Br J Pharmacol. 2021 Mar 30. doi: 10.1111/bph.15467. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: TGFβ1-mediated myofibroblast activation contributes to pathological fibrosis in many diseases including idiopathic pulmonary fibrosis (IPF), where myofibroblast resistance to oxidant-mediated apoptosis is also evident. We therefore investigated the involvement of redox-sensitive TRPA1 ion channels in human lung myofibroblast (HLMF) cell death and TGFβ1-mediated pro-fibrotic responses.

EXPERIMENTAL APPROACH: We studied HLMFs derived from IPF patients and non-fibrotic patient controls, looking at the effect of TGFβ1 stimulation on TRPA1 expression and cell death sensitivity. We also examined a human lung model of TGFβ1-dependent fibrogenesis.

KEY RESULTS: We found that TRPA1 mRNA, protein and ion currents were expressed in HLMFs derived from both non-fibrotic patient controls and IPF patients, and expression was reduced by TGFβ1. TRPA1 mRNA was also downregulated by TGFβ1 in a human model of lung fibrogenesis. TRPA1 over-expression or activation induced HLMF apoptosis, and TRPA1 activation by H2 O2 induced necrosis. TRPA1 inhibition resulting from TGFβ1 downregulation or pharmacological inhibition protected HLMFs from both apoptosis and necrosis. Lentiviral vector mediated TRPA1 expression was also found to induce sensitivity to H2 O2 induced cell death in a TRPA1-negative HEK293T cell line.

CONCLUSION AND IMPLICATIONS: TGFβ1 induces resistance of HLMFs to TRPA1 agonist- and H2 O2 -mediated cell death via downregulation of TRPA1. Our data suggest that therapeutic strategies which prevent TGFβ1-dependent downregulation of TRPA1 may reduce myofibroblast survival in IPF and therefore improve clinical outcomes.

PMID:33786825 | DOI:10.1111/bph.15467

Respiration. 2021 Mar 30:1-13. doi: 10.1159/000514320. Online ahead of print.

ABSTRACT

BACKGROUND: In patients with idiopathic pulmonary fibrosis (IPF) with isolated exertional desaturation, there are limited data regarding the effectiveness of oxygen supplementation during exercise training; the underlying mechanisms that contribute to these responses are unknown.

OBJECTIVES: To examine in these IPF patients the effects of oxygen supplementation during submaximal exercise (vs. medical air) on cerebral/skeletal muscle oxygenation and systemic hemodynamics.

METHODS: In this randomized, cross-over, placebo-controlled trial, IPF patients (n = 13; 63.4 ± 9.6 years) without resting hypoxemia but a significant desaturation during maximal cardiopulmonary exercise testing underwent 2 steady-state exercise trials (65% peak-work-load), breathing either oxygen-enriched or medical air. Cerebral/skeletal muscle oxygenation (near-infrared spectroscopy) and beat-by-beat hemodynamics (photoplethysmography) were monitored.

RESULTS: In the air protocol, from the initial minutes of submaximal exercise, patients exhibited a marked decline in cerebral oxygenated hemoglobin (O2Hb) and an abrupt rise in deoxygenated hemoglobin (HHb). Oxygen supplementation alleviated desaturation, lessened dyspnea, and prolonged exercise duration (p < 0.01). Oxygen supplementation during exercise (i) attenuated cerebral deoxygenation (cerebral-HHb: 0.7 ± 1.9 vs. 2.5 ± 1.5 μmol/L, O2 and air protocol; p = 0.009) and prevented cerebral-Hbdifference decline (2.1 ± 2.7 vs. -1.7 ± 2.0 μmol/L; p = 0.001), (ii) lessened the decline in muscle O2-saturation index, and (iii) at isotime exercise, it resulted in lower muscle-HHb (p = 0.05) and less leg fatigue (p < 0.05). No differences between protocols were observed in exercise cardiac output and vascular resistance.

