Adv Ther. 2023 Jan 24. doi: 10.1007/s12325-022-02395-9. Online ahead of print.

ABSTRACT

The most common type of idiopathic interstitial pneumonia is idiopathic pulmonary fibrosis (IPF), an irreversible, progressive disorder that has lately come into question for possible associations with COVID-19. With few geographical exceptions, IPF is a rare disease but its prevalence has been increasing markedly since before the pandemic. Environmental exposures are frequently implicated in IPF although genetic factors play a role as well. In IPF, healthy lung tissue is progressively replaced with an abnormal extracellular matrix that impedes normal alveolar function while, at the same time, natural repair mechanisms become dysregulated. While chronic viral infections are known risk factors for IPF, acute infections are not and the link to COVID-19 has not been established. Macrophagy may be a frontline defense against any number of inflammatory pulmonary diseases, and the inflammatory cascade that may occur in patients with COVID-19 may disrupt the activity of monocytes and macrophages in clearing up fibrosis and remodeling lung tissue. It is unclear if COVID-19 infection is a risk factor for IPF, but the two can occur in the same patient with complicating effects. In light of its increasing prevalence, further study of IPF and its diagnosis and treatment is warranted.

PMID:36692679 | DOI:10.1007/s12325-022-02395-9

RMD Open. 2023 Jan;9(1):e002667. doi: 10.1136/rmdopen-2022-002667.

ABSTRACT

OBJECTIVE: No studies have demonstrated the real-world efficacy of antifibrotics for progressive fibrosing interstitial lung disease (PF-ILD). Therefore, we evaluated the efficacy of antifibrotics in patients with PF-ILD.

METHODS: We retrospectively reviewed the medical records of patients with ILD from January 2012 to July 2021. Patients were diagnosed with PF-ILD if they had ≥10% fibrosis on high-resolution CT (HRCT) and a relative forced vital capacity (FVC) decline of either ≥10% or >5% to <10% with clinical deterioration or progression of fibrosis on HRCT during overlapping windows of 2 years and with a %FVC of ≥45%. We compared FVC changes and overall survival (OS) between patients with and without antifibrotics. FVC changes were analysed using generalised estimating equations. We used inverse probability weighting (IPW) and statistical matching to adjust for covariates.

RESULTS: Of the 574 patients, 167 were diagnosed with PF-ILD (idiopathic pulmonary fibrosis (IPF), n=64; non-IPF, n=103). Antifibrotics improved the FVC decline in both IPF (p=0.002) and non-IPF (p=0.05) (IPW: IPF, p=0.015; non-IPF, p=0.031). Among patients with IPF, OS was longer in the antifibrotic group (log-rank p=0.001). However, among patients with non-IPF, OS was not longer in the antifibrotic group (p=0.3263) (IPW and statistical matching: IPF, p=0.0534 and p=0.0018; non-IPF, p=0.5663 and p=0.5618).

CONCLUSION: This is the first real-world study to show that antifibrotics improve the FVC decline in PF-ILD. However, among patients with non-IPF, we found no significant difference in mortality between those with and without antifibrotics. Future studies must clarify whether antifibrotics improve the prognosis of non-IPF.

PMID:36690385 | DOI:10.1136/rmdopen-2022-002667

Am J Pathol. 2023 Jan 20:S0002-9440(23)00032-9. doi: 10.1016/j.ajpath.2022.12.015. Online ahead of print.

ABSTRACT

MicroRNAs (miRs) are a class of non-coding RNAs of ∼22nt long that play an important role in regulating gene expression at a post-transcriptional level. Aberrant levels of miRs have been associated with profibrotic processes in idiopathic pulmonary fibrosis (IPF). However, most of these studies used whole IPF tissue or in vitro monocultures in which fibrosis has been artificially induced. In this study, we used laser microdissection to collect fibroblastic foci (FF), the key pathological lesion in IPF, then isolate miRs and compare their expression levels to those found in whole IPF lung tissue and/or in vitro cultured fibroblast from IPF or normal lungs. Sequencing libraries were generated and data generated bioinformatically analysed. 18 miRs were significantly over-expressed in FF tissue when compared with whole IPF tissue, of these molecules 15 were unique to FF. Comparison of FF with cultured IPF fibroblasts also revealed differences in miR composition that impact on a number of signalling pathways. The miR composition of FF is both overlapping and distinct from that of whole IPF tissue or cultured IPF fibroblasts and highlights the importance of characterising FF biology as a phenotypically and functionally discrete tissue microenvironment.

