Front Immunol. 2021 Nov 22;12:762594. doi: 10.3389/fimmu.2021.762594. eCollection 2021.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) has high mortality worldwide. The CD247 molecule (CD247, as known as T-cell surface glycoprotein CD3 zeta chain) has been reported as a susceptibility locus in systemic sclerosis, but its correlation with IPF remains unclear.

METHODS: Datasets were acquired by researching the Gene Expression Omnibus (GEO). CD247 was identified as the hub gene associated with percent predicted diffusion capacity of the lung for carbon monoxide (Dlco% predicted) and prognosis according to Pearson correlation, logistic regression, and survival analysis.

RESULTS: CD247 is significantly downregulated in patients with IPF compared with controls in both blood and lung tissue samples. Moreover, CD247 is significantly positively associated with Dlco% predicted in blood and lung tissue samples. Patients with low-expression CD247 had shorter transplant-free survival (TFS) time and more composite end-point events (CEP, death, or decline in FVC >10% over a 6-month period) compared with patients with high-expression CD247 (blood). Moreover, in the follow-up 1st, 3rd, 6th, and 12th months, low expression of CD247 was still the risk factor of CEP in the GSE93606 dataset (blood). Thirteen genes were found to interact with CD247 according to the protein-protein interaction network, and the 14 genes including CD247 were associated with the functions of T cells and natural killer (NK) cells such as PD-L1 expression and PD-1 checkpoint pathway and NK cell-mediated cytotoxicity. Furthermore, we also found that a low expression of CD247 might be associated with a lower activity of TIL (tumor-infiltrating lymphocytes), checkpoint, and cytolytic activity and a higher activity of macrophages and neutrophils.

CONCLUSION: These results imply that CD247 may be a potential T cell-derived disease severity and prognostic biomarker for IPF.

PMID:34880861 | PMC:PMC8645971 | DOI:10.3389/fimmu.2021.762594

Front Pharmacol. 2021 Nov 22;12:739220. doi: 10.3389/fphar.2021.739220. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis is a progressive fatal disease characterized by interstitial remodeling, with high lethality and a lack of effective medical therapies. Tetrandrine has been proposed to present anti-fibrotic effects, but the efficacy and mechanisms have not been systematically evaluated. We sought to study the potential therapeutic effects and mechanisms of tetrandrine against lung fibrosis. The anti-fibrotic effects of tetrandrine were evaluated in bleomycin-induced mouse models and TGF-β1-stimulated murine lung fibroblasts. We performed Chromatin Immunoprecipitation (ChIP), Immunoprecipitation (IP), and mRFP-GFP-MAP1LC3B adenovirus construct to investigate the novel mechanisms of tetrandrine-induced autophagy. Tetrandrine decreased TGF-β1-induced expression of α-smooth muscle actin, fibronectin, vimentin, and type 1 collagen and proliferation in fibroblasts. Tetrandrine restored TGF-β1-induced impaired autophagy flux, accompanied by enhanced interaction of SQSTM1 and MAP1LC3-Ⅱ. ChIP studies revealed that tetrandrine induced autophagy via increasing binding of NRF2 and SQSTM1 promoter. Furthermore, tetrandrine inhibited TGF-β1-induced phosphorylation of mTOR by reducing activation of Rheb. In vivo tetrandrine suppressed the bleomycin-induced expression of fibrotic markers and improved pulmonary function. Our data suggest that protective effect of tetrandrine against lung fibrosis might be through promoting Rheb-mTOR and NRF2-SQSTM1 mediated autophagy. Tetrandrine may thus be potentially employed as a novel therapeutic medicine against IPF.

PMID:34880752 | PMC:PMC8645995 | DOI:10.3389/fphar.2021.739220

Thorax. 2021 Dec 8:thoraxjnl-2021-218192. doi: 10.1136/thoraxjnl-2021-218192. Online ahead of print.

NO ABSTRACT

PMID:34880138 | DOI:10.1136/thoraxjnl-2021-218192

Nat Rev Rheumatol. 2021 Dec 7. doi: 10.1038/s41584-021-00721-z. Online ahead of print.