CONCLUSIONS: IPF patients with isolated exertional hypoxemia exhibit an inability to increase/maintain cerebral oxygenation during submaximal exercise. Correcting desaturation with O2 supplementation prevented the decline in brain oxygenation, improved muscle oxygenation, and lessened dyspnea, suggesting an efficacy of acute oxygen supplementation during exercise training in protecting brain hypoxia in these IPF patients.

PMID:33784706 | DOI:10.1159/000514320

Am J Respir Crit Care Med. 2021 Mar 30. doi: 10.1164/rccm.202008-3100OC. Online ahead of print.

ABSTRACT

RATIONALE: The receptor-like protein tyrosine phosphatase eta (CD148/PTPRJ) exerts anti-fibrotic effects in experimental pulmonary fibrosis via interactions with its ligand syndecan-2; however, the role of CD148 in human pulmonary fibrosis remains incompletely characterized.

OBJECTIVES: We investigated the role of CD148 in the profibrotic phenotype of fibroblasts in idiopathic pulmonary fibrosis (IPF).

METHODS: Conditional CD148 fibroblast-specific knockout mice were generated and exposed to bleomycin, and then assessed for pulmonary fibrosis. Lung fibroblasts (mouse lung, and human IPF lung), and precision cut lung slices (PCLS) from human IPF patients were isolated and subjected to experimental treatments. A CD148-activating 18-aa mimetic peptide (SDC2-pep) derived from syndecan-2 was evaluated for its therapeutic potential.

MEASUREMENTS AND MAIN RESULTS: CD148 expression was downregulated in IPF lungs and fibroblasts. In human IPF lung fibroblasts, silencing of CD148 increased extracellular matrix production and resistance to apoptosis, whereas overexpression of CD148 reversed the profibrotic phenotype. CD148 fibroblast-specific knockout mice displayed increased pulmonary fibrosis after bleomycin challenge compared to control mice. CD148-deficient fibroblasts exhibited hyperactivated PI3K/Akt/mTOR signaling, reduced autophagy and increased p62 accumulation, which induced NF-kB activation and profibrotic gene expression. SDC2-pep reduced pulmonary fibrosis in vivo, and inhibited IPF-derived fibroblast activation. In PCLS from IPF and control patients, SDC2-pep attenuated profibrotic gene expression in IPF and normal lungs stimulated with pro-fibrotic stimuli.

CONCLUSIONS: Lung fibroblast CD148 activation reduces p62 accumulation, which exerts anti-fibrotic effects by inhibiting NF-kB mediated profibrotic gene expression. Targeting the CD148 phosphatase with activating ligands such as SDC2-pep may represent a potential therapeutic strategy in IPF.

PMID:33784491 | DOI:10.1164/rccm.202008-3100OC

Thorac Cancer. 2021 Mar 30. doi: 10.1111/1759-7714.13924. Online ahead of print.

ABSTRACT

Lung cancer (LC) is the most fatal complication of idiopathic pulmonary fibrosis (IPF). However, the molecular pathogenesis of the development of LC from IPF is still unclear. Here, we report a case of IPF-associated LC for which we investigated the genetic alterations between IPF and LC. We extracted formalin-fixed paraffin-embedded DNA from each part of the surgical lung tissue using a laser-assisted microdissection technique. The mutations in each part were detected by next-generation sequencing (NGS) using 72 lung cancer-related mutation panels. Five mutations were found in IPF and four in LC. Almost all somatic mutations did not overlap between the IPF and LC regions. These findings suggest that IPF-associated LC may not be a result of the accumulation of somatic mutations in the regenerated epithelium of the honeycomb lung in the IPF region.

PMID:33784423 | DOI:10.1111/1759-7714.13924

Ther Adv Respir Dis. 2021 Jan-Dec;15:17534666211004238. doi: 10.1177/17534666211004238.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease characterized by worsening dyspnea and lung function and has a median survival of 2-3 years. Forced vital capacity (FVC) is the primary endpoint used most commonly in IPF clinical trials as it is the best surrogate for mortality. This study assessed quantitative scores from high-resolution computed tomography (HRCT) developed by machine learning as a secondary efficacy endpoint in a 26-week phase II study of BMS-986020 - an LPA1 receptor antagonist - in patients with IPF.

