Front Mol Biosci. 2021 Jun 21;8:633054. doi: 10.3389/fmolb.2021.633054. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is mainly characterized by aberrant extracellular matrix deposition, consequent to epithelial lung injury and myofibroblast activation, and inflammatory response. Glycogen synthase kinase 3 (GSK-3) is a serine-threonine kinase involved in several pathways, and its inhibition has been already suggested as a therapeutic strategy for IPF patients. There is evidence that GSK-3 is able to induce matrix metalloproteinase (MMP) expression and that its inhibition modulates MMP expression in the tissues. The aim of our study was to investigate the role of GSK-3 and its inhibition in the modulation of MMP-9 and -2 in an in vivo mouse model of lung fibrosis and in vitro using different cell lines exposed to pro-inflammatory or pro-fibrotic stimuli. We found that GSK-3 inhibition down-modulates gene expression and protein levels of MMP-9, MMP-2, and their inhibitors TIMP-1 and TIMP-2 in inflammatory cells harvested from bronchoalveolar lavage fluid (BALF) of mice treated with bleomycin as well as in interstitial alveolar macrophages and cuboidalized epithelial alveolar cells. To the same extent, GSK-3 inhibition blunted the increased MMP-9 and MMP-2 activity induced by pro-fibrotic stimuli in a human lung fibroblast cell line. Moreover, the αSMA protein level, a marker of fibroblast-to-myofibroblast transition involved in fibrosis, was decreased in primary fibroblasts treated with TGFβ following GSK-3 inhibition. Our results confirm the implication of GSK-3 in lung inflammation and fibrosis, suggesting that it might play its role by modulating MMP expression and activity but also pushing fibroblasts toward a myofibroblast phenotype and therefore enhancing extracellular matrix deposition. Thus, its inhibition could represent a possible therapeutic strategy.

PMID:34235177 | PMC:PMC8255387 | DOI:10.3389/fmolb.2021.633054

BMJ Open Respir Res. 2021 Jul;8(1):e000815. doi: 10.1136/bmjresp-2020-000815.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease (ILD) with a poor prognosis. Early diagnosis and treatment of IPF may increase lifespan and preserve quality of life. Chest CT is the best test to diagnose IPF, but it is expensive and impractical as a screening test. Fine crackles on chest auscultation may be the only best to screen for IPF.

METHODS: We prospectively assessed the presence and type of crackles on chest auscultation in all patients referred to the ILD Clinic at the Kingston Health Sciences Center in Ontario, Canada. Clinicians with varying levels of experience recorded the presence of fine crackles, coarse crackles or both independently and unaware of the final diagnosis. We applied multinomial logistic regression to adjust for ILD severity and factors that could affect the identification of crackles.

RESULTS: We evaluated 290 patients referred to the ILD Clinic. On initial presentation, 93% of patients with IPF and 73% of patients with non-IPF ILD had fine crackles on auscultation. In patients with IPF, fine crackles were more common than cough (86%), dyspnoea (80%), low diffusing capacity (87%), total lung capacity (57%) and forced vital capacity (50%). There was 90% observer agreement in identifying fine crackles at a subsequent visit. In multiple regression analysis, the identification of fine crackles was unaffected by lung function, symptoms, emphysema, chronic obstructive pulmonary disease, obesity or clinician experience (p>0.05).

CONCLUSIONS: Fine crackles on chest auscultation are a sensitive and robust screening tool that can lead to early diagnosis and treatment of patients with IPF.

PMID:34233892 | DOI:10.1136/bmjresp-2020-000815

Respir Res. 2021 Jul 7;22(1):197. doi: 10.1186/s12931-021-01791-z.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive debilitating lung disease with considerable morbidity. Heterogeneity in epidemiologic studies means the full impact of the disease is unclear.

METHODS: A targeted literature search for population-based, observational studies reporting incidence and/or prevalence of IPF from January 2009 to April 2020 was conducted. Identified studies were aggregated by country. For countries with multiple publications, a weighted average was determined. Incidence and prevalence data were adjusted for between-study differences where possible. The final model included adjusted estimates of incidence and prevalence per 10,000 of the population with 95% confidence intervals. As prevalence estimates vary depending on the definitions used, estimates were based on a specific case definition of IPF.