PMID:36690076 | DOI:10.1016/j.ajpath.2022.12.015

Naunyn Schmiedebergs Arch Pharmacol. 2023 Jan 23. doi: 10.1007/s00210-023-02390-z. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease that is characterized by abnormal proliferation of fibroblasts and extracellular matrix remodeling, ultimately leading to respiratory insufficiency or even death. Naringin (Nar), a natural compound derived from grapefruit and citrus fruits, has several pharmacological activities that are associated with therapeutic benefits for IPF. However, the specific molecular mechanisms underlying its pulmonary tissue-protective effects remain largely unknown. This study aimed to investigate the effects of Nar on endoplasmic reticulum stress (ERS) and mitophagy. A bleomycin (BLM)-induced mouse model of IPF was established for treatment with different doses of Nar. Histopathological changes in the lung were examined by hematoxylin and eosin (HE) staining and Masson staining. The extent of fibrosis was determined by measuring hydroxyproline and collagen expression levels. The levels of inflammatory cytokines and oxidative stress indicators were determined by Enzyme linked immunosorbent assay (ELISA) and biochemical kits. Western blot and immunofluorescence were used to evaluate the expression levels of the mitophagy-related markers. Cell apoptosis was estimated by western blot and TUNEL staining. Nar reduced the levels of inflammatory response, oxidative stress and decreased the proportion of apoptosis. Nar also inhibited the expression of the ERS and mitophagy-related genes and ERS-downstream proteins, thereby activating transcription factor (ATF) 3 and inhibiting the transcription of PTEN-induced kinase 1 (PINK1). Taken together, Nar is a promising therapeutic agent for treating IPF via inhibiting ERS, reducing apoptosis, and maintaining mitochondrial homeostasis, all of which may be associated with the regulation of the ATF3/PINK1 signaling axis.

PMID:36688958 | DOI:10.1007/s00210-023-02390-z

Front Genet. 2023 Jan 4;13:1102422. doi: 10.3389/fgene.2022.1102422. eCollection 2022.

ABSTRACT

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive pulmonary fibrotic disease with unknown etiology and poor outcomes. It severely affects the quality of life. In this study, we comprehensively analyzed the expression of N6-methyladenosine (m6A) RNA methylation regulators using gene expression data from various tissue sources in IPF patients and healthy volunteers. Methods: The gene expression matrix and clinical characteristics of IPF patients were retrieved from the Gene Expression Omnibus database. A random forest model was used to construct diagnosis signature m6A regulators. Regression analysis and correlation analysis were used to identify prognosis m6A regulators. Consensus cluster analysis was used to construct different m6A prognosis risk groups, then functional enrichment, immune infiltration and drug sensitivity analysis were performed. Result: Five candidate m6A genes from lung tissue were used to predict the incidence, and the incidence was validated using datasets from bronchoalveolar lavage fluid (BALF) and peripheral blood mononuclear cells. Subsequently, the BALF dataset containing outcomes data was used for the prognosis analysis of m6A regulators. METTL14, G3BP2, and ZC3H13 were independent protective factors. Using correlation analysis with lung function in the lung tissue-derived dataset, METTL14 was a protective factor in IPF. Based on METTL14 and G3BP2, a consensus cluster analysis was applied to distinguish the prognostic m6A regulation patterns. The low-risk group's prognosis was significantly better than the high-risk group. Biological processes regulated by various risk groups included fibrogenesis and cell adhesion. Analysis of immune cell infiltration showed upregulation of neutrophils in the m6A high-risk group. Subsequently, five m6A high-risk group sensitive drugs and one m6A low-risk group sensitive drug were identified. Discussion: These findings suggest that m6A regulators are involved in the diagnosis and prognosis of IPF, and m6A patterns are a method to identify IPF outcomes.