METHODS: HRCT scans from 96% (137/142) of randomized subjects were utilized. Quantitative lung fibrosis (QLF) scores were calculated from the HRCT images. QLF improvement was defined as ⩾2% reduction in QLF score from baseline to week 26.

RESULTS: In the placebo arm, 5% of patients demonstrated an improvement in QLF score at week 26 compared with 15% and 27% of patients in the BMS-986020 600 mg once daily (QD) and twice daily (BID) arms, respectively [versus placebo: p = 0.08 (600 mg QD); p = 0.0098 (600 mg BID)]. Significant correlations were found between changes in QLF and changes in percent predicted FVC, diffusing capacity for carbon monoxide (DLCO), and shortness of breath at week 26 (ρ = -0.41, ρ = -0.22, and ρ = 0.27, respectively; all p < 0.01).

CONCLUSIONS: This study demonstrated the utility of quantitative HRCT as an efficacy endpoint for IPF in a double-blind, placebo-controlled clinical trial setting.The reviews of this paper are available via the supplemental material section.

PMID:33781141 | DOI:10.1177/17534666211004238

Environ Sci Pollut Res Int. 2021 Mar 29. doi: 10.1007/s11356-021-13559-5. Online ahead of print.

ABSTRACT

Particulate matters (PMs) are significant components of air pollution in the urban environment. PMs with aerodynamic diameter less than 2.5 μm (PM2.5) can penetrate to the alveolar area and introduce numerous compounds to the pneumocystis that can initiate inflammatory response. There are several questions about this exposure as follows: does PM2.5-induced inflammation lead to a specific disease? If yes, what is the form of the progressed disease? This systematic review was designed and conducted to respond to these questions. Four databases, including Web of Science, Scopus, PubMed, and Embase, were reviewed systematically to find the related articles. According to the included articles, the only available data on the inflammatory effects of PM2.5 comes from either in vitro or animal studies. Both types of studies have shown that the induced inflammation is type I and includes secretion of proinflammatory cytokines. The exposure duration of longer than 28 weeks was not observed in any of the reviewed studies. However, as there is not a specific antigenic component in the urban particulate matters and based on the available evidence, the antigen-presenting is not a common process in the inflammatory responses to PM2.5. Therefore, neither signaling to repair cells such as fibroblasts nor over-secretion of extracellular matrix (ECM) proteins can occur following PM2.5-induced inflammation. These pieces of evidence weaken the probability of the development of fibrotic diseases. On the other hand, permanent inflammation induces the destruction of ECM and alveolar walls by over-secretion of protease enzymes and therefore results in progressive obstructive effects.

PMID:33779901 | DOI:10.1007/s11356-021-13559-5

Radiol Cardiothorac Imaging. 2021 Feb 25;3(1):e200279. doi: 10.1148/ryct.2021200279. eCollection 2021 Feb.

ABSTRACT

Imaging serves a key role in the diagnosis of patients suspected of having idiopathic pulmonary fibrosis (IPF). Accurate pattern classification at thin-section chest CT is a key step in multidisciplinary discussions, guiding the need for surgical lung biopsy and determining available pharmacologic therapies. The recent approval of new treatments for fibrosing lung disease has made it more critical than ever for radiologists to facilitate accurate and early diagnosis of IPF. This document was developed by the Radiology Working Group of the Pulmonary Fibrosis Foundation with the goal of providing a practical guide for radiologists. In this review, the critical imaging patterns of IPF, pitfalls in imaging classifications, confounding imaging findings with other fibrotic lung diseases, and reporting standards for cases of lung fibrosis will be discussed. Published under a CC BY 4.0 license. See also the commentary by White and Galvin in this issue.