ABSTRACT

Interstitial lung disease (ILD) is a cause of morbidity and mortality in patients with rheumatic diseases, such as connective-tissue diseases, rheumatoid arthritis and systemic vasculitis. Some patients with ILD secondary to rheumatic disease (RD-ILD) experience acute exacerbations, with sudden ILD progression and high mortality during or immediately after the exacerbation, and a very low 1-year survival rate. In the ILD subtype idiopathic pulmonary fibrosis (IPF), an acute exacerbation is defined as acute worsening or development of dyspnoea associated with new bilateral ground-glass opacities and/or consolidations at high-resolution CT, superimposed on a background pattern consistent with fibrosing ILD. However, acute exacerbation in RD-ILD (AE-RD-ILD) currently has no specific definition. The aetiology and pathogenesis of AE-RD-ILD remain unclear, but distinct triggers might include infection, mechanical stress, microaspiration and DMARD treatment. At this time, no effective evidence-based therapeutic strategies for AE-RD-ILD are available. In clinical practice, AE-RD-ILD is often empirically treated with high-dose systemic steroids and antibiotics, with or without immunosuppressive drugs. In this Review, we summarize the clinical features, diagnosis, management and prognosis of AE-RD-ILD, enabling the similarities and differences with acute exacerbation in IPF to be critically assessed.

PMID:34876670 | DOI:10.1038/s41584-021-00721-z

BMC Pulm Med. 2021 Dec 7;21(1):404. doi: 10.1186/s12890-021-01749-3.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating disease with a high clinical burden. The molecular signatures of IPF were analyzed to distinguish molecular subgroups and identify key driver genes and therapeutic targets.

METHODS: Thirteen datasets of lung tissue transcriptomics including 585 IPF patients and 362 normal controls were obtained from the databases and subjected to filtration of differentially expressed genes (DEGs). A functional enrichment analysis, agglomerative hierarchical clustering, network-based key driver analysis, and diffusion scoring were performed, and the association of enriched pathways and clinical parameters was evaluated.

RESULTS: A total of 2,967 upregulated DEGs was filtered during the comparison of gene expression profiles of lung tissues between IPF patients and healthy controls. The core molecular network of IPF featured p53 signaling pathway and cellular senescence. IPF patients were classified into two molecular subgroups (C1, C2) via unsupervised clustering. C1 was more enriched in the p53 signaling pathway and ciliated cells and presented a worse prognostic score, while C2 was more enriched for cellular senescence, profibrosing pathways, and alveolar epithelial cells. The p53 signaling pathway was closely correlated with a decline in forced vital capacity and carbon monoxide diffusion capacity and with the activation of cellular senescence. CDK1/2, CKDNA1A, CSNK1A1, HDAC1/2, FN1, VCAM1, and ITGA4 were the key regulators as evidence by high diffusion scores in the disease module. Currently available and investigational drugs showed differential diffusion scores in terms of their target molecules.

CONCLUSIONS: An integrative molecular analysis of IPF lungs identified two molecular subgroups with distinct pathobiological characteristics and clinical prognostic scores. Inhibition against CDKs or HDACs showed great promise for controlling lung fibrosis. This approach provided molecular insights to support the prediction of clinical outcomes and the selection of therapeutic targets in IPF patients.

PMID:34876074 | DOI:10.1186/s12890-021-01749-3

Am J Physiol Lung Cell Mol Physiol. 2021 Dec 7. doi: 10.1152/ajplung.00165.2021. Online ahead of print.

ABSTRACT

Background The mechanisms driving idiopathic pulmonary fibrosis (IPF) remain undefined, however it is postulated that coagulation imbalances may play a role. The impact of blood-derived clotting factors, including factor XII (FXII) has not been investigated in the context of IPF. Methods Plasma levels of FXII were measured by ELISA in patients with IPF and age-matched healthy donors. Expression of FXII in human lung tissue was quantified using multiplex immunohistochemistry and western blotting. Mechanistic investigation of FXII activity was assessed in vitro on primary lung fibroblasts using qPCR and specific receptor/FXII inhibition. The functional outcome of FXII on fibroblast migration was examined by high-content image analysis. Findings Compared to 35 healthy donors, plasma levels of FXII were not higher in IPF (n=27, p>0·05). Tissue FXII was elevated in IPF (n=11) and increased numbers of FXII+ cells were found in IPF (n=8) lung tissue compared to non-diseased controls (n=6, p<0·0001). Activated FXII induced IL6 mRNA and IL-6 protein in fibroblasts that was blocked by anti-FXII antibody, CSL312. FXII-induced IL-6 production via PAR-1 and NF-kB. FXII induced migration of fibroblasts in a concentration-dependent manner. Interpretation FXII is normally confined to the circulation but leaks from damaged vessels into the lung interstitium in IPF where it 1) induces IL-6 production and 2) enhances migration of resident fibroblasts, critical events that drive chronic inflammation and therefore, contribute to fibrotic disease progression. Targeting FXII-induced fibroblastic processes in IPF may ameliorate pulmonary fibrosis. Funding National Health and Medical Research Council CRE in Lung Fibrosis and CSL Ltd.