PMID:36685949 | PMC:PMC9846232 | DOI:10.3389/fgene.2022.1102422

Front Genet. 2023 Jan 6;13:1109903. doi: 10.3389/fgene.2022.1109903. eCollection 2022.

ABSTRACT

Background: Most patients with idiopathic pulmonary fibrosis (IPF) have poor prognosis; Effective predictive models for these patients are currently lacking. Epithelial-mesenchymal transition (EMT) often occurs during idiopathic pulmonary fibrosis development, and is closely related to multiple pathways and biological processes. It is thus necessary for clinicians to find prognostic biomarkers with high accuracy and specificity from the perspective of Epithelial-mesenchymal transition. Methods: Data were obtained from the Gene Expression Omnibus database. Using consensus clustering, patients were grouped based on Epithelial-mesenchymal transition-related genes. Next, functional enrichment analysis was performed on the results of consensus clustering using gene set variation analysis. The gene modules associated with Epithelial-mesenchymal transition were obtained through weighted gene co-expression network analysis. Prognosis-related genes were screened via least absolute shrinkage and selection operator (LASSO) regression analysis. The model was then evaluated and validated using survival analysis and time-dependent receiver operating characteristic (ROC) analysis. Results: A total of 239 Epithelial-mesenchymal transition-related genes were obtained from patients with idiopathic pulmonary fibrosis. Six genes with strong prognostic associations (C-X-C chemokine receptor type 7 [CXCR7], heparan sulfate-glucosamine 3-sulfotransferase 1 [HS3ST1], matrix metallopeptidase 25 [MMP25], murine retrovirus integration site 1 [MRVI1], transmembrane four L6 family member 1 [TM4SF1], and tyrosylprotein sulfotransferase 1 [TPST1]) were identified via least absolute shrinkage and selection operator and Cox regression analyses. A prognostic model was then constructed based on the selected genes. Survival analysis showed that patients with high-risk scores had worse prognosis based on the training set [hazard ratio (HR) = 7.31, p < .001] and validation set (HR = 2.85, p = .017). The time-dependent receiver operating characteristic analysis showed that the area under the curve (AUC) values in the training set were .872, .905, and .868 for 1-, 2-, and 3-year overall survival rates, respectively. Moreover, the area under the curve values in the validation set were .814, .814, and .808 for 1-, 2-, and 3-year overall survival rates, respectively. Conclusion: The independent prognostic model constructed from six Epithelial-mesenchymal transition-related genes provides bioinformatics guidance to identify additional prognostic markers for idiopathic pulmonary fibrosis in the future.

PMID:36685840 | PMC:PMC9853015 | DOI:10.3389/fgene.2022.1109903

Front Genet. 2023 Jan 6;13:985217. doi: 10.3389/fgene.2022.985217. eCollection 2022.

ABSTRACT

Background: Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease whose etiology remains unknown. This study aims to explore diagnostic biomarkers and pathways involved in IPF using bioinformatics analysis. Methods: IPF-related gene expression datasets were retrieved and downloaded from the NCBI Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened, and weighted correlation network analysis (WGCNA) was performed to identify key module and genes. Functional enrichment analysis was performed on genes in the clinically significant module. Then least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine-recursive feature elimination (SVM-RFE) algorithms were run to screen candidate biomarkers. The expression and diagnostic value of the biomarkers in IPF were further validated in external test datasets (GSE110147). Results: 292 samples and 1,163 DEGs were screened to construct WGCNA. In WGCNA, the blue module was identified as the key module, and 59 genes in this module correlated highly with IPF. Functional enrichment analysis of blue module genes revealed the importance of extracellular matrix-associated pathways in IPF. IL13RA2, CDH3, and COMP were identified as diagnostic markers of IPF via LASSO and SVM-RFE. These genes showed good diagnostic value for IPF and were significantly upregulated in IPF. Conclusion: This study indicates that IL13RA2, CDH3, and COMP could serve as diagnostic signature for IPF and might offer new insights in the underlying diagnosis of IPF.

