numbers of MCs in fibrotic and non-fibrotic areas of lung tissue specimens of idiopathic pulmonary fibrosis (IPF) patients with or without an acute exacerbation of IPF, and to correlate the MC density with clinical parameters. MCs of IPF patients were quantified from surgical lung biopsy (SLB) specimens (n = 47) and lung tissue specimens taken at autopsy (n = 7). MC density was higher in the fibrotic areas of lung tissue compared with spared alveolar areas or in controls. Female gender, low diffusion capacity for carbon monoxide, diffuse alveolar damage, and smoking were associated with a low MC density. MC densities of fibrotic areas had declined significantly in five subjects in whom both SLB in the stable phase and autopsy after an acute exacerbation of IPF had been performed. There were no correlations of MC densities with survival time or future acute exacerbations. The MC density in fibrotic areas was associated with several clinical parameters. An acute exacerbation of IPF was associated with a significant decline in MC counts. Further investigations will be needed to clarify the role of these cells in IPF and in the pathogenesis of acute exacerbation as this may help to identify some potential targets for medical treatment for this serious disease.

PMID:34686945 | DOI:10.1007/s10753-021-01582-0

Cells. 2021 Oct 15;10(10):2763. doi: 10.3390/cells10102763.

ABSTRACT

Pulmonary epithelial cells are widely considered to be the first line of defence in the lung and are responsible for coordinating the innate immune response to injury and subsequent repair. Consequently, epithelial cells communicate with multiple cell types including immune cells and fibroblasts to promote acute inflammation and normal wound healing in response to damage. However, aberrant epithelial cell death and damage are hallmarks of pulmonary disease, with necrotic cell death and cellular senescence contributing to disease pathogenesis in numerous respiratory diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and coronavirus disease (COVID)-19. In this review, we summarise the literature that demonstrates that epithelial damage plays a pivotal role in the dysregulation of the immune response leading to tissue destruction and abnormal remodelling in several chronic diseases. Specifically, we highlight the role of epithelial-derived damage-associated molecular patterns (DAMPs) and senescence in shaping the immune response and assess their contribution to inflammatory and fibrotic signalling pathways in the lung.

PMID:34685744 | PMC:PMC8534416 | DOI:10.3390/cells10102763

Life (Basel). 2021 Oct 15;11(10):1092. doi: 10.3390/life11101092.

ABSTRACT

Idiopathic pulmonary fibrosis, which is one of the lung diseases, is quite rare but fatal in nature. The disease is progressive, and detection of severity takes a long time as well as being quite tedious. With the advent of intelligent machine learning techniques, and also the effectiveness of these techniques, it was possible to detect many lung diseases. So, in this paper, we have proposed a model that could be able to detect the severity of IPF at the early stage so that fatal situations can be controlled. For the development of this model, we used the IPF dataset of the Korean interstitial lung disease cohort data. First, we preprocessed the data while applying different preprocessing techniques and selected 26 highly relevant features from a total of 502 features for 2424 subjects. Second, we split the data into 80% training and 20% testing sets and applied oversampling on the training dataset. Third, we trained three state-of-the-art machine learning models and combined the results to develop a new soft voting ensemble-based model for the prediction of severity of IPF disease in patients with this chronic lung disease. Hyperparameter tuning was also performed to get the optimal performance of the model. Fourth, the performance of the proposed model was evaluated by calculating the accuracy, AUC, confusion matrix, precision, recall, and F1-score. Lastly, our proposed soft voting ensemble-based model achieved the accuracy of 0.7100, precision 0.6400, recall 0.7100, and F1-scores 0.6600. This proposed model will help the doctors, IPF patients, and physicians to diagnose the severity of the IPF disease in its early stages and assist them to take proactive measures to overcome this disease by enabling the doctors to take necessary decisions pertaining to the treatment of IPF disease.

PMID:34685461 | PMC:PMC8541448 | DOI:10.3390/life11101092

Nutrients. 2021 Oct 14;13(10):3599. doi: 10.3390/nu13103599.

