Respir Med. 2021 Jul 26;187:106551. doi: 10.1016/j.rmed.2021.106551. Online ahead of print.

ABSTRACT

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a fatal event that can occur during the clinical course of idiopathic pulmonary fibrosis (IPF). Although data from clinical trials suggest that the antifibrotic agents pirfenidone and nintedanib might reduce the risk of AE-IPF, the incidence of AE-IPF in patients receiving antifibrotic agents in clinical settings is unclear.

OBJECTIVES: To determine the incidence of AE-IPF in patients receiving antifibrotic agents and compare AE-IPF frequency in patients receiving pirfenidone and nintedanib.

METHODS: We retrospectively reviewed the clinical records of 199 patients with IPF who were started on pirfenidone or nintedanib at our institution during the period from 2009 through 2018. Baseline characteristics, incidence of AE-IPF, and outcome after AE-IPF onset were analyzed.

RESULTS: During the observation period, the 1-, 2-, and 3-year cumulative incidences of AE-IPF were 9.3 %, 22.1 %, and 25.0 %, respectively. The 1-, 2-, and 3-year cumulative incidence rates for AE-IPF in the pirfenidone group and nintedanib group were 5.1 % vs. 18.6 %, 20.4 % vs. 25.2 %, and 22.6 % vs. 29.6 %, respectively. AE-IPF incidence was significantly lower in patients treated with pirfenidone than in those treated with nintedanib (log rank test, P = 0.035). The 3-month survival rate after AE-IPF onset was 61.1 % in the pirfenidone group and 61.5 % in the nintedanib group; thus, outcomes after AE-IPF onset were similar in the 2 groups.

CONCLUSION: The reduction in AE-IPF risk might be greater for pirfenidone than for nintedanib.

PMID:34343721 | DOI:10.1016/j.rmed.2021.106551

Am J Respir Crit Care Med. 2021 Aug 3. doi: 10.1164/rccm.202103-0585OC. Online ahead of print.

ABSTRACT

RATIONALE: To improve disease outcomes in idiopathic pulmonary fibrosis (IPF) it is essential to understand its early pathophysiology so that it can be targeted therapeutically.

OBJECTIVES: Perform three-dimensional (3D) assessment of the IPF lung micro-structure using stereology and multi-resolution computed tomography (CT) imaging.

METHODS: Explanted lungs from IPF patients (n=8) and donor controls (n=8) were inflated with air and frozen. CT scans were used to assess large airways. Unbiased, systematic uniform random (SUR) samples (n=8/lung) were scanned with microCT for stereological assessment of small airways (number, airway wall and lumen area) and parenchymal fibrosis (volume fraction of tissue, alveolar surface area, and septal wall thickness).

RESULTS: The total number of airways on clinical CT was greater in IPF lungs than control lungs (p<0.01), due to an increase in the wall (p<0.05) and lumen area (p<0.05) resulting in more visible airways with a lumen larger than 2 mm. In IPF tissue samples without microscopic fibrosis, assessed by the volume fraction of tissue using microCT, there was a reduction in the number of the terminal (p<0.01) and transitional (p<0.001) bronchioles, and an increase in terminal bronchiole wall area (p<0.001) compared to control lungs. In IPF tissue samples with microscopic parenchymal fibrosis, terminal bronchioles had increased airway wall thickness (p<0.05), and dilated airway lumens (p<0.001) leading to honeycomb cyst formations.

CONCLUSION: This study has important implications for the current thinking on how the lung tissue is remodeled in IPF, and highlights small airways as a potential target to modify IPF outcomes.

PMID:34343057 | DOI:10.1164/rccm.202103-0585OC

Am J Respir Cell Mol Biol. 2021 Aug 3. doi: 10.1165/rcmb.2020-0408OC. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease which leads to significant morbidity and mortality from respiratory failure. The two drugs currently approved for clinical use slow the rate of decline in lung function but have not been shown to halt disease progression or reverse established fibrosis. Thus, new therapeutic targets are needed. Endothelial injury and the resultant vascular permeability are critical components in the response to tissue injury, and are present in patients with IPF. However, it remains unclear how vascular permeability affects lung repair and fibrosis following injury. Lipid mediators such as sphingosine-1-phosphate (S1P) are known to regulate multiple homeostatic processes in the lung including vascular permeability. We demonstrate that endothelial cell (EC) specific deletion of the S1P receptor 1 (S1PR1) in mice (EC-S1pr1-/-) results in increased lung vascular permeability at baseline. Following a low dose intratracheal bleomycin challenge, EC-S1pr1-/- mice had increased and persistent vascular permeability compared to wild-type mice, which was strongly correlated with the amount and localization of resulting pulmonary fibrosis. EC-S1pr1-/- mice also had increased immune cell infiltration and activation of the coagulation cascade within the lung. However, increased circulating S1P ligand in ApoM overexpressing mice was insufficient to protect against bleomycin-induced pulmonary fibrosis. Overall, these data demonstrate that endothelial cell S1PR1 controls vascular permeability in the lung, is associated with changes in immune cell infiltration and extravascular coagulation, and modulates the fibrotic response to lung injury.