PMID:36685820 | PMC:PMC9857386 | DOI:10.3389/fgene.2022.985217

Eur J Pharmacol. 2023 Jan 19:175438. doi: 10.1016/j.ejphar.2022.175438. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease, and its 5-year mortality rate is even higher than the mortality rate of some cancers. Fibrosis can cause irreversible damage to lung structure and function. Treatment options for IPF remain limited, and there is an urgent need to develop effective therapeutic drugs. Protease activated receptor-1 (PAR-1) is a G-protein-coupled receptor and is considered a potential target for the treatment of fibrotic diseases. Vorapaxar is a clinically approved PAR-1 antagonist for cardiovascular protection. The purpose of this study was to explore the potential effect and mechanism of Vorapaxar on pulmonary fibrosis in vivo and in vitro. In the experimental animal model, Vorapaxar can effectively alleviate bleomycin (BLM)-induced pulmonary fibrosis. Treatment with 2.5, 5 or 10 mg/kg Vorapaxar once a day reduced the degree of fibrosis in a dose-dependent manner. The expression of fibronectin, collagen and α smooth muscle actin decreased significantly at the messenger RNA (mRNA) and protein levels in treated mice. In vitro, our results showed that Vorapaxar could inhibit the activation of fibroblasts induced by thrombin in a dose-dependent manner. In terms of mechanism, Vorapaxar inhibits the signal transduction of JAK2/STAT1/3 by inhibiting the activation of protease activated receptor 1, which reduces the expression of HSP90β and the interaction between HSP90β and transforming growth factor-β (TGFβ) receptor II and inhibits the TGFβ/Smad signaling pathway. In conclusion, Vorapaxar inhibits the activation of pulmonary fibroblasts induced by thrombin by targeting protease activated receptor 1 and alleviates BLM-induced pulmonary fibrosis in mice.

PMID:36682482 | DOI:10.1016/j.ejphar.2022.175438

Nutrition. 2023 Jan 3;108:111964. doi: 10.1016/j.nut.2022.111964. Online ahead of print.

ABSTRACT

OBJECTIVES: Malnutrition in pulmonary fibrosis may influence clinical outcomes negatively. This project aimed to investigate if weight, unintended weight loss (UWL) at baseline and weight development, and signs of sarcopenia measured by the strength, assistance with the walking, rising from a chair, climbing stairs, and falls questionnaire (SARC-F) are associated with hospital admissions and mortality for idiopathic pulmonary fibrosis outpatients in ≤1 y as well as referral to pulmonary rehabilitation.

METHODS: At baseline, prevalence of weight and UWL were sought in a cross-sectional questionnaire study, consecutively, including 100 patients in an outpatient clinic. Medical records were sought for time from diagnosis and comorbidities. One year after inclusion weight, UWL and SARC-F were collected by phone interviews, and medical records were revisited for clinical outcomes.

RESULTS: Of the 100 patients, two patients died and seven were lost to follow-up. The prevalence of UWL increased within the year (10-13%), and the amount of UWL increased (9.1-11.8 kg). Patients with a UWL at baseline had a significantly higher risk of mortality (odds ratio = 29.8; P = 0.037). UWL at baseline was associated with risk of hospital admissions (odds ratio = 14.7; P = 0.009). Based on the results from SARC-F, 20.9% have signs of sarcopenia. UWL at follow-up was associated with the risk of sarcopenia by SARC-F. Patients with risk of sarcopenia and those with body mass index ≥30 kg/m2 were to a higher degree offered pulmonary rehabilitation; however, participation was low.

CONCLUSIONS: UWL at baseline was significantly associated with risk of hospital admissions and mortality in ≤1 y in idiopathic pulmonary fibrosis outpatients. Patients with signs of sarcopenia and body mass index ≥30 kg/m2 were most often referred to pulmonary rehabilitation.