PMID:34873957 | DOI:10.1152/ajplung.00165.2021

Monaldi Arch Chest Dis. 2021 Dec 6. doi: 10.4081/monaldi.2021.2027. Online ahead of print.

ABSTRACT

Interstitial lung diseases (ILDs) are an intriguing group of pulmonary disorders, which still require the study of epidemiological, genetic, pathophysiological, clinical, and radiological parameters. Pulmonary hypertension (PH) is an underreported complication in interstitial lung diseases which is associated with worse outcome. In our study, we have reported the spectrum of ILDs and estimated the prevalence of pulmonary hypertension among these subjects at a tertiary care centre. A cross-sectional study was performed in which demographical, clinical, radiological, and histological data of subjects with ILD, attending the department of Respiratory Medicine in the University was collected from 1st September 2018 to 31st August 2019. Serological tests were done wherever indicated. Standard criteria along with multidisciplinary opinion were needed to arrive at the final diagnosis. All subjects were screened for pulmonary hypertension via 2-D echocardiography. Mean pulmonary artery pressure ≥20 mmHg was used to define PH. In the defined period, 239 subjects were enrolled (58% females, n=141; mean age 52.38±13.40 years). A tissue diagnosis was obtained in 34% cases. The most common ILD was hypersensitivity pneumonitis (32.2%), followed by autoimmune-ILD (31.4%), idiopathic pulmonary fibrosis (IPF) (15.9%) and sarcoidosis (12.6%), non-IPF idiopathic interstitial pneumonitis (2.1%) and rest 21 (5.9%) subjects were diagnosed as other types of ILD. Pulmonary hypertension was seen in 46.0% of subjects.

PMID:34873902 | DOI:10.4081/monaldi.2021.2027

bioRxiv. 2021 Nov 30:2021.11.28.470269. doi: 10.1101/2021.11.28.470269. Preprint.

ABSTRACT

BACKGROUND: In the aftermath of Covid-19, a long-haul form of mysterious and progressive fibrotic lung disease has emerged, i.e., p ost- C OVID-19 l ung d isease (PCLD), for which we currently lack insights into pathogenesis, disease models, or treatment options.

METHOD: Using an AI-guided approach, we analyzed > 1000 human lung transcriptomic datasets associated with various lung conditions using two viral pandemic (ViP and sViP) and one covid lung gene signatures. Upon identifying similarities between COVID-19 and idiopathic pulmonary fibrosis (IPF), we subsequently dissected the basis for such similarity from molecular, cytopathic, and immunologic perspectives using a panel of IPF-specific gene signatures, alongside signatures of alveolar type II (AT2) cytopathies and of prognostic monocyte-driven processes that are known drivers of IPF. To pinpoint the AT2 processes that are shared points of convergence between COVID-19 and IPF, transcriptome-derived findings were used to construct protein - protein interaction (PPI) network. Key findings were validated in hamster and human adult lung organoid (ALO) pre-clinical models of COVID-19 using immunohistochemistry and qPCR.

FINDINGS: We found that COVID-19 resembles IPF at a fundamental level; it recapitulates the gene expression patterns (ViP and IPF signatures), cytokine storm (IL15-centric) and the AT2 cytopathic changes, e.g., injury, DNA damage, arrest in a transient, damage-induced progenitor state, and senescence-associated secretory phenotype (SASP). These immunocytopathic features were induced in pre-clinical COVID models (ALO and hamster) and reversed with effective anti-CoV-2 therapeutics in hamsters. PPI-network analyses pinpointed ER stress as one of the shared early triggers of both diseases, and IHC studies validated the same in the lungs of deceased subjects with COVID-19 and SARS-CoV-2-challenged hamster lungs. Lungs from tg - mice, in which ER stress is induced specifically in the AT2 cells, faithfully recapitulate the host immune response and alveolar cytopathic changes that are induced by SARS-CoV-2.

INTERPRETATION: Like IPF, COVID-19 may be driven by injury-induced ER stress that culminates into progenitor state arrest and SASP in AT2 cells. The ViP signatures in monocytes may be key determinants of prognosis. The insights, signatures, disease models identified here are likely to spur the development of therapies for patients with IPF and other fibrotic interstitial lung disease.