RESULTS: Overall, 22 studies covering 12 countries met the inclusion criteria, with 15 reporting incidence and 18 reporting prevalence estimates. The adjusted incidence estimates (per 10,000 of the population) ranged from 0.35 to 1.30 in Asia-Pacific countries, 0.09 to 0.49 in Europe, and 0.75 to 0.93 in North America. Unadjusted and adjusted incidence estimates were consistent. The adjusted prevalence estimates ranged from 0.57 to 4.51 in Asia-Pacific countries, 0.33 to 2.51 in Europe, and 2.40 to 2.98 in North America. South Korea had the highest incidence and prevalence estimates. When prevalence estimates were compared to country-specific rare disease thresholds, IPF met the definition of a rare disease in all countries except South Korea. There were notable geographic gaps for IPF epidemiologic data.

CONCLUSIONS: Due to differences in study methodologies, there is worldwide variability in the reported incidence and prevalence of IPF. Based on the countries included in our analysis, we estimated the adjusted incidence and prevalence of IPF to be in the range of 0.09-1.30 and 0.33-4.51 per 10,000 persons, respectively. According to these prevalence estimates, IPF remains a rare disease. For consistency, future epidemiologic studies of IPF should take age, sex, smoking status, and the specificity of case definitions into consideration.

PMID:34233665 | DOI:10.1186/s12931-021-01791-z

J Thromb Thrombolysis. 2021 Jul 7. doi: 10.1007/s11239-021-02518-z. Online ahead of print.

ABSTRACT

Interstitial lung disease (ILD) encompasses various parenchymal lung disorders, which has the potential to increase the risk of venous thromboembolism (VTE). To evaluate, in patients with ILD and VTE, the risk of recurrent VTE during follow-up after stopping anticoagulation. This was a cohort of patients with a first VTE recruited between 1997 and 2015. The primary outcome was adjudicated fatal or nonfatal recurrent VTE after stopping anticoagulation. Main secondary outcomes were major or clinically relevant non-major bleeding under anticoagulation. Among 4314 patients with VTE, 50 had ILD diagnosed before VTE. Of these, anticoagulation was stopped in 30 patients after a median duration of 180 days and continued indefinitely in 20 patients. During a median follow-up of 27.8 months after anticoagulation discontinuation, recurrent VTE occurred in 15 on 30 patients (annual incidence of 19.2 events per 100-person-years [95%CI 12.0-29.3], case-fatality rate of 6.7% [95%CI 1.21-29.8]). The risk of recurrence was threefold higher when VTE was unprovoked and case-fatality rate of recurrence was increased by 3 when VTE index was PE. During the anticoagulant period, (median duration of 8.6 months), 6 patients had a major or clinically relevant bleeding (annual incidence of 7.3 events per 100-person-years [95%CI 3.4-15.1], case-fatality rate of 16.7% [95%CI 3.0-56.4]). In patients with ILD, the risk of recurrent VTE after stopping anticoagulation and the risk of bleeding under anticoagulation were very high. Our results suggest that anticoagulation should not be prolonged beyond 3-6 months of anticoagulation in most of cases.

PMID:34232453 | DOI:10.1007/s11239-021-02518-z

Medicine (Baltimore). 2021 Jul 9;100(27):e25915. doi: 10.1097/MD.0000000000025915.

ABSTRACT

Early right ventricular dysfunction in patients with non-advanced idiopathic pulmonary fibrosis (IPF) has not been fully elucidated. Thus, we aimed to assess right ventricular functions in IPF patients and controls by speckle-tracking strain echocardiography at rest and peak exercise.We screened 116 IPF patients from February to August 2019 to include 20 patients with no history of oxygen therapy, peripheral saturation levels ≥92% at rest, Gender-Age-Physiology Index score ≤5, and modified Medical Research Council score ≤3. Additionally, we enrolled 10 matched controls. Transthoracic echocardiography images were acquired at rest and during a cardiopulmonary exercise test. We analyzed 2-dimensional echocardiographic parameters and right ventricular function using the global longitudinal strain assessed by the 2-dimensional speckle-tracking technique.In the control group, we found normal values of right ventricle longitudinal strain (RVLS) at rest and at peak exercise, the latter being much more negative (-23.6 ± 2.2% and -26.8 ± 3.1%, respectively; P < .001). By contrast, RVLS values in the IPF group increased from -21.1 ± 3.8% at rest to -17.0 ± 4.5% at peak exercise (P < .001). The exercise revealed a difference between the 2 groups as the mean RVLS values moved during peak exercise in opposite directions. Patients with IPF got worse, whereas control patients presented improved right ventricular contractility.Right ventricular dysfunction was unveiled by speckle-tracking echocardiography during exercise in non-advanced IPF patients. We suggest that this reflects an inadequate right ventricular-arterial coupling decreasing the right ventricular longitudinal contraction during exercise in these patients. This parameter may be useful as an early index of suspected pulmonary hypertension.