PMID:34343038 | DOI:10.1165/rcmb.2020-0408OC

Ann Acad Med Singap. 2021 Jul;50(7):556-565.

ABSTRACT

INTRODUCTION: Non-cystic fibrosis bronchiectasis (NCFB) is a highly heterogenous disease. We describe the clinical characteristics of NCFB patients and evaluate the performance of Bronchiectasis Severity Index (BSI) in predicting mortality.

METHODS: Patients attending the bronchiectasis clinic between August 2015 and April 2020 with radiologically proven bronchiectasis on computed tomography were recruited. Clinical characteristics, spirometry, radiology, microbiology and clinical course over a median period of 2.4 years is presented.

RESULTS: A total of 168 patients were enrolled in this prospective cohort study. They were predominantly women (67.8%), Chinese (87.5%) and never-smokers (76.9%). Median age of diagnosis was 64 years (interquartile range 56-71) and the most common aetiology was "idiopathic" bronchiectasis (44.6%). Thirty-nine percent had normal spirometries. Compared to female patients, there were more smokers among the male patients (53.8% versus 8.5%, P<0.001) and a significantly larger proportion with post-tuberculous bronchiectasis (37.0% vs 15.8%, P=0.002). Fifty-five percent of our cohort had a history of haemoptysis. Lower body mass index, presence of chronic obstructive pulmonary disease, ever-smoker status, modified Reiff score, radiological severity and history of exacerbations were risk factors for mortality. Survival was significantly shorter in patients with severe bronchiectasis (BSI>9) compared to those with mild or moderate disease (BSI<9). The hazard ratio for severe disease (BSI>9) compared to mild disease (BSI 0-4) was 14.8 (confidence interval 1.929-114.235, P=0.01).

CONCLUSION: The NCFB cohort in Singapore has unique characteristics with sex differences. Over half the patients had a history of haemoptysis. The BSI score is a useful predictor of mortality in our population.

PMID:34342336

Br J Hosp Med (Lond). 2021 Jul 2;82(7):1-14. doi: 10.12968/hmed.2020.0556. Epub 2021 Jul 20.

ABSTRACT

Interstitial lung diseases are a complex group of conditions that cause inflammation and scarring of the lung interstitium. This article discusses the diagnosis and management of common interstitial lung diseases including idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, connective tissue disease associated-interstitial lung disease, sarcoidosis and drug-induced interstitial lung disease. A multidisciplinary approach to diagnosis of interstitial lung disease is the gold standard; key history and examination features, blood panel, pulmonary function tests, high resolution computed tomography imaging, and when required bronchoalveolar lavage and lung biopsy results are discussed to reach a multidisciplinary consensus diagnosis. Advances, including the development of the disease-modifying anti-fibrotic medications nintedanib and pirfenidone, continue to shape the future management of interstitial lung disease. A holistic approach to the care of patients with interstitial lung disease is paramount, as they often have a high symptom burden and considerable palliative care needs.

PMID:34338019 | DOI:10.12968/hmed.2020.0556

Aging (Albany NY). 2021 Jul 30;13(undefined). doi: 10.18632/aging.203335. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) mainly occurs in elderly people over the age of sixty. IPF pathogenesis is associated with alveolar epithelial cells (AECs) senescence. Activation of PI3K/AKT signaling induced by insulin-like growth factor 1 (IGF1) participates in AEC senescence and IPF by releasing CTGF, TGF-β1, and MMP9. Our previous study demonstrated that core fucosylation (CF) modification, catalyzed by a specific core fucosyltransferase (FUT8) can regulate the activation of multiple signaling pathways, and inhibiting CF can alleviate pulmonary fibrosis in mice induced by bleomycin. However, whether CF is involved in IGF1-mediated AEC senescence in IPF remains unclear. In this study, we found that the IGF1/PI3K/AKT signaling pathway was activated in IPF lung tissue. Meanwhile, CF was present in senescent AECs. We also showed that IGF1 could induce AECs senescence with enhanced CF in vivo and in vitro. Inhibiting CF alleviated AECs senescence and pulmonary fibrosis induced by IGF1. In addition, activation of IGF1/PI3K/AKT signaling depends on CF. In conclusion, this study confirmed that CF is an important target regulating the IGF1 signaling pathway in AEC senescence and IPF, which might be a candidate target to treat IPF in the future.