PMID:33778653 | PMC:PMC7977697 | DOI:10.1148/ryct.2021200279

Radiol Cardiothorac Imaging. 2020 Jun 25;2(3):e200003. doi: 10.1148/ryct.2020200003. eCollection 2020 Jun.

NO ABSTRACT

PMID:33778586 | PMC:PMC7977694 | DOI:10.1148/ryct.2020200003

Am J Ophthalmol Case Rep. 2021 Mar 11;22:101056. doi: 10.1016/j.ajoc.2021.101056. eCollection 2021 Jun.

ABSTRACT

PURPOSE: Tacrolimus is a commonly used immunosuppressant medication after lung transplantation. In rare cases, tacrolimus causes a medication-induced optic neuropathy (TON) that can lead to significant vision loss.

OBSERVATIONS: In this series, we describe three cases of TON, 1-10 years after medication use. Two patients were young (22yr and 33yr) females with cystic fibrosis. The last case was a 65yr male with idiopathic pulmonary fibrosis. In 2/3 cases tacrolimus serum levels were normal. Visual acuity ranged from 20/20 to 20/300, and vision loss occurred acutely to sub-acutely, over a span of 2-3 months.

CONCLUSIONS AND IMPORTANCE: As presented here, TON can be highly variable. MRI findings are often non-specific, from normal brain findings to extensive white matter changes. There remains an unclear association with graft-versus-host disease and reduced kidney function. Visual findings are often subtle, including color vision aberration and peripheral visual field deficits, both of which usually require an ophthalmologic evaluation. When diagnosed in a timely fashion, TON is at least partially reversible in up to half of all cases. While rare, the cases described here support post-lung transplant ophthalmologic evaluation in those taking high-risk medications.

PMID:33778180 | PMC:PMC7985716 | DOI:10.1016/j.ajoc.2021.101056

Front Cell Dev Biol. 2021 Mar 12;9:651913. doi: 10.3389/fcell.2021.651913. eCollection 2021.

ABSTRACT

OBJECTIVE: Recent studies were widely concerned about the role of lncRNAs in hypoxic pulmonary hypertension (HPH). HAS2 was found significantly highly expressed in HPH, but the antisense of HAS2 (HAS2-AS1) has not been explored in HPH, providing a new potential therapeutic target of HPH.

METHODS: In this study, human fetal lung fibroblast-1 (HFL-1) cells were cultured under hypoxia conditions to stimulate the pathological process of HPH. Transwell and wound-healing assays were used to detect HFL-1 cell migration, and CCK 8 assay was used to detect cell proliferation. The upstream transcription factor of HAS2-AS1 was predicted by JASPAR website, and the binding site between C/EBPβ and HAS2-AS1 was predicted by JASPAR, too. In order to verify the association between C/EBPβ and the HAS2 promoter region, we used chromatin immunoprecipitation (ChIP) and dual luciferase reporter gene detection, western blot to detect the expression of inflammation-related proteins, and qRT-PCR to detect the expression of HAS2-AS1 and HAS2. Idiopathic pulmonary fibrosis (IPF) with HPH patient microarray data was downloaded from the GEO database and analyzed by R software.

RESULTS: Our study showed that HAS2-AS1 and C/EBPβ were highly expressed in hypoxic HFL-1 cells, and the knockdown of HAS2-AS1 expression could inhibit the proliferation, migration, and inflammatory response of HFL-1 cells. C/EBPβ binds to the promoter region of HAS2-AS1 and has a positive regulation effect on the transcription of HAS2-AS1. Furthermore, C/EBPβ can regulate the proliferation, migration, and inflammatory response of HFL-1 cells through HAS2-AS1.

CONCLUSION: This study suggested that C/EBPβ could upregulate HAS2-AS1 expression and induce HFL-1 cell proliferation, migration, and inflammation response.

PMID:33777961 | PMC:PMC7994614 | DOI:10.3389/fcell.2021.651913

Comput Struct Biotechnol J. 2021 Mar 23. doi: 10.1016/j.csbj.2021.03.023. Online ahead of print.