PMID:34232164 | DOI:10.1097/MD.0000000000025915

Curr Opin Pulm Med. 2021 Jul 6. doi: 10.1097/MCP.0000000000000805. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: The progressive fibrotic phenotype (PFP), a term that covers large sub-groups of patients with fibrotic lung diseases that clinically progress despite appropriate usual management, is now an everyday problem for patients and clinicians alike. This review covers recent data that are relevant to major clinical uncertainties.

RECENT FINDINGS: The clinical relevance of the PFP is covered by a brief review of data from which this entity was constructed. Estimates of the prevalence of the PFP are cited. The importance of an accurate initial diagnosis is emphasized - with refutation of the belief that diagnosis now matters less because of recent antifibrotic trial data. Pivotal trials are reviewed briefly with emphasis on the range of diseases studied and the efficacy signals. Included in this section are analyses of treatment effects in individual diseases and data that validate the progression criteria that define the PFP.

SUMMARY: Clinicians can now implement the findings from recent antifibrotic trials in non-idiopathic pulmonary fibrosis lung diseases. However, the appropriate application of recent data requires an understanding of the critical importance of initial diagnosis, key measures of disease progression and knowledge of the strengths and weaknesses of trial data. Important clinical uncertainties not informed by current data include the evaluation of the adequacy of traditional management (before antifibrotic therapy is introduced) and agreement on the exact definition of disease progression that should trigger consideration of antifibrotic therapy.

PMID:34231535 | DOI:10.1097/MCP.0000000000000805

Curr Opin Pulm Med. 2021 Jul 6. doi: 10.1097/MCP.0000000000000803. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Describe the concept and recent data for the concept of progressive fibrotic interstitial lung disease (ILD).

RECENT FINDINGS: Making an accurate diagnosis is critical to help determine appropriate therapy and predict prognosis. This is certainly true in the field of ILD where a diagnosis of idiopathic pulmonary fibrosis (IPF) leads a clinician to consider initiation of antifibrotic therapy, and avoidance of immunosuppression due to possible harm, at the time of diagnosis due to the high probability of disease progression. In other types of ILD immunosuppression may be helpful such as those associated with a connective tissue disease or in combination with antigen avoidance in hypersensitivity pneumonia. It is also recognized that despite initial approaches to therapy some non-IPF ILDs will develop progressive fibrosis leading to increased symptoms, decreased quality of life and early mortality. Once fibrosis is present, the biologic pathways responsible for progression can be redundant and respond in a similar fashion to antifibrotic therapy independent of the underlying disease.

SUMMARY: There are clinical and biological rationale for the justification of a progressive fibrotic phenotype that complements the therapeutic decisions and prognosis provided by initial diagnosis.

PMID:34231534 | DOI:10.1097/MCP.0000000000000803

J Cell Physiol. 2021 Jul 6. doi: 10.1002/jcp.30500. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia. It is unknown why fibrosis in IPF distributes in the peripheral or named sub-pleural area. Migration of pleural mesothelial cells (PMC) should contribute to sub-pleural fibrosis. Calpain is known to be involved in cell migration, but the role of calpain in PMC migration has not been investigated. In this study, we found that PMCs migrated into lung parenchyma in patients with IPF. Then using Wt1tm1(EGFP/Cre)Wtp /J knock-in mice, we observed PMC migration into lung parenchyma in bleomycin-induced pleural fibrosis models, and calpain inhibitor attenuated pulmonary fibrosis with prevention of PMC migration. In vitro studies revealed that bleomycin and transforming growth factor-β1 increased calpain activity in PMCs, and activated calpain-mediated focal adhesion (FA) turnover as well as cell migration, cell proliferation, and collagen-I synthesis. Furthermore, we determined that calpain cleaved FA kinase in both C-terminal and N-terminal regions, which mediated FA turnover. Lastly, the data revealed that activated calpain was also involved in phosphorylation of cofilin-1, and p-cofilin-1 induced PMC migration. Taken together, this study provides evidence that calpain mediates PMC migration into lung parenchyma to promote sub-pleural fibrosis in IPF.