ABSTRACT

We previously reported that female mice exhibit protection against chemically induced pulmonary fibrosis and suggested a potential role of estrogen. Phytoestrogens act, at least in part, via stimulation of estrogen receptors; furthermore, compared to residents of Western countries, residents of East Asian countries consume higher amounts of phytoestrogens and exhibit lower rates of pulmonary fibrosis. Therefore, we tested the hypothesis that dietary phytoestrogens ameliorate the severity of experimentally induced pulmonary fibrosis. Male mice placed on either regular soybean diet or phytoestrogen-free diet were instilled with 0.1 N HCl to provoke pulmonary fibrosis. Thirty days later, lung mechanics were measured as indices of lung function and bronchoalveolar lavage fluid (BALF) and lung tissue were analyzed for biomarkers of fibrosis. Mice on phytoestrogen-free diet demonstrated increased mortality and stronger signs of chronic lung injury and pulmonary fibrosis, as reflected in the expression of collagen, extracellular matrix deposition, histology, and lung mechanics, compared to mice on regular diet. We conclude that dietary phytoestrogens play an important role in the pathogenesis of pulmonary fibrosis and suggest that phytoestrogens (e.g., genistein) may be useful as part of a therapeutic regimen against hydrochloric acid-induced lung fibrosis and chronic lung dysfunction.

PMID:34684599 | PMC:PMC8536981 | DOI:10.3390/nu13103599

Medicina (Kaunas). 2021 Oct 18;57(10):1121. doi: 10.3390/medicina57101121.

ABSTRACT

Background and Objectives: Idiopathic pulmonary fibrosis (IPF) has a variable clinical course, which ranges from being asymptomatic to progressive respiratory failure. The purpose of this study was to evaluate the novel clinical parameters of IPF patients who receive an anti-fibrotic agent. Materials and Methods: From January 2011 to January 2021, we identified 39 IPF patients at Okinawa Chubu Hospital. Clinical information was obtained, such as laboratory data, pulmonary function test (PFT) results, and chest images, including of soft tissue thickness and the high-resolution computed tomography (HRCT) pattern at diagnosis. Results: The mean age was 72.9 ± 7.0 (53-85); 27 patients were men and 12 were women. The mean body mass index was 25.1 ± 3.9 (17.3-35). Twenty-four were active smokers and the median number of packs per year was 20. Regarding laboratory findings, mean white blood cell (WBC), lactate dehydrogenase (LDH), and Krebs Von den Lungen-6 (KL-6) values were 7816 ± 1859, 248 ± 47, and 1615 ± 1503, respectively. In PFT, the mean percent predicted FVC, percent predicted total lung capacity, percent predicted functional residual capacity (FRC), and percent predicted diffusion capacity of the lung for carbon monoxide (DLco) were 66.8 ± 14.9%, 71.8 ± 13.7%, 65 ± 39.6%, and 64.6 ± 27.9%, respectively. In chest radiological findings, soft tissue thickness at the right 9th rib was 26.4 ± 8.8 mm. Regarding chest HRCT patterns, 15 showed the definite usual interstitial pneumonia (UIP) pattern, 16 showed the probable UIP pattern, and eight showed the indeterminate for UIP pattern. In the treatment, 24 patients received pirfenidone and 15 patients took nintedanib. The mean observation period was 38.6 ± 30.6 months and 24 patients died. The median survival time was 32.4 months (0.9-142.5). Multivariate analysis adjusted for age showed that both soft tissue thickness [Hazard ratio (HR): 0.912, 95% confidence interval (CI): 0.859-0.979, p-value: 0.009] and percent FRC [HR: 0.980, 95% CI: 0.967-0.992, p-value: 0.002] were robust predictors of IPF mortality. Conclusions: In IPF patients treated with anti-fibrotic agents, both soft tissue thickness at the right 9th rib shown on the chest radiograph and %FRC can be novel predictors of IPF mortality.

PMID:34684158 | PMC:PMC8537035 | DOI:10.3390/medicina57101121

Microorganisms. 2021 Sep 26;9(10):2033. doi: 10.3390/microorganisms9102033.