FUNDING: This work was supported by the National Institutes for Health grants R01-GM138385 and AI155696 and funding from the Tobacco-Related disease Research Program (R01RG3780).

ONE SENTENCE SUMMARY: Severe COVID-19 triggers cellular processes seen in fibrosing Interstitial Lung Disease.

PANEL RESEARCH IN CONTEXT: Evidence before this study: In its aftermath, the COVID-19 pandemic has left many survivors, almost a third of those who recovered, with a mysterious long-haul form of the disease which culminates in a fibrotic form of interstitial lung disease (post-COVID-19 ILD). Post-COVID-19 ILD remains a largely unknown entity. Currently we lack insights into the core cytopathic features that drives this condition.Added value of this study: Using an AI-guided approach, which involves the use of a sets of gene signatures, protein-protein network analysis, and a hamster model of COVID-19, we have revealed here that COVID-19 -lung fibrosis resembles IPF, the most common form of ILD, at a fundamental level-showing similar gene expression patterns in the lungs and blood, and dysfunctional AT2 processes (ER stress, telomere instability, progenitor cell arrest and senescence). These findings are insightful because AT2 cells are known to contain an elegant quality control network to respond to intrinsic or extrinsic stress; a failure of such quality control results in diverse cellular phenotypes, of which ER stress appears to be a point of convergence, which appears to be sufficient to drive downstream fibrotic remodeling in the lung.Implications of all the available evidence: Because unbiased computational methods identified the shared fundamental aspects of gene expression and cellular processes between COVID-19 and IPF, the impact of our findings is likely to go beyond COVID-19 or any viral pandemic. The insights, tools (disease models, gene signatures, and biomarkers), and mechanisms identified here are likely to spur the development of therapies for patients with IPF and other fibrotic interstitial lung disease, all of whom have limited or no treatment options. to dissect the validate prognostic biomarkers to assess and track the risk of pulmonary fibrosis and develop therapeutics to halt fibrogenic progression.

PMID:34873597 | PMC:PMC8647648 | DOI:10.1101/2021.11.28.470269

Ann Palliat Med. 2021 Nov;10(11):11598-11614. doi: 10.21037/apm-21-2676.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a lung disease involving chronic progressive fibrosis, with unclear pathogenesis. In recent years, people have paid increasing attention to the role of immune mechanism. In this study, bioinformatics analysis was used to determine the potential immune-related biomarkers for the diagnosis of IPF, and further analyze the role of immune cell infiltration in the pathogenesis of IPF.

METHODS: The IPF data set (GSE150910) was downloaded from the Gene Expression Omnibus (GEO) database. We used R software to screen differential immune-related genes (IRGs). Least absolute shrinkage and selection operator (LASSO) regression, random forest algorithm, and support vector machine (SVM) were used to screen and determine IPF IRGs to be diagnostic biomarkers. The GSE32537 and GSE10667 data sets were combined into 1 data set to verify the diagnostic efficacy of biomarkers. Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) was used to evaluate the infiltration of immune cells in IPF tissues, and analyze the relationship between diagnostic markers and immune cell infiltration. Meanwhile, clinical specimens were used to verify the diagnostic efficacy of biomarkers and their relationship with immune cell infiltration.

RESULTS: In this study, 408 participants were involved in the screening to find that PLXNA4 and SLIT2 can be used as diagnostic biomarkers of IPF, and the results were verified by clinical samples. Immune cell infiltration analysis found that regulatory T cells (Tregs), memory B cells, plasma cells, and eosinophils might be involved in the process of IPF. In addition, Tregs were most closely related to PLXNA4 and SLIT2. In clinical samples, forkhead box p3 (FOXP3), a specific marker of Tregs, was positively correlated with PLXNA4 and negatively correlated with SLIT2, which is consistent with the results of bioinformatics analysis.

CONCLUSIONS: The genes PLXNA4 and SLIT2 can be used as diagnostic markers of IPF, and immune cell infiltration plays an important role in the occurrence and development of IPF.

PMID:34872285 | DOI:10.21037/apm-21-2676

Front Med (Lausanne). 2021 Nov 18;8:798164. doi: 10.3389/fmed.2021.798164. eCollection 2021.

NO ABSTRACT

PMID:34869509 | PMC:PMC8637212 | DOI:10.3389/fmed.2021.798164

Pulm Med. 2021 Nov 25;2021:3432362. doi: 10.1155/2021/3432362. eCollection 2021.

