Respir Res. 2021 Feb 8;22(1):49. doi: 10.1186/s12931-021-01640-z.

ABSTRACT

BACKGROUND: Mitochondrial dysfunction has emerged as an important player in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a common cause of idiopathic interstitial lung disease in adults. Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder that causes a similar type of pulmonary fibrosis in younger adults, although the role of mitochondrial dysfunction in this condition is not understood.

METHODS: We performed a detailed characterization of mitochondrial structure and function in lung tissues and alveolar epithelial cells deficient in the adaptor protein complex 3 beta 1 (Ap3b1) subunit, the gene responsible for causing subtype 2 of HPS (HPS-2).

RESULTS: We observed widespread changes in mitochondrial homeostasis in HPS-2 cells, including the acquisition of abnormally shaped mitochondria, with reduced number of cristae, and markedly reduced activity of the electron transport chain and the tricarboxylic acid cycle. We also found that mitochondrial redox imbalance and activity of the mitochondrial unfolded protein response were dysregulated in HPS-2 cells and this associated with various other changes that appeared to be compensatory to mitochondrial dysfunction. This included an increase in glycolytic activity, an upregulation in the expression of mitochondrial biogenesis factors and enhanced activation of the energy-conserving enzyme AMP-activated protein kinase.

CONCLUSION: In summary, our findings indicate that mitochondrial function is dramatically altered in HPS-2 lung tissues, suggesting dysfunction of this organelle might be a driver of HPS lung disease.

PMID:33557836 | PMC:PMC7871590 | DOI:10.1186/s12931-021-01640-z

Curr Opin Pharmacol. 2021 Feb 5;57:71-80. doi: 10.1016/j.coph.2020.12.007. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic chronic lung disease affecting predominantly older adults, with a history of smoking. The current model of disease natural course is that recurrent injury of the alveolar epithelium in the context of advanced aging/cellular senescence is followed by defective re-epithelialization and scar tissue formation. Currently, two drugs, nintedanib and pirfenidone, that modify disease progression have been approved worldwide for the treatment of IPF. However, despite treatment, patients with IPF are not cured, and eventually, disease advances in most treated patients. Enhancing biogenomic and metabolic research output, its translation into clinical precision and optimal service delivery through patient-centeredness are key elements to support effective IPF care. In this review, we summarize therapeutic options currently investigated for IPF based on the major pathogenetic pathways and molecular targets that drive pulmonary fibrosis.

PMID:33556824 | DOI:10.1016/j.coph.2020.12.007

Respir Investig. 2021 Feb 4:S2212-5345(21)00005-8. doi: 10.1016/j.resinv.2020.12.008. Online ahead of print.

ABSTRACT

BACKGROUND: The clinical course of idiopathic pulmonary fibrosis (IPF) is characterized by a progressive decline in lung function; however, predicting changes in lung function is difficult. We sought to determine whether the prior 6-month trend in forced vital capacity (FVC) could predict mortality and the subsequent 6-month trend in FVC.

METHODS: We retrospectively analyzed consecutive patients with newly diagnosed IPF who underwent serial pulmonary function tests. The immediate two years after the initial evaluation were divided into four terms of six months each and stratified on the basis of presence or absence of a ≥10% relative decline in FVC at six months (declined and stable groups, respectively).

RESULTS: We included 107 patients with %predicted FVC of 80.8% and %predicted diffusing capacity of the lung for carbon monoxide of 58.9%. In multivariate analysis, a decline in %predicted FVC in the initial six months was found to be an independent prognostic factor (hazard ratio 4.45, 95% confidence interval 2.62-7.56, p < 0.01). Among the 46 terms in which the FVC declined during the initial 1.5-year study period, a decline in FVC was exhibited in 23 (50.0%) of the subsequent terms. Among 231 terms in which FVC remained stable, a decline was observed in 32 (13.9%) of the subsequent terms (relative risk 3.61, p < 0.01). The frequency of FVC decline in each term was 16-27%. FVC was stable or declined in all four terms in 50.5% and 15.9% of cases, respectively.

CONCLUSIONS: Six-month decline in FVC predicts subsequent FVC change and mortality in IPF patients in the era of antifibrotic agents.