PMID:34329195 | DOI:10.18632/aging.203335

Ann Am Thorac Soc. 2021 Aug;18(8):1285-1286. doi: 10.1513/AnnalsATS.202105-536ED.

NO ABSTRACT

PMID:34328404 | DOI:10.1513/AnnalsATS.202105-536ED

Histopathology. 2021 Jul 30. doi: 10.1111/his.14530. Online ahead of print.

ABSTRACT

Telomere biology disorders (TBD), including dyskeratosis congenita (DC), are a group of accelerated aging diseases caused by mutations in genes encoding factors involved in telomere maintenance. Hepatic involvement affects 10-40% of TBD patients with nodular regenerative hyperplasia (NRH) and cirrhosis being the most common hepatic manifestations, both of which can result in portal hypertension (1-3). Lung involvement includes interstitial lung disease (ILD) such as idiopathic pulmonary fibrosis (IPF) and hepatopulmonary syndrome (HPS) which can be associated with portal hypertension. Vascular complications in TBD include pulmonary arteriovenous malformations, gastrointestinal telangiectasias and exudative vitreoretinopathy.

PMID:34327718 | DOI:10.1111/his.14530

Sci Rep. 2021 Jul 29;11(1):15502. doi: 10.1038/s41598-021-94907-w.

ABSTRACT

Several biomarkers for detecting pulmonary hypertension (PH) have been reported. However, these biomarkers are deemed insufficient to detect PH in its early stages. We evaluated the utility of serum angiopoietin (ANGP), a glycoprotein related to angiogenesis, as a diagnostic and prognostic biomarker of PH. Patients with PH who underwent right-heart catheterization, were retrospectively studied. Serum concentrations of ANGP-1 and ANGP-2 were measured using an enzyme-linked immunosorbent assay in patients with PH (n = 32), those with idiopathic pulmonary fibrosis (IPF) without PH (as a disease control, n = 75), and age-matched healthy controls (HC, n = 60). Nineteen patients (59.4%) with PH had World Health Organization group 3 PH. Serum ANGP-2 concentration, but not ANGP-1, in patients with PH was significantly higher compared with that in HC (p = 0.025) and in patients with IPF without PH (p = 0.008). Serum ANGP-2 concentration in patients with PH positively and significantly correlated with N-terminal pro-B-type natriuretic peptide (r = 0.769, p < 0.001), right ventricular diameter on echocardiography (r = 0.565, p = 0.035), and mean pulmonary arterial pressure (r = 0.449, p = 0.032) and pulmonary vascular resistance (r = 0.451, p = 0.031) on right-heart catheterization. ANGP-1 and ANGP-2 were expressed on lung vascular endothelial cells, as shown by immunohistochemistry. Patients with PH with higher ANGP-2 concentration (≥ 2.48 ng/mL) had significantly worse survival (p = 0.022). Higher ANGP-2 concentration was a significant worse prognostic factor (hazard ratio = 6.063, p = 0.037), while serum ANGP-1 concentration was not. In conclusion, serum ANGP-2 may be a useful diagnostic and prognostic biomarker in patients with PH, especially in patients with group 3 PH.

PMID:34326408 | DOI:10.1038/s41598-021-94907-w

Eur Respir J. 2021 Jul 29:2101531. doi: 10.1183/13993003.01531-2021. Online ahead of print.

NO ABSTRACT

PMID:34326190 | DOI:10.1183/13993003.01531-2021

BMJ Open Respir Res. 2021 Jul;8(1):e000889. doi: 10.1136/bmjresp-2021-000889.