ABSTRACT

OBJECTIVES: We studied the safety and efficacy of warfarin compared to direct acting oral anticoagulant use in patients with IPF.

METHODS: We conducted a retrospective cohort study of all patients with IPF who were prescribed warfarin or direct acting oral anticoagulants (DOACs) for cardiac or thromboembolic indications and followed at our institute for their care. Univariate tests and multivariable logistic regression analyses were used for assessing association of variables with outcomes.

RESULTS: A total of 73 patients were included in the study with 28 and 45 patients in the warfarin and DOAC groups, respectively. Univariable analysis revealed a significant difference in mortality in one year between warfarin and DOAC groups (7/28 vs. 3/45, p value 0.027). Significantly more patients in the warfarin group suffered an exacerbation that required hospitalization within one year (9/28 vs. 5/45, p value 0.026). Multivariate logistic regression analysis showed that anticoagulation with warfarin was independently associated with mortality at one-year follow-up (OR: 77.4, 95% CI: 5.94-409.3, p value: 0.007).

CONCLUSION: In our study of patients with IPF requiring anticoagulants, we noted statistically significant higher mortality with warfarin anticoagulation when compared to DOAC use. Further larger prospective studies are needed to confirm these findings.

PMID:34868680 | PMC:PMC8639231 | DOI:10.1155/2021/3432362

Front Immunol. 2021 Nov 17;12:645548. doi: 10.3389/fimmu.2021.645548. eCollection 2021.

ABSTRACT

Within the Interstitial Lung Diseases (ILD), patients with idiopathic pulmonary fibrosis (IPF) and a subset of those with non-IPF fibrotic ILD have a distinct clinical phenotype of progression despite management. This group of patients has been collectively termed the progressive fibrotic phenotype (PFP). Their early recognition may facilitate access to antifibrotic therapies to prevent or slow progression. Macrophages/monocytes within the lung orchestrate the progression and maintenance of fibrosis. A novel role for monocyte-derived macrophages during tissue damage and wound healing is the expression of collagens. We examined Collagen 1a1 expression in airway macrophages from ILD patients at diagnosis. COL1A1 mRNA levels from BAL cells were elevated in IPF and Non-IPF patients. The presence of a UIP pattern and a subsequent progressive phenotype were significantly associated with the higher BAL COL1A1 levels. In Non-IPF patients, higher COL1A1 levels were associated with a more than twofold increase in mortality. The intracellular localisation of COL1A1 in airway macrophages was demonstrated by confocal microscopy in CD45 and CD163 co-staining assays. Additionally, airway macrophages co-expressed COL1A1 with the profibrotic SPP1 gene product osteopontin. The levels of SPP1 mRNA and OPN in the BAL were significantly higher in IPF and Non-IPF patients relative to healthy. Our results suggest that profibrotic airway macrophages are increased in the BAL of patients with IPF and other ILDs and co-express COL1A1 and OPN. Importantly, COL1A1 expression by pro-fibrotic airway macrophages could be a marker of disease progression and poor survival in ILDs.

PMID:34867934 | PMC:PMC8635798 | DOI:10.3389/fimmu.2021.645548

Korean J Intern Med. 2021 Dec 7. doi: 10.3904/kjim.2021.025. Online ahead of print.

ABSTRACT

BACKGROUND/AIMS: The prevalence and effects of airway diseases, including asthma, eosinophilic bronchitis (EB), chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap (ACO) have not been thoroughly studied in patients with idiopathic pulmonary fibrosis (IPF). This study aimed to evaluate the prevalence of airway diseases in patients with IPF and to identify the differences in symptoms based on the presence of airway diseases.

METHODS: This single-institution prospective cohort study was conducted from June 2017 to September 2018, at the Seoul National University Hospital. Spirometry with bronchodilator, methacholine bronchial provocation test, induced sputum with eosinophil stain, and exhaled nitric oxide were performed to confirm the presence of airway disease. The modified Medical Research Council (mMRC) dyspnea scale, COPD assessment test (CAT), St. George's Respiratory Questionnaire (SGRQ), EuroQol-5 dimension (EQ-5D) index, and cough-specific quality of life questionnaire (CQLQ) data were collected to assess symptom severity.