PMID:33551330 | DOI:10.1016/j.resinv.2020.12.008

Respir Investig. 2021 Feb 3:S2212-5345(21)00003-4. doi: 10.1016/j.resinv.2020.12.006. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) are at risk of acute exacerbations (AEs) that manifest as respiratory distress. However, the clinical course after AEs of IPF (AE-IPFs) has not been well described. Therefore, we aimed to elucidate the clinical course and prognosis in survivors of AE-IPFs.

METHODS: Consecutive patients with IPF who presented to our institution with their first AE-IPFs between January 2008 and December 2019 were included in this study. Data were retrospectively collected, and the clinical course, survival, and cause of death were further analyzed.

RESULTS: Ninety-seven patients were included in this retrospective study. Among them, 67 (69.1%) were discharged alive, with a median survival time after discharge of 1081 days. AE recurrence and pneumonia were the most common causes of death, each accounting for 22.2% of cases among survivors of AE-IPFs. AEs were the most frequent during the first 3 years after discharge, whereas pneumonia was more common thereafter.

CONCLUSIONS: Survivors of AE-IPFs have a relatively favorable long-term prognosis. Among the survivors of first AE-IPFs, AE recurrence and pneumonia were the most common causes of death after discharge. Therefore, preventing AE recurrence and lung infections is crucial for prolonging survival in survivors of AE-IPFs.

PMID:33549542 | DOI:10.1016/j.resinv.2020.12.006

Respir Res. 2021 Feb 6;22(1):44. doi: 10.1186/s12931-021-01632-z.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung diseases with a poor prognosis. Long non-coding RNAs (lncRNAs) have been reported to be involved in IPF in several studies. However, the role of lncRNA SNHG16 in IPF is largely unknown.

METHODS: Firstly, experimental pulmonary fibrosis model was established by using bleomycin (BML). Histology and Western blotting assays were used to determine the different stages of fibrosis and expression of several fibrosis biomarkers. The expression of SNHG16 was detected by quantitative real-time polymerase chain reaction (qRT-PCR). EdU staining and wound-healing assay were utilized to analyze proliferation and migration of lung fibroblast cells. Molecular mechanism of SNHG16 was explored by bioinformatics, dual-luciferase reporter assay, RNA immunoprecipitation assay (RIP), and qRT-PCR.

RESULTS: The expression of SNHG16 was significantly up-regulated in bleomycin-(BLM) induced lung fibrosis and transforming growth factor-β (TGF-β)-induced fibroblast. Knockdown of SNHG16 could attenuate fibrogenesis. Mechanistically, SNHG16 was able to bind and regulate the expression of miR-455-3p. Moreover, SNHG16 also regulated the expression of Notch2 by targeting miR-455-3p. Finally, SNHG16 could promote fibrogenesis by regulating the expression of Notch2.

CONCLUSION: Taken together, our study demonstrated that SNHG16 promoted pulmonary fibrosis by targeting miR-455-3p to regulate the Notch2 pathway. These findings might provide a novel insight into pathologic process of lung fibrosis and may provide prevention strategies in the future.

PMID:33549106 | PMC:PMC7866661 | DOI:10.1186/s12931-021-01632-z

Am J Ind Med. 2021 Feb 5. doi: 10.1002/ajim.23231. Online ahead of print.

ABSTRACT

BACKGROUND: Cigarette smoking and occupational exposures each have been reported to increase the risk of idiopathic pulmonary fibrosis (IPF), a disease previously considered of unknown origin. We investigated the risk of IPF mortality associated with combined smoking and occupational exposures.

METHODS: A registry study of Swedish construction workers (N = 389,132), linked baseline smoking and occupational data with registry data on cause of death and hospital care diagnoses. Occupation was classified by the likelihood of exposure to vapors, gases, dusts, or fumes using a job-exposure matrix. Those likely exposed to asbestos or silica were excluded from the analysis. Age-adjusted relative risks [RRs] were calculated using Poisson regression. Follow-up observation began at age 40 and ended at age 89.

RESULTS: Heavy smokers at baseline who were exposed to inorganic dusts during their working life had an increased risk of IPF mortality (RR 1.70; 95% confidence interval [CI] 1.11-2.60), while there was no statistically increased risk in the other exposure groups. There were dose-response relationships between smoking at baseline and IPF mortality among both unexposed and dust exposed workers, with similar risk for dust exposed and unexposed, except among baseline heavy smokers, where workers exposed to inorganic dust manifested the highest risk (RR 4.22; 95% CI 2.69-6.60). Excluding workers with chronic obstructive pulmonary disease or emphysema did not affect the results substantively.