ABSTRACT

Helicobacter pylori (H. pylori) is a Gram-negative bacterium involved in the development of gastritis, peptic ulcer disease, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue. Unexplained iron deficiency anemia, idiopathic thrombocytopenic purpura and vitamin B12 deficiency have also been related to H. pylori infection, whereas for other extra-gastric diseases, the debate is still open. In this review, we evaluate and discuss the potential involvement of H. pylori infection in the pathogenesis of several respiratory diseases. A MEDLINE search of all studies published in English from 1965 to 2021 was carried out. Controversial findings have been reported in patients with bronchial asthma, chronic obstructive pulmonary disease, bronchiectasis, lung cancer, tuberculosis, cystic fibrosis, and sarcoidosis. Most of the available literature is concerned with case-control studies based on seroprevalence, with a small sample size and low consideration of confounders, which represents a potential issue. So far, there is no clear evidence of a causal association between H. pylori infection and respiratory diseases, and larger studies with appropriate epidemiological design are required.

PMID:34683354 | PMC:PMC8537719 | DOI:10.3390/microorganisms9102033

Int J Mol Sci. 2021 Oct 15;22(20):11152. doi: 10.3390/ijms222011152.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is characterized by fibrotic change in alveolar epithelial cells and leads to the irreversible deterioration of pulmonary function. Transforming growth factor-beta 1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) in type 2 lung epithelial cells contributes to excessive collagen deposition and plays an important role in IPF. Atractylodin (ATL) is a kind of herbal medicine that has been proven to protect intestinal inflammation and attenuate acute lung injury. Our study aimed to determine whether EMT played a crucial role in the pathogenesis of pulmonary fibrosis and whether EMT can be utilized as a therapeutic target by ATL treatment to mitigate IPF. To address this topic, we took two steps to investigate: 1. Utilization of anin vitro EMT model by treating alveolar epithelial cells (A549 cells) with TGF-β1 followed by ATL treatment for elucidating the underlying pathways, including Smad2/3 hyperphosphorylation, mitogen-activated protein kinase (MAPK) pathway overexpression, Snail and Slug upregulation, and loss of E-cadherin. Utilization of an in vivo lung injury model by treating bleomycin on mice followed by ATL treatment to demonstrate the therapeutic effectiveness, such as, less collagen deposition and lower E-cadherin expression. In conclusion, ATL attenuates TGF-β1-induced EMT in A549 cells and bleomycin-induced pulmonary fibrosis in mice.

PMID:34681813 | DOI:10.3390/ijms222011152

Biomolecules. 2021 Sep 29;11(10):1424. doi: 10.3390/biom11101424.

ABSTRACT

Pirfenidone is a pyridinone derivative that has been shown to inhibit fibrosis in animal models and in patients with idiopathic pulmonary fibrosis. Its effect on orbital fibroblasts remains poorly understood. We investigated the in vitro effect of pirfenidone in transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation and extracellular matrix (ECM) homeostasis in primary cultured orbital fibroblasts from patients with Graves' ophthalmopathy (GO). The expression of fibrotic proteins, including α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), fibronectin, and collagen type I, was determined by Western blots. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for the ECM homeostasis were examined. After pretreating the GO orbital fibroblasts with pirfenidone (250, 500, and 750 μg/mL, respectively) for one hour followed by TGF-β1 for another 24 h, the expression of α-SMA, CTGF, fibronectin, and collagen type I decreased in a dose-dependent manner. Pretreating the GO orbital fibroblasts with pirfenidone not only abolished TGF-β1-induced TIMP-1 expression but recovered the MMP-2/-9 activities. Notably, pirfenidone inhibited TGF-β1-induced phosphorylation of p38 and c-Jun N-terminal kinase (JNK), the critical mediators in the TGF-β1 pathways. These findings suggest that pirfenidone modulates TGF-β1-mediated myofibroblast differentiation and ECM homeostasis by attenuating downstream signaling of TGF-β1.

PMID:34680057 | PMC:PMC8533421 | DOI:10.3390/biom11101424

Biomed Pharmacother. 2021 Oct 19;144:112270. doi: 10.1016/j.biopha.2021.112270. Online ahead of print.