ABSTRACT

BACKGROUND: Acute exacerbation (AE) has been reported to herald a poor prognosis in idiopathic pulmonary fibrosis and is now thought to do so in idiopathic interstitial pneumonias (IIPs). However, the pathophysiology of AE-IIPs is not sufficiently understood. In our previously reported SETUP trial, we found better survival in patients with AE-IIPs treated with corticosteroids and thrombomodulin than in those treated with corticosteroids alone. In that study, we collected serum samples to evaluate changes in cytokine levels and retrospectively examined the prognostic significance and pathophysiological role of serum cytokines in patients with AE-IIPs.

METHODS: This study included 28 patients from the SETUP trial for whom serial serum samples had been prospectively obtained. AE-IIPs were diagnosed using the Japanese Respiratory Society criteria. All patients were treated with intravenous thrombomodulin and corticosteroids from 2014 to 2016. Serum levels of 27 cytokines were measured using Bio-Plex. The high-resolution CT pattern at the time of diagnosis of AE was classified as diffuse or non-diffuse.

RESULTS: Univariate analysis revealed that higher serum levels of interleukin (IL)-2, IL-7, IL-9, IL-12, IL13, basic fibroblast growth factor, granulocyte-macrophage colony-stimulating factor, interferon-γ inducible protein-10, platelet-derived growth factor and regulated on activation, normal T cell expressed and secreted (RANTES) at AE were significant predictors of 90-day survival. The HRCT pattern was also a significant clinical predictor of 90-day survival. Multivariate analysis with stepwise selection identified a higher serum RANTES level at AE to be a significant predictor of 90-day survival, including after adjustment for HRCT pattern. Multivariate analysis with stepwise selection suggested that a marked increase in the serum IL-10 level on day 8 could predict 90-day mortality.

CONCLUSIONS: A higher serum RANTES level at AE the time of diagnosis predicted a good survival outcome, and an elevated serum IL-10 level on day 8 predicted a poor survival outcome.

TRIAL REGISTRATION NUMBER: UMIN000014969.

PMID:34326155 | DOI:10.1136/bmjresp-2021-000889

Chin Med. 2021 Jul 28;16(1):66. doi: 10.1186/s13020-021-00474-7.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a serious chronic disease of the respiratory system, but its current treatment has certain shortcomings and adverse effects. In this study, we evaluate the antifibrotic activity of pterostilbene (PTE) using an in vitro IPF model induced by transforming growth factor (TGF)-β1.

METHODS: A549 and alveolar epithelial cells (AECs) were incubated with 10 ng/ml TGF-β1 to induce lung fibroblast activation. Then, 30 μmol/L of PTE was used to treat these cells. The epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) accumulation, and autophagy in cells were evaluated by western blot. Apoptosis was validated by flow cytometry analysis and western blot. Transcriptome high-throughput sequencing was performed on A549 cells incubated with TGF-β1 alone or TGF-β1 and PTE (TGF-β1 + PTE), and differentially expressed genes in PTE-treated cells were identified. The acid sensing ion channel subunit 2 (ASIC2) overexpression plasmid was used to rescue the protein levels of ASIC2 in A549 and AECs.

RESULTS: TGF-β1 caused EMT and ECM accumulation, and blocked the autophagy and apoptosis of A549 and AECs. Most importantly, 30 μmol/L of PTE inhibited pulmonary fibrosis induced by TGF-β1. Compared with TGF-β1, PTE inhibited EMT and ECM accumulation and rescued cell apoptosis and autophagy. The results of transcriptome high-throughput sequencing revealed that PTE greatly reduced the protein level of ASIC2. Compared with the TGF-β1 + PTE group, the transfection of ASIC2 overexpression plasmid stimulated the EMT and ECM accumulation and inhibited apoptosis and autophagy, suggesting that PTE inhibited pulmonary fibrosis by downregulating ASIC2.

CONCLUSIONS: This study suggests that PTE and ASIC2 inhibitors may have potential as IPF treatments in the future.

PMID:34321072 | DOI:10.1186/s13020-021-00474-7

Int Immunol. 2021 Jul 28:dxab048. doi: 10.1093/intimm/dxab048. Online ahead of print.