CONCLUSION: A clear dose-response relationship was seen between smoking at baseline and IPF, supporting a causal relationship. Occupational exposure to inorganic dusts, excluding silica and asbestos, was associated with increased risk of IPF in baseline heavy current smokers.

PMID:33547652 | DOI:10.1002/ajim.23231

Med Phys. 2021 Feb 5. doi: 10.1002/mp.14754. Online ahead of print.

ABSTRACT

PURPOSE: Domain knowledge (DK) acquired from prior studies is important for medical diagnosis. This paper leverages the population-level DK using an optimality design criterion to train a deep learning model in an end-to-end manner. In this study, the problem of interest is at the patient-level to diagnose a subject with idiopathic pulmonary fibrosis (IPF) among subjects with interstitial lung disease (ILD) using a computed tomography (CT). IPF diagnosis is a complicated process with multidisciplinary discussion with experts and is subject to inter-observer variability, even for experienced radiologists. To this end, we propose a new statistical method to construct a time/memory-efficient IPF diagnosis model using axial chest CT and DK, along with an optimality design criterion via a DK-enhanced loss function of deep learning.

METHODS: Four state-of-the-art two-dimensional convolutional neural network (2D-CNN) architectures (MobileNet, VGG16, ResNet-50, and DenseNet-121) and one baseline 2D-CNN are implemented to automatically diagnose IPF among ILD patients. Axial lung CT images are retrospectively acquired from 389 IPF patients and 700 non-IPF ILD patients in five multi-center clinical trials. To enrich the sample size and boost model performance, we sample 20 three-slice samples (triplets) from each CT scan, where these three slices are randomly selected from the top, middle, and bottom of both lungs respectively. Model performance is evaluated using a five-fold cross-validation, where each fold was stratified using a fixed proportion of IPF versus non-IPF.

RESULTS: Using DK-enhanced loss function increases the model performance of the baseline CNN model from 0.77 to 0.89 in terms of study-wise accuracy. Four other well-developed models reach satisfactory model performance with an overall accuracy greater than 0.95 but the benefits brought on by the DK-enhanced loss function is not noticeable.

CONCLUSIONS: We believe this is the first attempt that (1) uses population-level DK with an optimal design criterion to train deep learning-based diagnostic models in an end-to-end manner and (2) focuses on patient-level IPF diagnosis. Further evaluation of using population-level DK on prospective studies is warranted and is underway.

PMID:33547645 | DOI:10.1002/mp.14754

Respir Res. 2021 Feb 5;22(1):40. doi: 10.1186/s12931-021-01634-x.

ABSTRACT

BACKGROUND: Observational data under real-life conditions in idiopathic pulmonary fibrosis (IPF) is scarce. We explored anti-fibrotic treatment, disease severity and phenotypes in patients with IPF from the Swedish IPF Registry (SIPFR).

METHODS: Patients enrolled between September 2014 and April 2020 and followed ≥ 6 months were investigated. Demographics, comorbidities, lung function, composite variables, six-minute walking test (6MWT), quality of life, and anti-fibrotic therapy were evaluated. Agreements between classification of mild physiological impairment (defined as gender-age-physiology (GAP) stage 1) with physiological and composite measures of severity was assessed using kappa values and their impact on mortality with hazard ratios. The factor analysis and the two-step cluster analysis were used to identify phenotypes. Univariate and multivariable survival analyses were performed between variables or groups.

RESULTS: Among 662 patients with baseline data (median age 72.7 years, 74.0% males), 480 had a follow up ≥ 6 months with a 5 year survival rate of 48%. Lung function, 6MWT, age, and BMI were predictors of survival. Patients who received anti-fibrotic treatment ≥ 6 months had better survival compared to untreated patients [p = 0.007, HR (95% CI): 1.797 (1.173-2.753)] after adjustment of age, gender, BMI, smoking status, forced vital capacity (FVC) and diffusion capacity of carbon monoxide (DLCO). Patients with mild physiological impairment (GAP stage 1, composite physiological index (CPI) ≤ 45, DLCO ≥ 55%, FVC ≥ 75%, and total lung capacity (TLC) ≥ 65%, respectively) had better survival, after adjustment for age, gender, BMI and smoking status and treatment. Patients in cluster 1 had the worst survival and consisted mainly of male patients with moderate-severe disease and an increased prevalence of heart diseases at baseline; Cluster 2 was characterized by mild disease with more than 50% females and few comorbidities, and had the best survival; Cluster 3 were younger, with moderate-severe disease and had few comorbidities.