ABSTRACT

Susceptibility to severe illness from COVID-19 is anticipated to be associated with cigarette smoking as it aggravates the risk of cardiovascular and respiratory illness, including infections. This is particularly important with the advent of a new strain of coronaviruses, the severe acute respiratory syndrome coronavirus (SARS-CoV-2) that has led to the present pandemic, coronavirus disease 2019 (COVID-19). Although, the effects of smoking on COVID-19 are less described and controversial, we presume a link between smoking and COVID-19. Smoking has been shown to enhance the expression of the angiotensin-converting enzyme-2 (ACE-2) and transmembrane serine protease 2 (TMPRSS2) key entry genes utilized by SARS-CoV-2 to infect cells and induce a 'cytokine storm', which further increases the severity of COVID-19 clinical course. Nevertheless, the impact of smoking on ACE-2 and TMPRSS2 receptors expression remains paradoxical. Thus, further research is necessary to unravel the association between smoking and COVID-19 and to pursue the development of potential novel therapies that are able to constrain the morbidity and mortality provoked by this infectious disease. Herein we present a brief overview of the current knowledge on the correlation between smoking and the expression of SARS-CoV-2 key entry genes, clinical manifestations, and disease progression.

PMID:33777332 | PMC:PMC7985684 | DOI:10.1016/j.csbj.2021.03.023

Biomed Pharmacother. 2021 Mar 25;138:111475. doi: 10.1016/j.biopha.2021.111475. Online ahead of print.

ABSTRACT

The purpose of this study was to investigate the antifibrotic effect and anticoagulant ability of salvianolic acid B (SAB) inhalation solution on bleomycin (BLM)-induced idiopathic pulmonary fibrosis (IPF) in rats. We investigated how the osmotic pressure and concentration of SAB in an aerosol exerted effects. We also determined the aerodynamic particle size distribution and the uniformity of the delivery dose; these parameters were found to be suitable for inhalation. Compared with BLM group, the levels of hydroxyproline (HYP), collagen-1 (Col-1), tissue factor (TF) / coagulation factor VII (TF-VIIa), activated coagulation factor X (FXa), thrombin-antithrombin complex (TAT), fibrinogen degradation product (FDP) and plasminogen activator inhibitor-1 (PAI-1) decreased in SAB group. The increased expression of coagulation factor Ⅱ (FⅡ), coagulation factor X (FX), tissue type plasminogen activator (t-PA) and urokinase type plasminogen activator (u-PA) proved that SAB has obvious antifibrotic and anticoagulant effects. Western blotting and immunofluorescence further showed that compared with the BLM group, the SAB group of rats exhibited significant reductions in the expression levels of protease-activated receptors-1 (PAR-1) and phospho-protein kinase C (p-PKC) and increased expression levels of protein kinase C (PKC) in lung tissue. Furthermore, SAB reduced the infiltration of lymphocytes and neutrophils, protected the basic structure of the lung from destruction, inhibited the proliferation of fibrous tissue. Collectively, our data revealed that SAB may exert its antifibrotic and anticoagulant effects by preventing the expression of PAR-1 and phosphorylation of PKC.

PMID:33774314 | DOI:10.1016/j.biopha.2021.111475

Pharmacol Ther. 2021 Mar 24:107839. doi: 10.1016/j.pharmthera.2021.107839. Online ahead of print.

ABSTRACT

Structural changes involving tissue remodelling and fibrosis are major features of many pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Abnormal deposition of extracellular matrix (ECM) proteins is a key factor in the development of tissue remodelling that results in symptoms and impaired lung function in these diseases. Tissue remodelling in the lungs is complex and differs between compartments. Some pathways are common but tissue remodelling around the airways and in the parenchyma have different morphologies. Hence it is critical to evaluate both common fibrotic pathways and those that are specific to different compartments; thereby expanding the understanding of the pathogenesis of fibrosis and remodelling in the airways and parenchyma in asthma, COPD and IPF with a view to developing therapeutic strategies for each. Here we review the current understanding of remodelling features and underlying mechanisms in these major respiratory diseases. The differences and similarities of remodelling are used to highlight potential common therapeutic targets and strategies. One central pathway in remodelling processes involves transforming growth factor (TGF)-β induced fibroblast activation and myofibroblast differentiation that increases ECM production. The current treatments and clinical trials targeting remodelling are described, as well as potential future directions. These endeavours are indicative of the renewed effort and optimism for drug discovery targeting tissue remodelling and fibrosis.