PMID:34231213 | DOI:10.1002/jcp.30500

Glycobiology. 2021 Jul 6:cwab072. doi: 10.1093/glycob/cwab072. Online ahead of print.

ABSTRACT

Galectin-3 (Gal-3), a β-galactoside binding lectin, has been implicated in a plethora of pathological disorders including fibrosis, inflammation, cancer, and metabolic diseases. TD139 - a thio-digalactoside inhibitor developed by Galecto Biotech as a potential therapeutic for idiopathic pulmonary fibrosis, is the most advanced small-molecule galectin-3 inhibitor in clinical studies. It binds to human Gal-3 with high affinity but has lower affinity towards mouse and rat homologs, which is also manifested in the differential inhibition of Gal-3 function. Using biophysical methods and high resolution X-ray co-crystal structures of TD139 and Gal-3 proteins, we demonstrate that a single amino acid change corresponding to A146 in human Gal-3 is sufficient for the observed reduction in the binding affinity of TD139 in rodents. Site-directed mutagenesis of A146V (in human Gal-3) & V160A (in mouse Gal-3) was sufficient to interchange the affinities, mainly by affecting the off rates of the inhibitor binding. Additionally, molecular dynamics simulations of both wild type and mutant structures revealed the sustained favorable non-covalent interactions between the fluorophenyl ring and the active site A146 (human Gal-3 and mouse V160A) that corroborate the finding from biophysical studies. Current findings have ramifications in the context of optimization of drug candidates against Gal-3.

PMID:34228782 | DOI:10.1093/glycob/cwab072

Thorax. 2021 Jul 5:thoraxjnl-2021-217377. doi: 10.1136/thoraxjnl-2021-217377. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterised by exuberant tissue remodelling and associated with high unmet medical needs. Outcomes are even worse when IPF results in secondary pulmonary hypertension (PH). Importantly, exaggerated resistance to cell death, excessive proliferation and enhanced synthetic capacity are key endophenotypes of both fibroblasts and pulmonary artery smooth muscle cells, suggesting shared molecular pathways. Under persistent injury, sustained activation of the DNA damage response (DDR) is integral to the preservation of cells survival and their capacity to proliferate. Checkpoint kinases 1 and 2 (CHK1/2) are key components of the DDR. The objective of this study was to assess the role of CHK1/2 in the development and progression of IPF and IPF+PH.

METHODS AND RESULTS: Increased expression of DNA damage markers and CHK1/2 were observed in lungs, remodelled pulmonary arteries and isolated fibroblasts from IPF patients and animal models. Blockade of CHK1/2 expression or activity-induced DNA damage overload and reverted the apoptosis-resistant and fibroproliferative phenotype of disease cells. Moreover, inhibition of CHK1/2 was sufficient to interfere with transforming growth factor beta 1-mediated fibroblast activation. Importantly, pharmacological inhibition of CHK1/2 using LY2606368 attenuated fibrosis and pulmonary vascular remodelling leading to improvement in respiratory mechanics and haemodynamic parameters in two animal models mimicking IPF and IPF+PH.

CONCLUSION: This study identifies CHK1/2 as key regulators of lung fibrosis and provides a proof of principle for CHK1/2 inhibition as a potential novel therapeutic option for IPF and IPF+PH.

PMID:34226205 | DOI:10.1136/thoraxjnl-2021-217377

Drug Deliv. 2021 Dec;28(1):1419-1431. doi: 10.1080/10717544.2021.1921073.

ABSTRACT

Glucocorticoid (GC) hormone has been commonly used to treat systemic inflammation and immune disorders. However, the side effects associated with long-term use of high-dose GC hormone limit its clinical application seriously. GC hormone that can specifically target the lung might decrease the effective dosage and thus reduce GC-associated side effects. In this study, we successfully prepared human lung-targeting liposomal methylprednisolone crosslinked with nanobody (MPS-NSSLs-SPANb). Our findings indicate that MPS-NSSLs-SPANb may reduce the effective therapeutic dosage of MPS, achieve better efficacy, and reduce GC-associated side effects. In addition, MPS-NSSLs-SPANb showed higher efficacy and lower toxicity than conventional MPS.