CONCLUSION: Disease severity, phenotypes, and anti-fibrotic treatment are closely associated with the outcome in IPF, with treated patients surviving longer. Phenotypes may contribute to predicting outcomes of patients with IPF and suggest the patients' need for special management, whereas single or composite variables have some limitations as disease predictors.

PMID:33546682 | PMC:PMC7866760 | DOI:10.1186/s12931-021-01634-x

BMC Pulm Med. 2021 Feb 5;21(1):51. doi: 10.1186/s12890-021-01418-5.

ABSTRACT

BACKGROUND: Malnutrition and altered body composition are well-documented in chronic pulmonary diseases; however, investigation of nutritional status in interstitial lung disease (ILD) is limited. This study aimed to describe the nutritional status of ILD patients within three diagnostic groups and explore the relationship between nutritional status and quality of life (QoL).

METHODS: Consecutive patients attending an ILD clinic within a tertiary referral hospital in Sydney, Australia were studied. Weight, body-mass-index, anthropometrics, handgrip strength (HGS), subjective global assessment and QoL questionnaires (EQ-5D-5L and King's-Brief Interstitial-Lung-Disease 'K-BILD') were collected. Associations between nutritional status and QoL were analysed.

RESULTS: Ninety participants were recruited and categorised: (1) Idiopathic Pulmonary Fibrosis (IPF) (2) Connective-Tissue Disease associated-ILD (CTD-ILD) or (3) Other (non-IPF/non-CTD ILD). Median age was 66.5 (18) years. Four-percent of patients were underweight and 50% were overweight or obese. Median HGS was 71%-(25.3) of predicted and was correlated to all measures of QoL including EQ-5D health-state index (r = 0.376, p < 0.0001), patient-reported EQ-5D-5L Visual Analogue Score (r = 0.367, p < 0.0001) and K-BILD total score (r = 0.346, p = 0.001). Twenty-three percent of the variance in K-BILD total score (F = 12.888, p < 0.0001) was explained by HGS (ß = 0.273, p = 0.006) and forced vital capacity % predicted (ß = 0.331, p = 0.001).

CONCLUSIONS: Although a small number of ILD patients were malnourished, a large proportion of the cohort were overweight or obese. Handgrip strength was compromised and correlated to QoL. Future research with a larger cohort is required to explore the role of HGS as a predictor of QoL.

PMID:33546667 | PMC:PMC7863253 | DOI:10.1186/s12890-021-01418-5

Am J Respir Crit Care Med. 2021 Feb 5. doi: 10.1164/rccm.202010-3994ED. Online ahead of print.

NO ABSTRACT

PMID:33545013 | DOI:10.1164/rccm.202010-3994ED

Thorax. 2021 Feb 4:thoraxjnl-2020-215135. doi: 10.1136/thoraxjnl-2020-215135. Online ahead of print.

ABSTRACT

BACKGROUND: Exercise-induced hypoxaemia is a hallmark of chronic fibrotic interstitial lung disease (f-ILD). It remains unclear whether patients' severe hypoxaemia may exaggerate locomotor muscle fatigue and, if so, to what extent oxygen (O2) supplementation can ameliorate these abnormalities.

METHODS: Fifteen patients (12 males, 9 with idiopathic pulmonary fibrosis) performed a constant-load (60% peak work rate) cycle test to symptom limitation (Tlim) while breathing medical air. Fifteen age-matched and sex-matched controls cycled up to patients' Tlim. Patients repeated the exercise test on supplemental O2 (42%±7%) for the same duration. Near-infrared spectroscopy assessed vastus lateralis oxyhaemoglobin concentration ((HbO2)). Pre-exercise to postexercise variation in twitch force (∆Tw) induced by femoral nerve magnetic stimulation quantified muscle fatigue.