RESULTS: Total 147 patients with IPF were screened, and 70 patients were analyzed. The prevalence of airway diseases in the participants was as follows: 5.0% had COPD, 1.7% had asthma, 3.3% had ACO, and 1.7% had EB. The mMRC, CAT, SGRQ, EQ-5D, and CQLQ scores did not differ regardless of combined airway disease. After 3 months, the SGRQ (p = 0.028) and CQLQ (p = 0.030) scores were significantly higher in patients with airway disease than in those without.

CONCLUSIONS: The prevalence of airway diseases in patients with IPF is low, but when airway diseases are accompanied by IPF, symptom severity and quality of life may worsen rapidly.

PMID:34865413 | DOI:10.3904/kjim.2021.025

Talanta. 2021 Dec 1;239:123120. doi: 10.1016/j.talanta.2021.123120. Online ahead of print.

ABSTRACT

Pulmonary fibrosis (PF) is a common but fatal disease that threatens human health worldwide. Developing effective diagnostic methods is of great importance for the early detection of PF in patients. In this study, bleomycin (BLM) was used in mice to mimic idiopathic pulmonary fibrosis (IPF). The exhaled breath of BLM-induced PF, PF plus DDAH1 overexpression, and healthy control mice were analyzed in real-time using a newly developed associative ionization time-of-flight mass spectrometry method (AI-TOFMS), which is uniquely sensitive, especially to oxygenated volatile organic compounds (VOCs). Multivariate data analyses and discriminant modeling analyses revealed that four exhaled compounds, i.e., acrolein, ethanol, nitric oxide, and ammonia, had a strong correlation with PF symptoms. An Orthogonal Partial Least Square Discriminant Analysis (OPLS-DA) score plot showed an excellent separation between these three groups. The area under the receiver operating characteristic (ROC) curve for these four compounds distinguished PF mice from healthy controls at 0.989. In addition, the degrees of acute inflammation and fibrosis were assessed with Hematoxylin and Eosin (H&E) staining and Masson's Trichrome staining. Finally, combined with pathological characteristics and mRNA expression levels, the formation of the above-mentioned volatile compounds was explored. The obtained experimental results indicated that these four breath compounds, acrolein, ethanol, nitric oxide, and ammonia, were potential exhaled biomarkers for pulmonary fibrosis.

PMID:34864537 | DOI:10.1016/j.talanta.2021.123120

J Control Release. 2021 Dec 2:S0168-3659(21)00650-7. doi: 10.1016/j.jconrel.2021.11.047. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial pulmonary disease due to chronic inflammatory responses. The prognosis of IPF is very poor, however, the therapeutic options are very limited. Previously we developed a polymeric micellar drug delivery system of carbon monoxide (CO) that is a pivotal anti-inflammatory gaseous molecule, i.e., SMA/CORM2, which exhibited therapeutic potentials against dextran sulfate sodium (DSS)-induced mouse colitis and acetaminophen (APAP) induced liver injury. Along this line, here we investigate the applicability of SMA/CORM2 on IPF using a bleomycin (BLM)-induced pulmonary fibrosis model. Severe inflammation and the consequent pulmonary fibrosis were triggered by BLM, whereas SMA/CORM2 treatment remarkably suppressed the inflammation progression and ameliorated formation. CO is the effector molecule of SMA/CORM2, which exerted the therapeutic/protective effect mostly through suppressing the reprogramming of anti-inflammatory macrophages as revealed by the decreased expressions of CD206 and arginase-1 that were remarkably upregulated by BLM exposure. The suppression of macrophage polarization accompanied the downregulated hypoxia-inducible factor-1α (HIF-1α) and its target molecule heme oxygenase-1 (HO-1), suggesting a HIF-1α/HO-1 pathway for modulating macrophage reprogramming. As the downstream event of anti-inflammatory macrophage polarization, the alveolar epithelial to mesenchymal transition that is the major source of myofibroblast, the hallmark of IPF, was significantly suppressed by SMA/CORM2 via a TGF-β/Smad2/3 pathway. Compared to native CORM2 of equivalent dose, SMA/CROM2 exhibited a much better protective effect indicating its superior bioavailability as enhanced permeability and retention (EPR) effect-based nanomedicine. We thus anticipate the application of SMA/CORM2 as a therapeutic candidate for IPF as well as other inflammatory diseases and disorders.