PMID:36682268 | DOI:10.1016/j.nut.2022.111964

Sci Rep. 2023 Jan 21;13(1):1225. doi: 10.1038/s41598-023-28536-w.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease that causes irreversible damage to lung tissue characterized by excessive deposition of extracellular matrix (ECM) and remodeling of lung parenchyma. The current diagnosis of IPF is complex and usually completed by a multidisciplinary team including clinicians, radiologists and pathologists they work together and make decision for an effective treatment, it is imperative to introduce novel practical methods for IPF diagnosis. This study provided a new diagnostic model of idiopathic pulmonary fibrosis based on machine learning. Six genes including CDH3, DIO2, ADAMTS14, HS6ST2, IL13RA2, and IGFL2 were identified based on the differentially expressed genes in IPF patients compare to healthy subjects through a random forest classifier with the existing gene expression databases. An artificial neural network model was constructed for IPF diagnosis based these genes, and this model was validated by the distinctive public datasets with a satisfactory diagnostic accuracy. These six genes identified were significant correlated with lung function, and among them, CDH3 and DIO2 were further determined to be significantly associated with the survival. Putting together, artificial neural network model identified the significant genes to distinguish idiopathic pulmonary fibrosis from healthy people and it is potential for molecular diagnosis of IPF.

PMID:36681777 | DOI:10.1038/s41598-023-28536-w

Biomed Pharmacother. 2023 Jan 19;159:114253. doi: 10.1016/j.biopha.2023.114253. Online ahead of print.

ABSTRACT

RATIONALE: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) has a poor prognosis and high mortality. However, there is limited information regarding the mechanisms of AE-IPF.

AIMS: We aimed to explore the function of macrophage-inducible C-type lectin (Mincle) in AE-IPF.

METHODS: In the present study, Mincle was detected in the lung tissues of AE-IPF patients. Mincle-deficient (Mincle-/-) mice and wild-type C57BL/6 mice were administered bleomycin (BLM), followed by HSV1 viral infection to establish the AE-IPF model.

RESULTS: Mincle was increased in the lung tissues of AE-IPF patients compared with those with stable IPF (P = 0.04) and healthy controls (P = 0.009). The survival rate of the Mincle-/-+BLM+HSV group was higher than that of the WT+BLM+HSV group. The mice in the Mincle-/-+BLM+HSV group exhibited milder inflammation and lower acute lung injury scores (P = 0.008). Mincle was expressed on inflammatory monocytes and neutrophils (CD11b+Gr1 +F4/80-) and monocyte-derived macrophages (Mo-AMs, CD11b+Gr1 +F4/80 +) in the BALF of AE-IPF mice. Mo-AMs were significantly increased in the WT+BLM+HSV group compared with the WT+BLM+PBS (P < 0.0001) and Mincle-/-+BLM+HSV (P = 0.0009) groups. Deletion of Mincle decreased the proportion of Th17 cells and Mo-AMs in the Mincle-/-+BLM+HSV group.

CONCLUSIONS: Mincle contributed to acute inflammation in AE-IPF by promoting Th17 differentiation.

PMID:36680813 | DOI:10.1016/j.biopha.2023.114253

Viruses. 2023 Jan 12;15(1):213. doi: 10.3390/v15010213.

ABSTRACT

The coronavirus disease (COVID-19) is a pandemic that started in the City of Wuhan, Hubei Province, China, caused by the spread of coronavirus (SARS-CoV-2). Drug discovery teams around the globe are in a race to develop a medicine for its management. It takes time for a novel molecule to enter the market, and the ideal way is to exploit the already approved drugs and repurpose them therapeutically. We have attempted to screen selected molecules with an affinity towards multiple protein targets in COVID-19 using the Schrödinger suit for in silico predictions. The proteins selected were angiotensin-converting enzyme-2 (ACE2), main protease (MPro), and spike protein. The molecular docking, prime MM-GBSA, induced-fit docking (IFD), and molecular dynamics (MD) simulations were used to identify the most suitable molecule that forms a stable interaction with the selected viral proteins. The ligand-binding stability for the proteins PDB-IDs 1ZV8 (spike protein), 5R82 (Mpro), and 6M1D (ACE2), was in the order of nintedanib &gt; quercetin, nintedanib &gt; darunavir, nintedanib &gt; baricitinib, respectively. The MM-GBSA, IFD, and MD simulation studies imply that the drug nintedanib has the highest binding stability among the shortlisted. Nintedanib, primarily used for idiopathic pulmonary fibrosis, can be considered for repurposing for us against COVID-19.