ABSTRACT

Exosomes are nano-sized vesicles released by almost all cell types, with a central role as mediators of intercellular communication. In addition to physiological conditions, these extracellular vesicles seem to play a pivotal role in inflammatory processes. This assumption offers the opportunity to study exosomes as promising biomarkers and therapeutic tools for chronic respiratory disorders. Indeed, although it is well-known that at the basis of conditions like asthma, chronic obstructive pulmonary disease, alpha-1 antitrypsin deficiency and idiopathic pulmonary fibrosis there is a dysregulated inflammatory process, an unequivocal correlation between different phenotypes and their pathophysiological mechanisms has not been established yet. In this review, we report and discuss some of the most significant studies on exosomes from body fluids of subjects affected by airway diseases. Furthermore, the most widespread techniques for exosome isolation and characterization are described. Further studies are needed to answer the unresolved questions about the functional link between exosomes and chronic respiratory diseases.

PMID:34678722 | DOI:10.1016/j.biopha.2021.112270

Eur Respir J. 2021 Oct 21:2101181. doi: 10.1183/13993003.01181-2021. Online ahead of print.

ABSTRACT

RATIONALE: Idiopathic Pulmonary Fibrosis (IPF) is a progressive lung disease in which circulatory biomarkers has the potential for guiding management in clinical practice.

OBJECTIVES: We assessed the prognostic role of serum biomarkers in three independent IPF cohorts, the Australian IPF Registry (AIPFR), Trent Lung Fibrosis (TLF) and Prospective Observation of Fibrosis in the Lung Clinical Endpoints (PROFILE).

METHODS: In the AIPFR, candidate proteins were assessed by ELISA as well as in an unbiased proteomic approach. Least absolute shrinkage and selection operator (LASSO) regression was used to restrict the selection of markers that best accounted for the progressor phenotype at one-year in AIPFR, and subsequently prospectively selected for replication in the validation TLF cohort and assessed retrospectively in PROFILE. Four significantly replicating biomarkers were aggregated into a progression index (PI) model based on tertiles of circulating concentrations.

MAIN RESULTS: One-hundred and eighty-nine participants were included in the AIPFR cohort, 205 participants from the TLF, and 122 participants from the PROFILE cohorts. Differential biomarker expression was observed by ELISA and replicated for osteopontin, matrix metallopeptidase-7, intercellular adhesion molecule-1 and periostin for those with a progressor phenotype at one-year. Proteomic data did not replicate. The PI in the AIPFR, TLF and PROFILE predicted risk of progression, mortality and progression-free survival. A statistical model incorporating PI demonstrated the capacity to distinguish disease progression at 12 months, which was increased beyond the clinical GAP model alone in all cohorts, and significantly so within incidence based TLF and PROFILE cohorts.

CONCLUSION: A panel of circulatory biomarkers can provide potentially valuable clinical assistance in the prognosis of IPF patients.

PMID:34675050 | DOI:10.1183/13993003.01181-2021

Respir Res. 2021 Oct 21;22(1):270. doi: 10.1186/s12931-021-01869-8.

ABSTRACT

This letter raised some concerns about the study by Karampitsakos et al. in a recent issue of Respiratory Research.

PMID:34674703 | DOI:10.1186/s12931-021-01869-8

Arch Pathol Lab Med. 2021 Nov 1;145(11):1325-1326. doi: 10.5858/arpa.2021-0234-LE.

NO ABSTRACT

PMID:34673908 | DOI:10.5858/arpa.2021-0234-LE

Heart Fail Rev. 2021 Oct 20. doi: 10.1007/s10741-021-10175-w. Online ahead of print.