PMID:34223777 | DOI:10.1080/10717544.2021.1921073

Front Mol Biosci. 2021 Jun 16;8:681669. doi: 10.3389/fmolb.2021.681669. eCollection 2021.

ABSTRACT

The application of transbronchial lung cryobiopsy (TBLC) and uniportal and tubeless video-assisted thoracic surgery (UT-VATS) in the multidisciplinary diagnosis of interstitial lung disease (ILD) has not been demonstrated in real-world clinical practice. This prospective study included 137 patients with no definitive diagnosis who were the subject of two multidisciplinary discussion (MDD) sessions. As indicated in the first MDD, 67 patients underwent UT-VATS and 70 underwent TBLC. The specificity of biopsy information and its contribution to final MDD diagnosis were evaluated in the second MDD. The post-operative complications and hospitalization costs associated with the two biopsy methods were compared. UT-VATS was favored for patients initially diagnosed with idiopathic pulmonary fibrosis (IPF), bronchiolitis-associated interstitial lung disease (RB-ILD)/desquamative interstitial pneumonia (DIP) and undefined idiopathic interstitial pneumonia (UIIP), while TBLC was preferred for pulmonary lymphangioleiomyomatosis (PLAM) and pulmonary alveolar proteinosis (PAP). The spirometry parameters were better in patients who underwent UT-VATS than those who underwent TBLC. UT-VATS provided more specific pathological results than TBLC (85.7 vs 73.7%, p = 0.06). In patients initially diagnosed with UIIP, pathological information from UT-VATS was more clinically useful than that obtained from TBLC, although both tests contributed similarly to cases initially diagnosed as interstitial pneumonia with auto-immune features (IPAF)/connective tissue disease-related ILD (CTD-ILD). The safety of UT-VATS was comparable with TBLC although TBLC was cheaper during hospitalization (US$4,855.7 vs US$3,590.9, p < 0.001). multidisciplinary discussion decisions about biopsies were driven by current knowledge of sampling and diagnosis capacity as well as potential risks of different biopsy methods. The current MDD considered UT-VATS more informative than TBLC in cases initially diagnosed as UIIP although they were equally valuable in patients initially diagnosed with IPAF/CTD-ILD.

PMID:34222336 | PMC:PMC8241905 | DOI:10.3389/fmolb.2021.681669

Front Med (Lausanne). 2021 Jun 17;8:679487. doi: 10.3389/fmed.2021.679487. eCollection 2021.

ABSTRACT

Background: Comorbidities in idiopathic pulmonary fibrosis (IPF) affect quality of life, symptoms, disease progression and survival. It is unknown what are the comorbidities in patients with IPF in Latin America (LA) and if there are differences between countries. Our objective was to compare IPF comorbidities in four countries and analyze possible differences by altitude. Methods: Patients with IPF according 2012 ATS/ERS/JRS/ALAT guidelines, from two cities with an altitude of ≥2,250 m: Mexico City (Mexico) and Bogotá (Colombia) and from three at sea level: Buenos Aires (Argentina) and Lima and Trujillo (Peru). Comorbidities and pulmonary function tests were taken from clinical records. Possible pulmonary hypertension (PH) was defined by findings in the transthoracic echocardiogram of systolic pulmonary arterial pressure (sPAP) >36 mmHg or indirect signs of PH in the absence of other causes of PH. Emphysema as the concomitant finding of IPF criteria on chest tomography plus emphysema in the upper lobes. ANOVA or Kruskal Wallis and χ2-tests were used for comparison. Results: Two hundred and seventy-six patients were included, 50 from Argentina, 86 from Colombia, 91 from Mexico and 49 from Peru. There prevalence of PH was higher in Colombia and Mexico (p < 0.001), systemic arterial hypertension in Argentina (p < 0.015), gastro-esophageal reflux and dyslipidemia in Colombia and Argentina (p < 0.001) and diabetes mellitus in Mexico (p < 0.007). Other comorbidities were obesity (28.4%), coronary artery disease (15.2%) and emphysema (14.9%), with no differences between countries. There was more PH in the altitude cities than those at sea level (51.7 vs. 15.3%, p < 0.001). In patients from Bogotá and Mexico City, arterial oxygen pressure, saturation (p < 0.001) and carbon monoxide diffusing capacity (p = 0.004) were significantly lower than in cities at sea level. Conclusions: In this study with a significant number of patients, we were able to describe and compare the comorbidities of IPF in four LA countries, which contributes to the epidemiological data of this disease in the region. The main results were the differences in comorbidities between the countries and more PH in the subjects residing in the cities of higher altitude, a finding that should be validated in future studies.