PMID:34864115 | DOI:10.1016/j.jconrel.2021.11.047

BMC Pulm Med. 2021 Dec 4;21(1):396. doi: 10.1186/s12890-021-01753-7.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by a poor prognosis, with a progressive decline in lung function and considerable variability in the disease's natural history. Besides lung transplantation (LTx), the only available treatments are anti-fibrosing drugs, which have shown to slow down the disease course. Therefore, predicting the prognosis is of pivotal importance to avoid treatment delays, which may be fatal for patients with a high risk of progression. Previous studies showed that a multi-dimensional approach is practical and effective in the development of a reliable prognostic score for IPF. In the RIsk Stratification scorE (RISE), physiological parameters, an objective measure of patient-reported dyspnea and exercise capacity are combined to capture different domains of the complex pathophysiology of IPF.

METHODS: This is an observational, multi-centre, prospective cohort study, designed to reflect common clinical practice in IPF. A development cohort and a validation cohort will be included. Patients newly diagnosed with IPF based on the ATS/ERS criteria and multi-disciplinary discussion will be included in the study. A panel of chest radiologists and lung pathologists will further assess eligibility. At the first visit (time of diagnosis), and every 4-months, MRC dyspnea score, pulmonary function tests (FEV1, FVC and DLCO), and 6-min walking distance will be recorded. Patients will be prospectively followed for 3 years. Comorbidities will be considered. The radiographic extent of fibrosis on HRCT will be recalculated at a 2-year interval. RISE, Gender-Age-Physiology, CPI and Mortality Risk Scoring System will be calculated at 4-month intervals. Longitudinal changes of each variable considered will be assessed. The primary endpoint is 3-year LTx-free survival from the time of diagnosis. Secondary endpoints include several, clinically-relevant information to ensure reproducibility of results across a wide range of disease severity and in concomitance of associated pulmonary hypertension or emphysema.

DISCUSSION: The objective of this study is to validate RISE as a simple, straightforward, inexpensive and reproducible tool to guide clinical decision making in IPF, and potentially as an endpoint for future clinical trials.

TRIAL REGISTRATION: U.S National Library of Medicine Clinicaltrials.gov, trial n. NCT02632123 "Validation of the risk stratification score in idiopathic pulmonary fibrosis". Date of registration: December 16th, 2015.

PMID:34863146 | DOI:10.1186/s12890-021-01753-7

Am J Respir Cell Mol Biol. 2021 Dec 3. doi: 10.1165/rcmb.2021-0342TR. Online ahead of print.

ABSTRACT

Organ fibrosis is characterized by epithelial injury and aberrant tissue repair, where activated effector cells, mostly fibroblasts and myofibroblasts, excessively deposit collagen into the extracellular matrix. Fibrosis frequently results in organ failure and has been estimated to contribute to at least one third of all global deaths. Also lung fibrosis, in particular idiopathic pulmonary fibrosis (IPF), is a fatal disease with rising incidence worldwide. As current treatment options targeting fibrogenesis are insufficient, there is an urgent need for novel therapeutic strategies. During the last decade, several studies have proposed to target intra- and extracellular components of the collagen biosynthesis, maturation, and degradation machinery. This includes intra- and extracellular targets directly acting on collagen gene products, but also such that anabolize essential building blocks of collagen, in particular glycine and proline biosynthetic enzymes. Collagen, however, is a ubiquitous molecule in the body and fulfils essential functions as a macromolecular scaffold, growth factor reservoir, and receptor binding site in virtually every tissue. This review summarizes recent advances and future directions in this field. Evidence for the proposed therapeutic targets and where they currently stand in terms of clinical drug development for treatment of fibrotic disease is provided. The drug targets are furthermore discussed in light of (1) specificity for collagen biosynthesis, maturation and degradation, and (2) specificity for disease-associated collagen. As therapeutic success and safety of these drugs may largely depend on targeted delivery, different strategies for specific delivery to the main effector cells and to the extracellular matrix are discussed.

PMID:34861139 | DOI:10.1165/rcmb.2021-0342TR

Front Med (Lausanne). 2021 Nov 11;8:739810. doi: 10.3389/fmed.2021.739810. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis is an age-dependent progressive and fatal lung disease of unknown etiology, which is characterized by the excessive accumulation of extracellular matrix inside the interstitial layer of the lung parenchyma that leads to abnormal scar architecture and compromised lung function capacity. Recent genetic studies have attributed the pathological genes or genetic mutations associated with familial idiopathic pulmonary fibrosis (IPF) and sporadic IPF to telomere-related components, suggesting that telomere dysfunction is an important determinant of this disease. In this study, we summarized recent advances in our understanding of how telomere dysfunction drives IPF genesis. We highlighted the key role of alveolar stem cell dysfunction caused by telomere shortening or telomere uncapping, which bridged the gap between telomere abnormalities and fibrotic lung pathology. We emphasized that senescence-associated secretory phenotypes, innate immune cell infiltration, and/or inflammation downstream of lung stem cell dysfunction influenced the native microenvironment and local cell signals, including increased transforming growth factor-beta (TGF-β) signaling in the lung, to induce pro-fibrotic conditions. In addition, the failed regeneration of new alveoli due to alveolar stem cell dysfunction might expose lung cells to elevated mechanical tension, which could activate the TGF-β signaling loop to promote the fibrotic process, especially in a periphery-to-center pattern as seen in IPF patients. Understanding the telomere-related molecular and pathophysiological mechanisms of IPF would provide new insights into IPF etiology and therapeutic strategies for this fatal disease.