RESULTS: Patients showed severe hypoxaemia (lowest O2 saturation by pulse oximetry=80.0%±7.6%) which was associated with a blunted increase in muscle (HbO2) during exercise vs controls (+1.3±0.3 µmol vs +4.4±0.4 µmol, respectively; p<0.001). Despite exercising at work rates ∼ one-third lower than controls (42±13 W vs 66±13 W), ∆Tw was greater in patients (∆Tw/external work performed by the leg muscles=-0.59±0.21 %/kJ vs -0.25±0.19 %/kJ; p<0.001). Reversal of exertional hypoxaemia with supplemental O2 was associated with a significant increase in muscle (HbO2), leading to a reduced decrease in ∆Tw in patients (-0.33±0.19 %/kJ; p<0.001 vs air). Supplemental O2 significantly improved leg discomfort (p=0.005).

CONCLUSION: O2 supplementation during exercise improves leg muscle oxygenation and fatigue in f-ILD. Lessening peripheral muscle fatigue to enhance exercise tolerance is a neglected therapeutic target that deserves clinical attention in this patient population.

PMID:33542089 | DOI:10.1136/thoraxjnl-2020-215135

Eur Respir J. 2021 Feb 4:2004507. doi: 10.1183/13993003.04507-2020. Online ahead of print.

ABSTRACT

Interstitial lung diseases (ILD) comprise a large and heterogeneous group of disorders of known and unknown etiology characterised by diffuse damage of the lung parenchyma. In the past years, it has become evident that patients with different types of ILD are at risk of developing progressive pulmonary fibrosis known as pulmonary fibrosing ILD (PF-ILD). This is a phenotype behaving similar to idiopathic pulmonary fibrosis, the archetypical example of progressive fibrosis. PF-ILD is not a distinct clinical entity but describes a group of ILD with a similar clinical behavior. This phenotype may occur in diseases displaying distinct etiologies and different biopathology during their initiation and development. Importantly, these entities may have the potential for improvement or stabilisation prior to entering in the progressive fibrosing phase. The crucial questions are (1) why a subset of patients develops a progressive and irreversible fibrotic phenotype even with appropriate treatment, and (2) what the pathogenic mechanisms driving progression possibly are. We here provide a framework highlighting putative mechanisms underlying progression, including genetic susceptibility, aging, epigenetics, the structural fibrotic distortion, the aberrant composition and stiffness of the extracellular matrix, and the emergence of distinct profibrotic cell subsets. Understanding the cellular and molecular mechanisms behind PF-ILD will provide the basis for identifying risk factors and appropriate therapeutical strategies.

PMID:33542060 | DOI:10.1183/13993003.04507-2020

Clin Chest Med. 2021 Mar;42(1):59-70. doi: 10.1016/j.ccm.2020.11.006.

ABSTRACT

Group 3 pulmonary hypertension (PH) is a known sequelae of chronic lung disease. Diagnosis and classification can be challenging in the background of chronic lung disease and often requires expert interpretation of numerous diagnostic studies to ascertain the true nature of the PH. Stabilization of the underlying lung disease and adjunctive therapies such as oxygen remain the mainstays of therapy, as there are no Food and Drug Administration-approved therapies for group 3 PH. Referral to PH centers for individualized management and clinical trial enrollment is paramount.

PMID:33541617 | DOI:10.1016/j.ccm.2020.11.006

Theranostics. 2021 Jan 9;11(7):3244-3261. doi: 10.7150/thno.54217. eCollection 2021.