PMID:36680253 | DOI:10.3390/v15010213

Pharmaceuticals (Basel). 2023 Jan 12;16(1):114. doi: 10.3390/ph16010114.

ABSTRACT

Oxy210, a semi-synthetic oxysterol derivative, displays cell-selective inhibition of Hedgehog (Hh) and transforming growth factor beta (TGF-β) signaling in epithelial cells, fibroblasts, and macrophages as well as antifibrotic and anti-inflammatory efficacy in models of liver fibrosis. In the present report, we examine the effects of Oxy210 in cellular models of lung and kidney fibrosis, such as human lung fibroblast cell lines IMR-90, derived from healthy lung tissue, and LL97A, derived from an idiopathic pulmonary fibrosis (IPF) patient. In addition, we examine the effects of Oxy210 in primary human renal fibroblasts, pericytes, mesangial cells, and renal tubular epithelial cells, known for their involvement in chronic kidney disease (CKD) and kidney fibrosis. We demonstrate in fibroblasts that the expression of several profibrotic TGF-β target genes, including fibronectin (FN), collagen 1A1 (COL1A1), and connective tissue growth factor (CTGF) are inhibited by Oxy210, both at the basal level and following TGF-β stimulation in a statistically significant manner. The inhibition of COL1A1 gene expression translated directly to significantly reduced COL1A1 protein expression. In human primary small airway epithelial cells (HSAECs) and renal tubular epithelial cells, Oxy210 significantly inhibited TGF-β target gene expression associated with epithelial-mesenchymal transition (EMT). Oxy210 also inhibited the proliferation of fibroblasts, pericytes, and mesangial cells in a dose-dependent and statistically significant manner.

PMID:36678611 | DOI:10.3390/ph16010114

Life (Basel). 2023 Jan 11;13(1):212. doi: 10.3390/life13010212.

ABSTRACT

Interstitial lung diseases (ILD) are part of a large heterogeneous group of diseases that differ in many ways (in their cause, clinical presentation, and response to therapy, etc.), but there are similar pathophysiological mechanisms involved in the development of the inflammation and/or fibrosis of the lungs. Currently, several criteria for pulmonary fibrosis (PF) and progressive pulmonary fibrosis (PPF) are proposed, and the information on the prevalence and characteristics of these conditions is limited. The aim of this study was to evaluate the spectrum of PF and PPF according to the registry of patients with ILD in eastern Siberia.

MATERIALS AND METHODS: The study included patients with ILD from all of the medical institutions in the Irkutsk region (eastern Siberia). Each case of ILD (n = 270) was reviewed by a multidisciplinary discussion panel. The ILD patient registry included information on the clinical findings, history, pulmonary function tests, high-resolution computed tomography (HRCT), and histological findings. The follow-up period for the patients varied from 1 to 5 years.

RESULTS: Pulmonary fibrosis was detected by HRCT in 104 patients with ILD (38.5%). PF was present in 100% of the patients with IPF and SS-ILD, in 90.9% of the patients with CHP, in 71.4% of the patients with NSIP, and in 60% of the patients with RA-ILD. Sixty-two patients met the criteria for PPF (23.0% of the entire ILD cohort and 59.6% of the patients with PF). PPF occurred most often in the patients with IPF, CHP, IPAF, and SSc-ILD: 100%, 72.7%, 40%, and 38.5% of them, respectively. The variables associated with fibrosis progression included Velcro crackles (OR 18.3, p &lt; 0.001) and late diagnosis (OR 4.1, p &lt; 0.001).

CONCLUSION: Pulmonary fibrosis and progressive pulmonary fibrosis are common in patients with ILD. The high mortality rate of PPF dictates the need for the active, early detection of a progressive fibrosing course of a wide range of ILD and suggests that further studies assessing the effectiveness of the interventions might be warranted.

PMID:36676161 | DOI:10.3390/life13010212

J Clin Med. 2023 Jan 7;12(2):498. doi: 10.3390/jcm12020498.