ABSTRACT

Regulation of messenger RNA (mRNA) decay plays a crucial role in the control of gene expression. Canonical mRNA decay pathways are initiated by deadenylation and decapping, and are followed by exonucleolytic degradation. However, recent studies revealed that endoribonucleolytic cleavage also mediates mRNA decay, and both exoribonucleolytic and endoribonucleolytic decay pathways are important for the regulation of immune responses. Regnase-1 functions as an endoribonuclease to control immunity by damping mRNAs. Particularly, Regnase-1 controls cytokines and other inflammatory mediators by recognizing their mRNAs via stem-loop structures present in the 3' untranslated regions. Regnase-1 was found to be critical for human inflammatory diseases such as ulcerative colitis and idiopathic pulmonary fibrosis. Furthermore, a set of Regnase-1-related RNases contribute to immune regulation as well as antiviral host defense. In this review, we provide an overview of recent findings as to immune-related RNA-binding proteins (RBPs) with an emphasis on stem-loop-mediated mRNA decay via Regnase-1 and related RNases and discuss how the function of these RBPs is regulated and contributes to inflammatory disorders.

PMID:34320195 | DOI:10.1093/intimm/dxab048

J Mater Chem B. 2021 Jul 28. doi: 10.1039/d1tb01307f. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a devastating and fatal interstitial lung disease due to various challenges in diagnosis and treatment. Due to its complicated pathogenesis and difficulty in early diagnosis, there is no effective cure. Cyclooxygenase-2 (COX-2) is inextricably associated with pulmonary fibrosis. The abnormal level of COX-2 leads to extremely exacerbated pulmonary fibrosis. Therefore, we reported a near-infrared fluorescent probe Cy-COX to detect the fluctuation of COX-2 levels during pulmonary fibrosis and explain its important protective effect. The probe Cy-COX showed a significant enhancement of fluorescence signal to COX-2 with excellent selectivity and sensitivity. In order to clarify the relationship between COX-2 and pulmonary fibrosis, we used the probe Cy-COX to detect COX-2 fluctuation in organisms with pulmonary fibrosis. The results showed that the COX-2 level increased in the early stage and decreased in the late stage with the aggravation of pulmonary fibrosis. Furthermore, up-regulation of COX-2 levels can effectively alleviate the severity of pulmonary fibrosis. Therefore, Cy-COX is a fast and convenient imaging tool with great potential to predict the early stage of pulmonary fibrosis and evaluate the therapeutic effects.

PMID:34320042 | DOI:10.1039/d1tb01307f

JMIR Res Protoc. 2021 Jun 11. doi: 10.2196/28873. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic Lung disorders like Chronic obstructive pulmonary disease (COPD) and Idiopathic pulmonary fibrosis (IPF) are characterised by exacerbations which are a significant problem: unpleasant for patients, and sometimes severe enough to cause hospital admission (and therefore National Health Service (NHS) pressures) and death. Reducing the impact of exacerbations is very important. Moreover, due to the coronavirus disease (COVID-19) pandemic, the vulnerable populations with these disorders are at high risk and hence their routine care cannot be done properly. Remote monitoring offers a low cost and safe solution of gaining visibility into the health of people in their daily life. Thus, remote monitoring of patients in their daily lives using mobile and wearable devices could be useful especially in high vulnerability groups. A scenario we consider here is to monitor patients and detect disease exacerbation and progression and investigate the opportunity of detecting exacerbations in real time with a future goal of real time intervention.

OBJECTIVE: The primary objective is to assess the feasibility and acceptability of remote monitoring using wearable and mobile phones in patients with pulmonary diseases. The aims will be evaluated over these areas: Participant acceptability, drop-out rates and interpretation of data, Detection of clinically important events such as exacerbations and disease progression, Quantification of symptoms (physical and mental health), Impact of disease on mood and wellbeing/Quality-of-Life(QoL) and The trajectory-tracking of main outcome variables, symptom fluctuations and order. The secondary objective of this study is to provide power calculations for a larger longitudinal follow-up study. Power calculations will be centered around understanding the number of exacerbations according to sample size and duration.

METHODS: Participants will be recruited from 2 NHS sites in 3 different cohorts - COPD, IPF and Post hospitalised Covid. A total of 60 participants will be recruited, 20 in each cohort. Data collection will be done remotely using the RADAR-Base (Remote Assessment of Disease And Relapse) mHealth (mobile health) platform for different devices - Garmin wearable devices, smart spirometers, mobile app questionnaires, surveys and finger pulse oximeters. Passive data collected includes wearable derived continuous heart rate, oxygen saturation (SpO2), respiration rate, activity, and sleep. Active data collected includes disease-specific Patient Reported Outcome Measures (PROMs), mental health questionnaires and symptoms tracking to track disease trajectory in addition to speech sampling, spirometry and finger Pulse Oximetry. Analyses are intended to assess the feasibility of RADAR-Base for lung disorder remote monitoring (include quality of data, cross-section of passive and active data, data completeness, the usability of the system, acceptability of the system). Where adequate data is collected, we will attempt to explore disease trajectory, patient stratification and identification of acute clinically interesting events such as exacerbations. A key part of this study is understanding the potential of real-time data collection, here we will simulate an intervention using the Exacerbation Rating Scale (ERS) to acquire responses at-time-of-event to assess the performance of a model for exacerbation identification from passive data collected.