ABSTRACT

Rationale: (Myo)fibroblasts are the ultimate effector cells responsible for the production of collagen within alveolar structures, a core phenomenon in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Although (myo)fibroblast-targeted therapy holds great promise for suppressing the progression of IPF, its development is hindered by the limited drug delivery efficacy to (myo)fibroblasts and the vicious circle of (myo)fibroblast activation and evasion of apoptosis. Methods: Here, a dual small interfering RNA (siRNA)-loaded delivery system of polymeric micelles is developed to suppress the development of pulmonary fibrosis via a two-arm mechanism. The micelles are endowed with (myo)fibroblast-targeting ability by modifying the Fab' fragment of the anti-platelet-derived growth factor receptor-α (PDGFRα) antibody onto their surface. Two different sequences of siRNA targeting protein tyrosine phosphatase-N13 (PTPN13, a promoter of the resistance of (myo)fibroblasts to Fas-induced apoptosis) and NADPH oxidase-4 (NOX4, a key regulator for (myo)fibroblast differentiation and activation) are loaded into micelles to inhibit the formation of fibroblastic foci. Results: We demonstrate that Fab'-conjugated dual siRNA-micelles exhibit higher affinity to (myo)fibroblasts in fibrotic lung tissue. This Fab'-conjugated dual siRNA-micelle can achieve remarkable antifibrotic effects on the formation of fibroblastic foci by, on the one hand, suppressing (myo)fibroblast activation via siRNA-induced knockdown of NOX4 and, on the other hand, sensitizing (myo)fibroblasts to Fas-induced apoptosis by siRNA-mediated PTPN13 silencing. In addition, this (myo)fibroblast-targeting siRNA-loaded micelle did not induce significant damage to major organs, and no histopathological abnormities were observed in murine models. Conclusion: The (myo)fibroblast-targeting dual siRNA-loaded micelles offer a potential strategy with promising prospects in molecular-targeted fibrosis therapy.

PMID:33537085 | PMC:PMC7847691 | DOI:10.7150/thno.54217

Int J Chron Obstruct Pulmon Dis. 2021 Jan 28;16:167-177. doi: 10.2147/COPD.S286360. eCollection 2021.

ABSTRACT

BACKGROUND: Combined pulmonary fibrosis and emphysema (CPFE) is an underrecognized syndrome characterized by chronic, progressive disease with a dismal prognosis. Frequent co-morbidities with a higher incidence than in idiopathic pulmonary fibrosis or emphysema alone are pulmonary hypertension (WHO group 3) in 47-90% of the patients and lung cancer in 46.8% of the patients.

OBJECTIVE: Review current evidence and knowledge concerning diagnosis, risk factors, disease evolution and treatment options of CPFE.

METHODS: We searched studies reporting CPFE in original papers, observational studies, case reports, and meta-analyses published between 1990 and August 2020, in the PubMed, Embase, Cochrane Library, Wiley Online Library databases and Google Scholar using the search terms [CPFE], [pulmonary fibrosis] OR [IPF] AND [emphysema]. Bibliographies of retrieved articles were searched as well. Further inclusion criteria were publications in English, French, German and Italian, with reference to humans. In vitro data and animal data were not considered unless they were mentioned in studies reporting predominantly human data.

RESULTS: Between May 1, 1990, and September 1, 2020, we found 16 studies on CPFE from the online sources and bibliographies. A total of 890 patients are described in the literature. Although male/female ratio was not reported in all studies, the large majority of patients were male (at least 78%), most of them were current or former heavy smokers.

CONCLUSION: CPFE is a syndrome presenting with dyspnea on exertion followed by disruptive cough and recurrent exacerbations. The disease may progress rapidly, be aggravated by pulmonary hypertension WHO group 3 and is associated with an increased risk of lung cancer. Smoking and male sex are important risk factors. There is a need for more research on CPFE especially relating to etiology, influence of genetics, treatment and prevention options. Antifibrotic therapy might be an interesting treatment option for these patients.

PMID:33536752 | PMC:PMC7850450 | DOI:10.2147/COPD.S286360

Br J Radiol. 2021 Feb 4:20201159. doi: 10.1259/bjr.20201159. Online ahead of print.

ABSTRACT

OBJECTIVES: To determine whether the revised 2018 ATS/ERS/JRS/ALAT radiological criteria for usual interstitial pneumonia (UIP) provide better diagnostic agreement compared to the 2011 guidelines.

METHODS: Cohort for this cross-sectional study (single center, nonacademic) was recruited from a multidisciplinary team discussion (MDD) from July 2010 until November 2018, with clinical suspicion of fibrosing interstitial lung disease (n= 325). Exclusion criteria were technical HRCT issues, known connective tissue disease (rheumatoid arthritis, systemic sclerosis, poly-or dermatomyositis), exposure to pulmonary toxins or lack of working diagnosis after MDD. Four readers with varying degrees in HRCT interpretation independently categorized 192 HRCTs, according to both the previous and current ATS/ERS/JRS/ALAT radiological criteria. An inter-rater variability analysis (Gwet's second-order agreement coefficient, AC2) was performed.