ABSTRACT

The identification of novel prognostic biomarkers might enhance individualized management strategies in patients with idiopathic pulmonary fibrosis (IPF). Although several patient characteristics are currently used to predict outcomes, the prognostic significance of the body mass index (BMI), a surrogate measure of excess fat mass, has not been specifically investigated until recently. We systematically searched PubMed, Web of Science, and Scopus, from inception to July 2022, for studies investigating associations between the BMI and clinical endpoints in IPF. The Joanna Briggs Institute Critical Appraisal Checklist was used to assess the risk of bias. The PRISMA 2020 statement on the reporting of systematic reviews was followed. Thirty-six studies were identified (9958 IPF patients, low risk of bias in 20), of which 26 were published over the last five years. Significant associations between lower BMI values and adverse outcomes were reported in 10 out of 21 studies on mortality, four out of six studies on disease progression or hospitalization, and two out of three studies on nintedanib tolerability. In contrast, 10 out of 11 studies did not report any significant association between the BMI and disease exacerbation. Our systematic review suggests that the BMI might be useful to predict mortality, disease progression, hospitalization, and treatment-related toxicity in IPF (PROSPERO registration number: CRD42022353363).

PMID:36675428 | DOI:10.3390/jcm12020498

Int J Mol Sci. 2023 Jan 16;24(2):1796. doi: 10.3390/ijms24021796.

ABSTRACT

Fibrotic diseases, such as systemic sclerosis (SSc), idiopathic pulmonary fibrosis, renal fibrosis and liver cirrhosis are characterized by tissue overgrowth due to excessive extracellular matrix (ECM) deposition. Fibrosis progression is caused by ECM overproduction and the inhibition of ECM degradation due to several events, including inflammation, vascular endothelial dysfunction, and immune abnormalities. Recently, it has been reported that urokinase plasminogen activator (uPA) and its receptor (uPAR), known to be fibrinolytic factors, orchestrate the inflammatory response, vascular homeostasis, and immune homeostasis system. The uPA/uPAR system may show promise as a potential therapeutic target for fibrotic diseases. This review considers the role of the uPA/uPAR system in the progression of fibrotic diseases.

PMID:36675310 | DOI:10.3390/ijms24021796

Int J Mol Sci. 2023 Jan 15;24(2):1708. doi: 10.3390/ijms24021708.

ABSTRACT

The extracellular matrix (ECM) of the lung is a filamentous network composed mainly of collagens, elastin, and proteoglycans that provides structural and physical support to its populating cells. Proliferation, migration and overall behaviour of those cells is greatly determined by micromechanical queues provided by the ECM. Lung fibrosis displays an aberrant increased deposition of ECM which likely changes filament organization and stiffens the ECM, thus upregulating the profibrotic profile of pulmonary cells. We have previously used AFM to assess changes in the Young's Modulus (E) of the ECM in the lung. Here, we perform further ECM topographical, mechanical and viscoelastic analysis at the micro- and nano-scale throughout fibrosis development. Furthermore, we provide nanoscale correlations between topographical and elastic properties of the ECM fibres. Firstly, we identify a softening of the ECM after rats are instilled with media associated with recovery of mechanical homeostasis, which is hindered in bleomycin-instilled lungs. Moreover, we find opposite correlations between fibre stiffness and roughness in PBS- vs bleomycin-treated lung. Our findings suggest that changes in ECM nanoscale organization take place at different stages of fibrosis, with the potential to help identify pharmacological targets to hinder its progression.

PMID:36675222 | DOI:10.3390/ijms24021708

Int J Mol Sci. 2023 Jan 9;24(2):1275. doi: 10.3390/ijms24021275.