RESULTS: RALPMH study provides a unique opportunity to assess the use of remote monitoring in the study of lung disorders. The study is set to be started in mid-June 2021. The data collection apparatus, questionnaires and wearable integrations have been set up and tested by clinical teams as of 24th April 2021. While waiting for ethics approval, real-time exacerbation identification models are currently being constructed. The models will be pre-trained daily on previous days data but the inference will be run in real-time (with inputs from the wearable sensor data collected which is real-time) to acquire responses at-time-of-event to assess the performance of a model.

CONCLUSIONS: Remote Assessment of Lung Disease and Impact on Physical and Mental Health (RALPMH) will provide a reference infrastructure for the use of wearable data for monitoring lung diseases. Specifically information regarding the feasibility and acceptability of remote monitoring and the potential of real-time remote data collection and analysis in the context of chronic lung disorders. Moreover, it provides a unique standpoint to look into the specifics of novel coronavirus without burdensome interventions. It will help plan and inform decisions in any future studies that make use of remote monitoring in the area of Respiratory health.

CLINICALTRIAL: Isrctn.com ISRCTN16275601, https://www.isrctn.com/ISRCTN16275601.

PMID:34319235 | DOI:10.2196/28873

JACC Case Rep. 2020 Jun 17;2(6):938-942. doi: 10.1016/j.jaccas.2020.03.037. eCollection 2020 Jun.

ABSTRACT

As a rare complication after lung transplant, cardiac constriction should not be missed. Physical exam, echocardiography, and catheterization are essential for diagnosis A 65-year-old man with previous coronary artery disease and idiopathic pulmonary fibrosis underwent bilateral lung transplant and subsequently presented for progressive dyspnea and volume overload. Cardiac imaging and cardiac catheterization confirmed constriction, and complete pericardiectomy was performed. The patient had rapid resolution of heart failure symptoms. Pericardial constriction is a rare complication following lung transplant, and we provide a review of the literature and discussion of potential contributing factors. (Level of Difficulty: Intermediate.).

PMID:34317386 | PMC:PMC8302063 | DOI:10.1016/j.jaccas.2020.03.037

Nat Commun. 2021 Jul 27;12(1):4566. doi: 10.1038/s41467-021-24853-8.

ABSTRACT

The airway epithelium serves as the interface between the host and external environment. In many chronic lung diseases, the airway is the site of substantial remodeling after injury. While, idiopathic pulmonary fibrosis (IPF) has traditionally been considered a disease of the alveolus and lung matrix, the dominant environmental (cigarette smoking) and genetic (gain of function MUC5B promoter variant) risk factor primarily affect the distal airway epithelium. Moreover, airway-specific pathogenic features of IPF include bronchiolization of the distal airspace with abnormal airway cell-types and honeycomb cystic terminal airway-like structures with concurrent loss of terminal bronchioles in regions of minimal fibrosis. However, the pathogenic role of the airway epithelium in IPF is unknown. Combining biophysical, genetic, and signaling analyses of primary airway epithelial cells, we demonstrate that healthy and IPF airway epithelia are biophysically distinct, identifying pathologic activation of the ERBB-YAP axis as a specific and modifiable driver of prolongation of the unjammed-to-jammed transition in IPF epithelia. Furthermore, we demonstrate that this biophysical state and signaling axis correlates with epithelial-driven activation of the underlying mesenchyme. Our data illustrate the active mechanisms regulating airway epithelial-driven fibrosis and identify targets to modulate disease progression.

PMID:34315881 | DOI:10.1038/s41467-021-24853-8

Eur J Med Chem. 2021 Jul 20;224:113714. doi: 10.1016/j.ejmech.2021.113714. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a lethal disease with limited therapeutic options and a particularly poor prognosis. Matrix metalloproteinases (MMPs), promising targets for the treatment of IPF, have been identified as playing a pivotal role in IPF. Although the pathological processes of MMPs and IPF have been verified, there are no MMP inhibitors for the treatment of IPF in the clinic. In this review, we will present the latest developments in MMP inhibitors, including pharmacophores, binding modes, selectivity and optimization strategies. In addition, we will also discuss the future development direction of MMP inhibitors based on emerging tools and techniques.