RESULTS: The resulting Gwet's AC2 for the 2011 and 2018 ATS/ERS/JRS/ALAT radiological criteria is 0.62 (±0.05) and 0.65 (±0.05), respectively. We report only minor differences in agreement level among the readers. Distribution according to the 2011 guidelines is as follows: 57.3% 'UIP pattern', 24% 'possible UIP pattern', 18.8% 'inconsistent with UIP pattern' and for the 2018 guidelines: 59.6% 'UIP', 14.5% 'probable UIP', 15.9% 'indeterminate for UIP' and 10% 'alternative diagnosis'.

CONCLUSIONS: No statistically significant higher degree of diagnostic agreement is observed when applying the revised 2018 ATS/ERS/JRS/ALAT radiological criteria for UIP compared to those of 2011. The inter-rater variability for categorizing the HRCT patterns is moderate for both classification systems, independent of experience in HRCT interpretation. The major advantage of the current guidelines is the better subdivision in the categories with a lower diagnostic certainty for UIP.

ADVANCES IN KNOWLEDGE: - In 2018, a revision of the 2011 ATS/ERS/JRS/ALAT radiological criteria for UIP was published, part of diagnostic guidelines for idiopathic pulmonary fibrosis.- The inter-rater agreement among radiologist is moderate for both classification systems, without a significantly higher degree of agreement when applying the revised radiological criteria.

PMID:33539231 | DOI:10.1259/bjr.20201159

Eur Respir Rev. 2021 Feb 2;30(159):200193. doi: 10.1183/16000617.0193-2020. Print 2021 Mar 31.

ABSTRACT

Pulmonary fibrosis is a progressive interstitial lung disease of unknown aetiology with a poor prognosis. Studying genetic diseases associated with pulmonary fibrosis provides insights into the pathogenesis of the disease. Hermansky-Pudlak syndrome (HPS), a rare autosomal recessive disorder characterised by abnormal biogenesis of lysosome-related organelles, manifests with oculocutaneous albinism and excessive bleeding of variable severity. Pulmonary fibrosis is highly prevalent in three out of 10 genetic types of HPS (HPS-1, HPS-2 and HPS-4). Thus, genotyping of individuals with HPS is clinically relevant. HPS-1 tends to affect Puerto Rican individuals due to a genetic founder effect. HPS pulmonary fibrosis shares some clinical features with idiopathic pulmonary fibrosis (IPF), including dyspnoea, cough, restrictive lung physiology and computed tomography (CT) findings of fibrosis. In contrast to IPF, HPS pulmonary fibrosis generally affects children (HPS-2) or middle-aged adults (HPS-1 or HPS-4) and may be associated with ground-glass opacification in CT scans. Histopathology of HPS pulmonary fibrosis, and not IPF, shows vacuolated hyperplastic type II cells with enlarged lamellar bodies and alveolar macrophages with lipofuscin-like deposits. Antifibrotic drugs approved as treatment for IPF are not approved for HPS pulmonary fibrosis. However, lung transplantation has been performed in patients with severe HPS pulmonary fibrosis. HPS pulmonary fibrosis serves as a model for studying fibrotic lung disease and fibrosis in general.

PMID:33536261 | DOI:10.1183/16000617.0193-2020

Stem Cell Res Ther. 2021 Feb 3;12(1):96. doi: 10.1186/s13287-020-02083-x.

ABSTRACT

BACKGROUND: Previous reports have identified that human bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) with their cargo microRNAs (miRNAs) are a promising therapeutic approach for the treatment of idiopathic pulmonary fibrosis (IPF). Therefore, we explored whether delivery of microRNA-186 (miR-186), a downregulated miRNA in IPF, by BMSC EVs could interfere with the progression of IPF in a murine model.

METHODS: In a co-culture system, we assessed whether BMSC-EVs modulated the activation of fibroblasts. We established a mouse model of PF to evaluate the in vivo therapeutic effects of BMSC-EVs and determined miR-186 expression in BMSC-EVs by polymerase chain reaction. Using a loss-of-function approach, we examined how miR-186 delivered by BMSC-EVs affected fibroblasts. The putative relationship between miR-186 and SRY-related HMG box transcription factor 4 (SOX4) was tested using luciferase assay. Next, we investigated whether EV-miR-186 affected fibroblast activation and PF by targeting SOX4 and its downstream gene, Dickkopf-1 (DKK1).