PMID:33774068 | DOI:10.1016/j.pharmthera.2021.107839

Cell Death Dis. 2021 Mar 26;12(4):327. doi: 10.1038/s41419-021-03603-0.

ABSTRACT

The endothelial-to-mesenchymal transition (EndMT) is an important source of fibrotic cells in idiopathic pulmonary fibrosis (IPF). However, how endothelial cells (ECs) are activated and how EndMT impact IPF remain largely elusive. Here, we use unsupervised pseudotemporal analysis to recognize the heterogeneity of ECs and reconstruct EndMT trajectory of bleomycin (BLM)-treated Tie2creER/+;Rosa26tdTomato/+ IPF mice. Genes like C3ar1 and Lgals3 (protein name galectin-3) are highly correlated with the transitional pseudotime, whose expression is gradually upregulated during the fate switch of ECs from quiescence to activation in fibrosis. Inhibition of galectin-3 via siRNA or protein antagonists in mice could alleviate the pathogenesis of IPF and the transition of ECs. With the stimulation of human pulmonary microvascular endothelial cells (HPMECs) by recombinant proteins and/or siRNAs for galectin-3 in vitro, β-catenin/GSK3β signaling and its upstream regulator AKT are perturbed, which indicates they mediate the EndMT progress. These results suggest that EndMT is essential to IPF process and provide potential therapeutic targets for vascular remodeling.

PMID:33771973 | DOI:10.1038/s41419-021-03603-0

BMJ Open Respir Res. 2021 Mar;8(1):e000782. doi: 10.1136/bmjresp-2020-000782.

ABSTRACT

BACKGROUND: Pirfenidone and nintedanib are the only disease-modifying treatments available for idiopathic pulmonary fibrosis (IPF). Our aim was to test their effectiveness and safety in clinical practice.

METHODS: This is a single-centre retrospective observational study undertaken at a specialised interstitial lung disease centre in England. Data including progression-free survival (PFS), mortality and drug tolerability were compared between patients with IPF on antifibrotic therapies and an untreated control group who had a forced vital capacity percentage (FVC %) predicted within the licensed antifibrotic treatment range.

RESULTS: 104 patients received antifibrotic therapies and 64 control patients were identified. PFS at 6 months was significantly greater in the antifibrotic group (75.0%) compared with the control group (56.3%) (p=0.012). PFS was not significant at 12 or 18 months when comparing the antifibrotic group with the control group. The 12-month post-treatment mean decline in FVC % predicted (-4.6±6.2%) was significantly less than the 12-month pretreatment decline (-10.4±11.8%) (p=0.039). The 12-month mortality rate was not significantly different between the antifibrotic group (25.3%) and the control group (35.5%) (p=0.132). Baseline Body Mass Index of≤25, baseline diffusion capacity for carbon monoxide percentage predicted of ≤35 and antifibrotic discontinuation within 3 months were independent predictors of 12-month mortality. Antifibrotic discontinuation was significantly higher by 3 and 6 months for patients on pirfenidone than those on nintedanib (p=0.006 and p=0.044, respectively). Discontinuation at 12 months was not significantly different (p=0.381).

CONCLUSIONS: This real-world study revealed that antifibrotics are having promising effects on PFS, lung function and mortality. These findings may favour commencement of nintedanib as first-line antifibrotic therapy, given the lower rates of early treatment discontinuation, although further studies are required to investigate this.