PMID:34315043 | DOI:10.1016/j.ejmech.2021.113714

Ann Am Thorac Soc. 2021 Jul 27. doi: 10.1513/AnnalsATS.202103-295OC. Online ahead of print.

ABSTRACT

RATIONALE: The development of novel therapies for idiopathic pulmonary fibrosis (IPF) has brought increased attention to the population burden of disease. However, little is known about the epidemiology of IPF among United States Veterans.

OBJECTIVES: This study examines temporal trends in incidence and prevalence, patient characteristics, and risk factors associated with IPF among a national cohort of United States Veterans.

METHODS: We used data from Veterans Health Administration (VHA) electronic health record system to describe the incidence, prevalence, and geographic distribution of IPF between January 2010 and December 2019. We evaluated patient characteristics associated with IPF using multivariate logistic regression.

RESULTS: Among 10.7 million Veterans who received care from the VHA between 2010 and 2019, 139,116 (1.26%) were diagnosed with IPF. Using a narrow case definition of IPF, the prevalence increased from 276 cases per 100,000 in 2010 to 725 cases per 100,000 in 2019. The annual incidence increased from 73 cases per 100,000 person-years in 2010 to 210 cases per 100,000 person-years in 2019. Higher absolute incidence and prevalence rates were noted when a broader case definition of IPF was used. Risk factors associated with IPF among Veterans included older age, White race, tobacco use, and rural residence. After accounting for interactions, the average marginal difference in IPF prevalence between males and female sex was small. There was significant geographic heterogeneity of disease across the U.S.

CONCLUSIONS: This study is the first comprehensive epidemiologic analysis of IPF among the U.S. Veteran population. The incidence and prevalence of IPF among Veterans has increased over the past decade. The effect of sex on risk of IPF was attenuated once accounting for other risk factors. The geographic distribution of disease is heterogenous across the U.S with rural residence associated with a higher odds of IPF. The reason for these trends deserves further study.

PMID:34314645 | DOI:10.1513/AnnalsATS.202103-295OC

PLoS One. 2021 Jul 27;16(7):e0255365. doi: 10.1371/journal.pone.0255365. eCollection 2021.

ABSTRACT

BACKGROUND: Interstitial lung diseases (ILDs) are chronic, parenchymal lung diseases with a variable clinical course and a poor prognosis. Within various clinical courses, acute exacerbation (AE) is a devastating condition with significant morbidity and high mortality. The aim of this study was to investigate the role of interleukin-6 (IL-6) to predict AE and prognosis in patients with ILD.

METHODS: Eighty-three patients who were diagnosed with ILD from 2016 to 2019 at the Haeundae Paik Hospital, Busan, South Korea, were included and their clinical data were retrospectively analyzed.

RESULTS: The median follow-up period was 20 months. The mean age was 68.1 years and 65.1% of the patients were men with 60.2% of patients being ever-smokers. Among ILDs, idiopathic pulmonary fibrosis was the most common disease (68.7%), followed by connective tissue disease-associated ILD (14.5%), cryptogenic organizing pneumonia (9.6%), and nonspecific interstitial pneumonia (6.0%). The serum levels of IL-6 were measured at diagnosis with ILD and sequentially at follow-up visits. During the follow-ups, 15 (18.1%) patients experienced an acute exacerbation (AE) of ILD and among them, four (26.7%) patients died. In the multivariable analysis, high levels of IL-6 (OR 1.014, 95% CI: 1.001-1.027, p = 0.036) along with lower baseline saturations of peripheral oxygen (SpO2) were independent risk factors for AE. In the receiver operating characteristic curve analysis, the area under the curve was 0.815 (p < 0.001) and the optimal cut-off value of serum IL-6 to predict AE was 25.20 pg/mL with a sensitivity of 66.7% and specificity of 80.6%. In the multivariable Cox analysis, a high level of serum IL-6 (HR 1.007, 95% CI: 1.001-1.014, p = 0.018) was only an independent risk factor for mortality in ILD patients.

CONCLUSIONS: In our study, a high level of serum IL-6 is a useful biomarker to predict AE and poor prognosis in patients with ILD.

PMID:34314462 | DOI:10.1371/journal.pone.0255365