PMID:34859008 | PMC:PMC8631932 | DOI:10.3389/fmed.2021.739810

Front Pharmacol. 2021 Nov 11;12:771804. doi: 10.3389/fphar.2021.771804. eCollection 2021.

ABSTRACT

Background: Multiple studies have revealed that idiopathic pulmonary fibrosis (IPF) patients are more at risk for cardiovascular diseases and that many IPF patients receive cardiovascular medications like statins, angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), and anticoagulants. Existing studies have reported divergent findings on the link between cardiovascular medications and fibrotic disease processes. The aim of this study is to synthesize the evidence on the efficacy of cardiovascular medications in IPF. Methods: We searched studies reporting the effect of cardiovascular medications on IPF in the PubMed, Embase, Web of Science, Cochrane Library, and two Chinese databases (China National Knowledge Infrastructure database and China Wanfang database). We calculated survival data, forced vital capacity (FVC) decline, and IPF-related mortality to assess the efficacy of cardiovascular medications in IPF. We also estimated statistical heterogeneity by using I2 and Cochran Q tests, and publication bias was evaluated by risk of bias tools ROBINS-I. Results: A total of 12 studies were included in the analysis. The included studies had moderate-to-serious risk of bias. Statin use was associated with a reduction in mortality (hazard ratio (HR), 0.89; 95% CI 0.83-0.97). Meta-analysis did not demonstrate any significant relationship between statin use and the FVC decline (HR, 0.86; 95% CI 0.73-1.02), ACEI/ARB use, and survival data (HR, 0.92; 95% CI 0.73-1.15) as well as anticoagulant use and survival data (HR, 1.16; 95% CI 0.62-2.19). Conclusion: Our study suggested that there is a consistent relationship between statin therapy and survival data in IPF population. However, there is currently insufficient evidence to conclude the effect of ACEI, ARB, and anticoagulant therapy on IPF population especially to the disease-related outcomes in IPF.

PMID:34858190 | PMC:PMC8632524 | DOI:10.3389/fphar.2021.771804

Intern Med. 2021;60(23):3701-3707. doi: 10.2169/internalmedicine.6716-20. Epub 2021 Dec 1.

ABSTRACT

Objective Evidence supporting the efficiency of clinically administered therapies against interstitial lung disease (ILD)-related cough is limited. Thus, we conducted a study to evaluate the efficacy of short-term use of chest bands on cough in patients with ILD. Methods This pre-post intervention study was performed at two university hospitals between April 2017 and August 2020. Scores of the visual analog scale (VAS) for cough severity (in terms of frequency and intensity), Leicester Cough Questionnaire (LCQ)-acute, and frequency scale for symptoms of gastroesophageal reflux disease (FSSG) were assessed before and after the use of the chest band (24/48 hours). Patients The study included patients with idiopathic interstitial pneumonias (IIPs) or connective tissue disease-associated interstitial lung disease (CTD-ILD). Results Four patients with IIPs and seven with CTD-ILD were included in the analysis. The cough intensity and LCQ-acute total score improved significantly after the use of the chest band (p=0.007 and p=0.005, respectively), although the cough frequency showed no significant reduction (p=0.074). Furthermore, the FSSG total and acid-reflux symptom scores improved (p=0.018 and p=0.027, respectively), and a negative correlation between the change in LCQ-acute total score and that in FSSG score for acid-reflux symptoms was observed (Spearman rho =-0.841, p=0.001). Conclusion The results of the current study suggest that chest bands might be useful for treating chronic refractory cough in patients with ILD and gastroesophageal reflux disease. However, these results should be interpreted with caution due to methodological limitations associated with this study.

PMID:34853257 | DOI:10.2169/internalmedicine.6716-20