PMID:33771813 | DOI:10.1136/bmjresp-2020-000782

Lung. 2021 Mar 26. doi: 10.1007/s00408-021-00434-w. Online ahead of print.

ABSTRACT

PURPOSE: To evaluate the association of peripheral blood (PBL) and broncho-alveolar lavage (BAL) biomarkers with inflammatory versus fibrotic high-resolution computed tomography (HRCT) findings in interstitial lung disease (ILD) patients.

METHODS: HRCT findings of 127 consecutive ILD-board patients were semi-quantitatively evaluated: reticulation/honeycombing (RET), traction bronchiectasis (TBR) and emphysema (EMP) were classified as non-inflammatory/fibrotic; consolidations (CON), ground glass opacities (GGO), parenchymal nodules (NDL) and mosaic attenuation (MOS) as active inflammatory. Each HRCT finding was assessed in six distinct lung regions, resulting scores were graded as minimal (0-1 regions involved), medium (2-4) or extensive (5-6). Associations of routinely assessed PBL/BAL biomarkers with these HRCT scores were evaluated using Spearman correlation coefficients and graphical presentation; significance was tested by applying Kruskal-Wallis tests.

RESULTS: Blood neutrophil, lymphocyte and eosinophil fraction, neutrophil to lymphocyte ratio (NLR) and BAL lymphocyte fraction consistently showed opposite correlations with inflammatory versus non-inflammatory/fibrotic HRCT finding scores. Blood lymphocyte fraction significantly differed by graded GGO (p = 0.032) and CON (p = 0.027) extent, eosinophil fraction by TBR (p = 0.006) and NLR by CON (p = 0.009). C-reactive protein was significantly related to GGO (p = 0.023) and CON (p = 0.004), BAL lymphocyte fraction to GGO (p = 0.017) extent.

CONCLUSION: Blood lymphocyte and eosinophil fraction, NLR, CRP and BAL lymphocyte fraction may aid to differentiate inflammatory from non-inflammatory/fibrotic ILD patterns.

TRIAL REGISTRATION: This evaluation was based on data from the ILD registry of Kepler University Hospital Linz, as approved by the ethics committee of the Federal State of Upper-Austria (EK Number. I-26-17).

PMID:33770227 | DOI:10.1007/s00408-021-00434-w

Lung. 2021 Mar 26. doi: 10.1007/s00408-021-00440-y. Online ahead of print.

ABSTRACT

PURPOSE: The differential diagnosis of interstitial lung diseases (ILDs), particularly idiopathic pulmonary fibrosis (IPF) versus other non-IPF ILDs, is important for selecting the appropriate treatment. This retrospective study aimed to explore the utility of gremlin-1 for the differential diagnosis.

METHODS: Serum gremlin-1 concentrations were measured using an ELISA in 50 patients with IPF, 42 patients with non-IPF ILD, and 30 healthy controls. The baseline clinical data, including pulmonary functions, prognosis, and three serum biomarkers (Krebs von den Lungen-6 [KL6], surfactant protein-D [SP-D], and lactate dehydrogenase [LDH]), were obtained through a medical record review for analyzing their associations with serum gremlin-1 concentrations. To evaluate the origin of gremlin-1, we performed immunostaining on lung sections.

RESULTS: Serum gremlin-1 concentrations were significantly higher in patients with IPF (mean concentration, 14.4 ng/mL), followed by those with non-IPF ILD (8.8 ng/mL) and healthy controls (1.6 ng/mL). The area under the curve for IPF versus non-IPF ILDs was 0.759 (95% confidence interval, 0.661-0.857), which was superior to that of KL6/SP-D/LDH. The sensitivity and specificity for gremlin-1 (cutoff, 10.4 ng/mL) was 72 and 69%, respectively. By contrast, serum gremlin-1 concentrations were not associated with the pulmonary functions nor the prognosis in all patients with ILDs. In immunostaining, the gremlin-1 was broadly upregulated in IPF lungs, particularly at myofibroblasts, bronchiolar/alveolar epithelium, and CD163-positive M2-like macrophages.