ABSTRACT

Myocardial fibrosis is a common feature of several heart diseases. The progressive deposition of extracellular matrix due to a persistent injury to cardiomyocytes may trigger a vicious cycle that leads to persistent structural and functional alterations of the myocardium. Some drugs (like renin-angiotensin-aldosterone system inhibitors) have been shown to reduce extracellular matrix deposition, but no primarily anti-fibrotic medications are currently used to treat patients with heart failure (HF). Pirfenidone is an oral antifibrotic agent approved for the treatment of idiopathic pulmonary fibrosis. Although its exact mechanism of action is not fully understood, pirfenidone might reduce the expression of profibrotic factors such as transforming growth factor-β (TGF-β), and proinflammatory cytokines, like tumor necrosis factor-α (TNF-α), interleukin (IL)-4, and IL-13, which could modulate the inflammatory response and inhibit collagen synthesis in lung tissue. There is some evidence that pirfenidone has antifibrotic activity in various animal models of cardiac disease. Furthermore, the positive results of the PIROUETTE trial, evaluating pirfenidone in patients with HF with preserved ejection fraction, have been very recently announced. This review summarizes the data about pirfenidone as a potential cardioprotective treatment.

PMID:34671871 | DOI:10.1007/s10741-021-10175-w

ERJ Open Res. 2021 Oct 18;7(4):00142-2021. doi: 10.1183/23120541.00142-2021. eCollection 2021 Oct.

ABSTRACT

INTRODUCTION: Current medications for idiopathic pulmonary fibrosis (IPF) have not been shown to impact patient-reported outcome measures (PROMs), highlighting the need for accurate minimal clinically important difference (MCID) values. Recently published consensus standards for MCID studies support using anchor-based over distribution-based methods. The aim of this study was to estimate MCID values for worsening in IPF using only an anchor-based approach.

METHODS: We conducted secondary analyses of three randomised controlled trials with different inclusion criteria and follow-up intervals. The health transition question in the 36-Item Short-Form Health Survey (SF-36) questionnaire was used as the anchor. We used receiver operating curves to assess responsiveness between the anchor and 10 variables (four physiological measures and six PROMs). We used an anchor-based method to determine the MCID values of variables that met the responsiveness criteria (area under the curve ≥0.70).

RESULTS: 6-min walk distance (6MWD), the St George's Respiratory Questionnaire (SGRQ), physical component score (PCS) of SF-36 and University of California, San Diego, Shortness of Breath Questionnaire (UCSD SOBQ) met the responsiveness criteria. The MCID value for 6MWD was -75 m; the MCID value for SF-36 PCS was -7 points; the MCID value for SGRQ was 11 points; and the MCID value for the UCSD SOBQ was 11 points.

CONCLUSIONS: The MCID estimates of 6MWD, SGRQ, SF-36 and UCSD SOBQ using only anchor-based methods were considerably higher compared to previously proposed values. A single MCID value may not be applicable across all classes of disease severity or durations of follow-up time.

PMID:34671666 | PMC:PMC8521018 | DOI:10.1183/23120541.00142-2021

Front Med (Lausanne). 2021 Oct 4;8:752316. doi: 10.3389/fmed.2021.752316. eCollection 2021.

ABSTRACT

Pulmonary fibrosis is characterized by loss of normal alveoli, accumulation of pathologic activated fibroblasts, and exuberant extracellular matrix deposition that over time can lead to progressive loss of respiratory function and death. This loss of respiratory function is associated with the loss of alveolar type 1 cells (AT1) that play a crucial role in gas exchange and the depletion of the alveolar type 2 cells (AT2) that act as progenitor cells to regenerate the AT1 and AT2 cell populations during repair. Understanding the mechanisms that regulate normal alveolar repair and those associated with pathologic repair is essential to identify potential therapeutic targets to treat or delay progression of fibrotic diseases. The Hippo/YAP developmental signaling pathway has been implicated as a regulator of normal alveolar development and repair. In idiopathic pulmonary fibrosis, aberrant activation of YAP/TAZ has been demonstrated in both the alveolar epithelium and activated fibroblasts associated with increased fibrotic remodeling, and there is emerging interest in this pathway as a target for antifibrotic therapies. In this review, we summarize current evidence as to the role of the Hippo-YAP/TAZ pathway in alveolar development, homeostasis, and repair, and highlight key questions that must be resolved to determine effective strategies to modulate YAP/TAZ signaling to prevent progressive pulmonary fibrosis and enhance adaptive alveolar repair.

PMID:34671628 | PMC:PMC8520933 | DOI:10.3389/fmed.2021.752316