ABSTRACT

The aim of this study was to determine the role of endothelin-1 (ET-1), a molecule involved in multiple vascular and fibrosing abnormalities, as a biomarker of interstitial lung disease (ILD), as well as its use for the differential diagnosis between idiopathic pulmonary fibrosis (IPF) and ILD associated with autoimmune diseases (AD-ILD), using a large and well-defined cohort of patients with ILD. A total of 112 patients with IPF, 91 patients with AD-ILD (28 rheumatoid arthritis (RA), 26 systemic sclerosis, 20 idiopathic inflammatory myositis and 17 interstitial pneumonia with autoimmune features) and 44 healthy controls were included. ET-1 serum levels were determined by enzyme-linked immunosorbent assay. A significant increase in ET-1 levels was found in patients with IPF compared to controls. Likewise, AD-ILD patients also showed higher ET-1 levels than controls when the whole cohort was stratified by the type of AD. Similar ET-1 levels were found in IPF and AD-ILD patients, regardless of the underlying AD. Interestingly, increased ET-1 levels were correlated with worse lung function in IPF and RA-ILD patients. Our study supports that serum ET-1 may be useful as a biomarker of ILD, although it could not help in the differential diagnosis between IPF and AD-ILD. Moreover, ET-1 levels may be associated with ILD severity.

PMID:36674789 | DOI:10.3390/ijms24021275

Int J Mol Sci. 2023 Jan 5;24(2):1019. doi: 10.3390/ijms24021019.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and refractory interstitial lung disease. Although there are two approved drugs for IPF, they were not able to completely cure the disease. Therefore, the development of new drugs is required for the effective treatment of IPF. In this study, we investigated the effect of theophylline, which has long been used for the treatment of asthma, on pulmonary fibrosis. The administration of theophylline attenuated the fibrotic changes of lung tissues and improved mechanical pulmonary functions in bleomycin (BLM)-induced pulmonary fibrosis. Theophylline treatment suppressed IL-17 production through inhibiting cytokines controlling Th17 differentiation; TGF-β, IL-6, IL-1β, and IL-23. The inhibition of IL-6 and IL-1β by theophylline is mediated by suppressing BLM-induced ROS production and NF-κB activation in epithelial cells. We further demonstrated that theophylline inhibited TGF-β-induced epithelial-to-mesenchymal transition in epithelial cells through suppressing the phosphorylation of Smad2/3 and AKT. The inhibitory effects of theophylline on the phosphorylation of Smad2/3 and AKT were recapitulated in BLM-treated lung tissues. Taken together, these results demonstrated that theophylline prevents pulmonary fibrosis by inhibiting Th17 differentiation and TGF-β signaling.

PMID:36674533 | DOI:10.3390/ijms24021019

Int J Mol Sci. 2023 Jan 4;24(2):925. doi: 10.3390/ijms24020925.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a form of chronic and irreversible fibrosing interstitial pneumonia of unknown etiology. Although antifibrotic treatments have shown a reduction of lung function decline and a slow disease progression, IPF is characterize by a very high mortality. Emerging evidence suggests that IPF increases the risk of lung carcinogenesis. Both diseases show similarities in terms of risk factors, such as history of smoking, concomitant emphysema, and viral infections, besides sharing similar pathogenic pathways. Lung cancer (LC) diagnosis is often difficult in IPF patients because of the diffuse lung injuries and abnormalities due to the underlying fibrosis. This is reflected in the lack of optimal therapeutic strategies for patients with both diseases. For this purpose, we performed a proteomic study on bronchoalveolar lavage fluid (BALF) samples from IPF, LC associated with IPF (LC-IPF) patients, and healthy controls (CTRL). Molecular pathways involved in inflammation, immune response, lipid metabolism, and cell adhesion were found for the dysregulated proteins in LC-IPF, such as TTHY, APOA1, S10A9, RET4, GDIR1, and PROF1. The correlation test revealed a relationship between inflammation- and lipid metabolism-related proteins. PROF1 and S10A9, related to inflammation, were up-regulated in LC-IPF BAL and serum, while APOA1 and APOE linked to lipid metabolism, were highly abundant in IPF BAL and low abundant in IPF serum. Given the properties of cytokine/adipokine of the nicotinamide phosphoribosyltransferase, we also evaluated its serum abundance, highlighting its down-regulation in LC-IPF. Our retrospective analyses of BAL samples extrapolated some potential biomarkers of LC-IPF useful to improve the management of these contemporary pathologies. Their differential abundance in serum samples permits the measurement of these potential biomarkers with a less invasive procedure.

PMID:36674438 | DOI:10.3390/ijms24020925