CONCLUSIONS: Gremlin-1 may be a useful biomarker to improve the diagnostic accuracy for IPF compared to non-IPF ILDs, suggesting a role of this molecule in the pathogenesis of IPF.

PMID:33770226 | DOI:10.1007/s00408-021-00440-y

Br J Nurs. 2021 Mar 25;30(6):359-366. doi: 10.12968/bjon.2021.30.6.359.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive incurable lung disease that affects a significant amount of people in the UK. Many health professionals have a limited understanding of IPF, which can result in a delayed diagnosis and inadequate care for individuals and their families. This article aims to provide an overview of IPF and help to enhance health professionals' understanding of the disease, thus contributing towards improving the care that IPF sufferers receive. This article provides a definition of IPF and explores its pathophysiology. It discusses the causes and risk factors for developing the condition, examines how IPF is diagnosed and details the treatment options available for IPF patients.

PMID:33769879 | DOI:10.12968/bjon.2021.30.6.359

Front Cell Dev Biol. 2021 Mar 9;9:639657. doi: 10.3389/fcell.2021.639657. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an interstitial disease of unknown etiology characterized by progressive pulmonary fibrosis. Pirfenidone and nintedanib are the only drugs that can prolong the time to disease progression, slow down the decline in lung function, and prolong survival. However, they do not offer a cure and are associated with tolerability issues. The pluripotency of mesenchymal stem cells (MSCs) and their ability to regulate immunity, inhibit inflammation, and promote epithelial tissue repair highlight the promise of MSC therapy for treating interstitial lung disease. However, optimal protocols are lacking for multi-parameter selection in MSC therapy. This review summarizes preclinical studies on MSC transplantation for the treatment of interstitial lung disease and clinical studies with known results. An analysis of relevant factors for the optimization of treatment plans is presented, including MSCs with different sources, administration routes and timing, dosages, frequencies, and pretreatments with MSCs. This review proposes an optimized plan for guiding the design of future clinical research to identify therapeutic options for this complex disease.

PMID:33768094 | PMC:PMC7985078 | DOI:10.3389/fcell.2021.639657

Eur Respir J. 2021 Mar 25:2100172. doi: 10.1183/13993003.00172-2021. Online ahead of print.

ABSTRACT

OBJECTIVE: Circulating fibrocytes are elevated in idiopathic pulmonary fibrosis, but the relationship between fibrocyte level with lung function decline and outcomes is lacking replication in prospective clinical study. We aim to validate the utility of circulating fibrocyte levels as a prognostic biomarker in idiopathic pulmonary fibrosis.

METHODS: We tested associations between circulating fibrocyte levels, mortality, disease progression and longitudinal lung function in a well-defined prospective observational study of pulmonary fibrosis (PROFILE; NCT01134822). A subset of recruited participants had blood samples processed for fibrocyte measurement, with flow cytometry based on CD45 and collagen-I gating. Associations were tested using univariable and multivariable generalised linear models. Mortality data were subsequently combined with an independent cohort in a mixed-effect multilevel analysis.

RESULTS: In 102 participants with idiopathic pulmonary fibrosis, a previously defined mortality risk threshold of 5% circulating fibrocytes was not reproducible. An empirically defined cutpoint of 2.22% was associated with a greater risk of overall mortality in adjusted analysis (Hazard Ratio 2.24 95% CI 1.06-4.72). A 2.5 fold greater risk of mortality was supported in a pooled analysis with a historic cohort for a larger sample of 162 participants with idiopathic pulmonary fibrosis (Hazard Ratio 2.49 95% CI 2.41-2.56). We found no association of fibrocytes with lung function or disease progression.

CONCLUSIONS: In a large sample of circulating fibrocytes from people with idiopathic pulmonary fibrosis, levels of 2.22% or above were associated with greater mortality, but not with disease related decline in lung function.

PMID:33766945 | DOI:10.1183/13993003.00172-2021