PMID:34222287 | PMC:PMC8245671 | DOI:10.3389/fmed.2021.679487

Acta Pharm Sin B. 2021 Jun;11(6):1412-1433. doi: 10.1016/j.apsb.2020.12.003. Epub 2020 Dec 9.

ABSTRACT

Anoctamin 1 (ANO1) or TMEM16A gene encodes a member of Ca2+ activated Cl- channels (CaCCs) that are critical for physiological functions, such as epithelial secretion, smooth muscle contraction and sensory signal transduction. The attraction and interest in ANO1/TMEM16A arise from a decade long investigations that abnormal expression or dysfunction of ANO1 is involved in many pathological phenotypes and diseases, including asthma, neuropathic pain, hypertension and cancer. However, the lack of specific modulators of ANO1 has impeded the efforts to validate ANO1 as a therapeutic target. This review focuses on the recent progress made in understanding of the pathophysiological functions of CaCC ANO1 and the current modulators used as pharmacological tools, hopefully illustrating a broad spectrum of ANO1 channelopathy and a path forward for this target validation.

PMID:34221860 | PMC:PMC8245819 | DOI:10.1016/j.apsb.2020.12.003

Front Immunol. 2021 Jun 15;12:661811. doi: 10.3389/fimmu.2021.661811. eCollection 2021.

ABSTRACT

Fibrotic Interstitial lung diseases (ILDs) are complex disorders of variable clinical behaviour. The majority of them cause significant morbidity, whilst Idiopathic Pulmonary Fibrosis (IPF) is recognised as the most relentless. NLRP3, AIM2, and NLRC4 inflammasomes are multiprotein complexes driving IL-1β release; a proinflammatory and profibrotic cytokine. Several pathogenetic factors associated with IPF are identified as inflammasome activators, including increases in mtROS and bacterial burden. Mitochondrial oxidation and alterations in bacterial burden in IPF and other ILDs may lead to augmented inflammasome activity in airway macrophages (AMs). IPF (n=14), non-IPF-ILDs (n=12) patients and healthy subjects (n=12) were prospectively recruited and AMs were isolated from bronchoalveolar lavage. IL-1β release resulting from NLRP3, AIM2 and NLRC4 inflammasomes stimulation in AMs were determined and baseline levels of mitochondrial ROS and microbial burden were also measured. Our results showed that NLRP3 was more inducible in IPF and other ILDs compared to controls. Additionally, following AIM2 activation IL-1β release was significantly higher in IPF compared to controls, whereas similar trends were observed in Non-IPF-ILDs. NLRC4 activation was similar across groups. mtROS was significantly associated with heightened NLRP3 and AIM2 activation, and mitochondrial antioxidant treatment limited inflammasome activation. Importantly, microbial burden was linked to baseline IL-1β release and AIM2 and IL-18 relative expression independently of mtROS. In conclusion, the above findings suggested a link between the overactivation of NLRP3 and AIM2 inflammasomes, driven by mitochondrial oxidation, in the pathogenesis of lung fibrosis while changes in the microbiota may prime the inflammasome in the lungs.

PMID:34220810 | PMC:PMC8248801 | DOI:10.3389/fimmu.2021.661811

Acad Radiol. 2021 Jul 1:S1076-6332(21)00253-1. doi: 10.1016/j.acra.2021.05.014. Online ahead of print.

ABSTRACT

RATIONALE AND OBJECTIVES: High-resolution computed tomography (HRCT) is paramount in the assessment of interstitial lung disease (ILD). Yet, HRCT interpretation of ILDs may be hampered by inter- and intra-observer variability. Recently, artificial intelligence (AI) has revolutionized medical image analysis. This technology has the potential to advance patient care in ILD. We aimed to systematically evaluate the application of AI for the analysis of ILD in HRCT.

MATERIALS AND METHODS: We searched MEDLINE/PubMed databases for original publications of deep learning for ILD analysis on chest CT. The search included studies published up to March 1, 2021. The risk of bias evaluation included tailored Quality Assessment of Diagnostic Accuracy Studies and the modified Joanna Briggs Institute Critical Appraisal checklist.