RESULTS: BMSC-EVs suppressed lung fibroblast activation and delayed IPF progression in mice. miR-186 was downregulated in IPF but enriched in the BMSC-EVs. miR-186 delivered by BMSC-EVs could suppress fibroblast activation. Furthermore, miR-186 reduced the expression of SOX4, a target gene of miR-186, and hence suppressed the expression of DKK1. Finally, EV-delivered miR-186 impaired fibroblast activation and alleviated PF via downregulation of SOX4 and DKK1.

CONCLUSION: In conclusion, miR-186 delivered by BMSC-EVs suppressed SOX4 and DKK1 expression, thereby blocking fibroblast activation and ameliorating IPF, thus presenting a novel therapeutic target for IPF.

PMID:33536061 | PMC:PMC7860043 | DOI:10.1186/s13287-020-02083-x

Int J Cancer. 2021 Feb 3. doi: 10.1002/ijc.33499. Online ahead of print.

ABSTRACT

Patients with idiopathic pulmonary fibrosis (IPF) are at higher risk of developing lung cancers including squamous cell lung carcinoma (SCC), which typically carries a poor prognosis. Although the molecular basis of cancer development subsequent to IPF has not been fully investigated, we recently reported two epigenetic phenotypes characterized by frequent and infrequent DNA hypermethylation in SCC, and an association of the infrequent hypermethylation phenotype with IPF-associated SCCs. Here, we conducted targeted exon sequencing in SCCs with and without IPF using the Human Lung Cancer Panel to investigate the genetic basis of IPF-associated SCC. SCCs with and without IPF displayed comparable numbers of total mutations (137 ± 22 vs 131 ± 27, P = .5), nonsynonymous mutations (72 ± 14 vs 69 ± 16, P = .5), indels (3.0 ± 3.5 vs 3.0 ± 3.9, P = 1) and synonymous mutations (62 ± 9.1 vs 60 ± 12, P = .5). Signature 1 was the predominant signature in SCCs with and without IPF. SETD2 and NFE2L2 mutations were significantly associated with IPF (44% vs 13%, P = .03 for SETD2; 38% vs 10%, P = .04 for NFE2L2). MYC amplification, assessed by copy number variant analysis, was also significantly associated with IPF (18.8% vs 0%, P = .04). Mutations in TP53 and CDKN2A were observed relatively frequently in SCCs with frequent hypermethylation (P = .02 for TP53 and P = .06 for CDKN2A). Survival analysis revealed that the SETD2 mutation was significantly associated with worse prognosis (P = .04). Collectively, we found frequent involvement of SETD2 and NFE2L2 mutations and MYC amplification in SCCs with IPF, and an association of a SETD2 mutation with poorer prognosis.

PMID:33533494 | DOI:10.1002/ijc.33499

Oncoimmunology. 2020 Sep 22;9(1):1824631. doi: 10.1080/2162402X.2020.1824631.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) patients have a high risk of developing lung cancer, with few treatment options available. Pirfenidone, an antifibrotic agent approved for the treatment of IPF, has been demonstrated to suppress the TGFβ signaling and modulate the expression of immune-related genes. However, for lung cancer patients with comorbid IPF, whether pirfenidone has any synergetic effect with immune checkpoint inhibitors has not been investigated. In this study, we showed that pirfenidone monotherapy attenuated tumor growth with an increased T cell inflammatory signature in tumors. Co-administration of pirfenidone with PD-L1 blockades significantly delayed the tumor growth and increased survival, compared with the effect of either treatment alone. Combination therapy promoted gene expression with a unique signature associated with innate and adaptive immune response resulted in the infiltration of immune cells and optimal T cell positioning. Furthermore, we showed a great benefit of combination therapy in alleviating the pulmonary fibrosis and reducing the tumor growth in a tumor-fibrosis model. Our results collectively demonstrated that pirfenidone facilitated antitumor immunity and enhanced the efficacy of PD-L1 blockades. It may act as an adjuvant to immunotherapy in cancer treatment, particularly, in lung cancer patients with preexisting IPF.

PMID:33457101 | PMC:PMC7781712 | DOI:10.1080/2162402X.2020.1824631