RESULTS: Data was extracted from 19 retrospective studies. Deep learning techniques included detection, segmentation, and classification of ILD on HRCT. Most studies focused on the classification of ILD into different morphological patterns. Accuracies of 78%-91% were achieved. Two studies demonstrated near-expert performance for the diagnosis of idiopathic pulmonary fibrosis (IPF). The Quality Assessment of Diagnostic Accuracy Studies tool identified a high risk of bias in 15/19 (78.9%) of the studies.

CONCLUSION: AI has the potential to contribute to the radiologic diagnosis and classification of ILD. However, the accuracy performance is still not satisfactory, and research is limited by a small number of retrospective studies. Hence, the existing published data may not be sufficiently reliable. Only well-designed prospective controlled studies can accurately assess the value of existing AI tools for ILD evaluation.

PMID:34219012 | DOI:10.1016/j.acra.2021.05.014

Chest. 2021 Jul 1:S0012-3692(21)01279-4. doi: 10.1016/j.chest.2021.06.049. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease associated with significant morbidity and mortality. Nintedanib and pirfenidone are two antifibrotic medications currently approved for slowing the rate of lung function decline in IPF, but information on treatment effect on mortality and risk of acute exacerbation (AE) remains limited or unknown.

RESEARCH QUESTION: Does antifibrotic treatment decrease risk of mortality and AE?

STUDY DESIGN AND METHODS: A comprehensive search of several databases, including Ovid MEDLINE(R), Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus, was conducted. Studies were included if they were original articles comparing mortality or AE events in IPF patients with and without antifibrotic treatment. Relative risk (RR) with 95% confident interval (CI) was pooled using random-effects meta-analyses with inverse variance method, assessing two primary outcomes of all-cause mortality and acute exacerbation (AE) risk.

RESULTS: A total of 12,956 patients across 26 studies (8 randomized controlled trials and 18 cohort studies) were included in the meta-analysis. Antifibrotic treatment was associated with decreased risk of all-cause mortality with a pooled RR 0.55 (95% CI, 0.45-0.66) and I2 of 82%. This effect was consistent across additional subgroup analyses, including stratification by study type, risk of bias, duration of follow-up, and antifibrotic subtype. Antifibrotic treatment also reduced the risk of AE, with a pooled RR of 0.63 (95% CI, 0.53-0.76), and I2 of 0%. Effect on AE risk was consistent across subgroup analyses by study type and for nintedanib but not for pirfenidone.

INTERPRETATION: Antifibrotic treatment appears to reduce the risk of all-cause mortality and AE in IPF. Despite greater heterogeneity with pooled analysis, its effect was robust in subgroup analyses by study type, duration of follow-up, and antifibrotic subtype.

PMID:34217681 | DOI:10.1016/j.chest.2021.06.049

Orphanet J Rare Dis. 2021 Jul 3;16(1):298. doi: 10.1186/s13023-021-01926-x.

ABSTRACT

BACKGROUND: Bronchoalveolar lavage (BAL) is one of the fundamental examinations for the differential diagnosis of interstitial lung diseases (ILDs), and lymphocytosis strongly indicates alternative diagnoses rather than idiopathic pulmonary fibrosis. However, the BALF lymphocytosis is observed in several ILDs. We considered that quantitative evaluation of the BALF lymphocyte nuclear morphology would be useful in the differential diagnosis of ILDs with increased BALF lymphocyte fraction.

RESULTS: One hundred and twenty-one patients with ILDs having increased BALF lymphocyte fraction were recruited (68 in the development cohort and 53 in the validation cohort). In the development cohort, BALF lymphocyte nuclei in sarcoidosis patients showed significantly smaller areas, shorter perimeters, lower radius ratios, and increased roundness than those of other ILD patients (p < 0.001 for each). Next, the fractions of lymphocytes with small areas, short perimeters, low radius ratios, and increased roundness, which were determined based on receiver operating characteristic (ROC) analyses-based thresholds, were demonstrated to be higher in sarcoidosis patients than in the other ILD patients (p < 0.001 for each). Furthermore, when we combined size-representing parameters with shape-representing parameters, the fraction of lymphocytes with small and round nuclei showed approximately 0.90 of area under the ROC curve in discriminating sarcoidosis both in the development cohort and the validation cohort.

CONCLUSION: This study is the first to demonstrate the usefulness of quantitative parameters of BALF lymphocyte nuclear morphology as novel biomarkers for sarcoidosis.

PMID:34217348 | DOI:10.1186/s13023-021-01926-x

Acta Histochem. 2021 Jun 30;123(5):151746. doi: 10.1016/j.acthis.2021.151746. Online ahead of print.

ABSTRACT

The precise etiology and pathogenesis of idiopathic pulmonary fibrosis are not completely understood, and no satisfactory treatment exists. This work aimed to examine the effects of calycosin (CA, an isoflavone compound) on pulmonary fibrosis (PF) and explore the underlying mechanism. In this study, we established a mice model of PF induced by 5 mg/mL bleomycin (BLM), and mice were orally administrated with 7 mg/kg or 14 mg/kg CA once a day for three weeks. In vitro, after pretreated with 80 μM CA, MLE-12 cells were stimulated with 10 ng/mL transforming growth factor-β1 (TGF-β1) for inducing epithelial-mesenchymal transition (EMT). The results showed that CA treatment ameliorated the severity of fibrosis and the lung tissue damage, as well as suppressed the secretion of inflammation factors in a dose-dependent manner of the PF mice model induced by BLM. Subsequently, CA inhibited the BLM-induced PF progression by repressing EMT, evidenced by the reverse of the downregulation of E-cadherin and the upregulation of vimentin, α-SMA, and fibronectin. Moreover, the elevated phosphorylation of AKT and GSK3β induced by BLM (or TGF-β1) was decreased by CA treatment, leading to the rescue of the high expression of β-catenin. CA prevented the translocation of β-catenin from the cytoplasm to the nucleus. The repressed effects of CA on the TGF-β1-induced EMT and the AKT/GSK3β/β-catenin axis, as well as the translocation of β-catenin were all reversed by a AKT activator SC79. Taken together, CA ameliorated PF by the EMT inhibition upon suppressing the AKT/GSK3β/β-catenin signaling pathway.

PMID:34217047 | DOI:10.1016/j.acthis.2021.151746

South Med J. 2021 Jul;114(7):424-431. doi: 10.14423/SMJ.0000000000001275.

ABSTRACT

OBJECTIVES: Obesity can be an independent predictor of fibrosis in tissues, including the liver, heart, and skin. We evaluated a rural Appalachian cohort of idiopathic pulmonary fibrosis (IPF) for its relation to obesity.

METHODS: Using American Thoracic Society 2018 diagnostic guidelines, an IPF cohort was systematically identified at an Appalachian academic medical center (2015-2019). The cohort was categorized in subgroups of body mass index (BMI) <30 or BMI ≥30 kg/m2. Demographics, clinical variables, and treatment details were collected retrospectively and evaluated for their associations with obesity.

RESULTS: In our IPF cohort (N = 138), a usual interstitial pneumonia pattern was less prevalent in the obese group (n = 49) relative to the nonobese group (69% vs 85%, respectively). The obese group was younger (mean age 73.27 ± 9.12 vs 77.97 ± 9.59 years) and had a higher prevalence of hypertension (90% vs 72%), hyperlipidemia (83% vs 68%), diabetes mellitus (47% vs 25%), sleep-disordered breathing (47% vs 25%), chronic pain disorders (28% vs 15%), and deep vein thrombosis (19% vs 7%). An increased proportion of obese-IPF patients was seen at a tertiary or an interstitial lung disease center, with more surgical lung biopsies performed and incident diagnosis (ie, within 6 months of presentation) assigned. Only a minority of patients underwent lung transplantation (3.6%), all of them from the obese-IPF subgroup. Approximately 30% of the total IPF cohort died, with a lower mortality observed in the obese group (35% vs 20%, P = 0.017). An increasing BMI predicted a better survival in the total IPF cohort (BMI 25-29.9, 20-24.9, and <20 had mortality rates of 20%, 47%, and 75%, respectively; P < 0.001).

CONCLUSIONS: Our study represents a first known effort to develop an IPF cohort in a rural Appalachian region. Although they shared an increased burden of comorbidities, the obese subgroup showed less advanced fibrosis with a lower mortality rate relative to nonobese subgroup, suggesting a potential "obesity paradox" in IPF. The study findings significantly advance our understanding of challenges posed by IPF in a rural population that also suffers from an alarming rate of obesity. We highlight the need for the multidisciplinary management of these patients and prospective studies to better define this complex relation.

PMID:34215896 | DOI:10.14423/SMJ.0000000000001275