Respiratory Research

Our medical research library holds 10 studies published in Respiratory Research (2015–2026). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 10 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: BioMed Central Ltd
• Published: 2000 to the present, England
• Language: English
• ISSN: 1465-9921 (print), 1465-993X (electronic)
• Its record in the NLM Catalog

2020s

• Downregulation of SLC40A1 leads to iron accumulation in fibrotic lung fibroblasts. Q. Dang, C. Huang, Y. Liang, et al. 2026;27(1):91. PubMed · Publisher · Free full text

  Abstract

  Iron is an essential nutrient for almost all organisms. However, excess iron generates reactive oxygen species and causes tissue injuries. Iron is implicated in idiopathic pulmonary fibrosis (IPF). In this study, we examined iron accumulation in fibrotic lung fibroblasts and the underlying mechanisms. We hypothesize that the downregulation of Solute Carrier Family 40 Member 1 (SLC40A1) results in iron accumulation in lung fibroblasts of IPF patients. Using a Prussian Blue iron staining, we found that iron accumulated in the fibrotic region of the lungs from IPF patients and bleomycin- and asbestos-induced lung fibrosis mice. Iron was partially co-localized with the fibroblast marker vimentin in IPF lungs. By using publicly available single cell RNA sequencing datasets, we identified SLC40A1, the only known gene involved in iron export, as a downregulated gene in alveolar fibroblasts of IPF. The downregulation of SLC40A1 was confirmed in the lung fibroblasts isolated from IPF patients and bleomycin-treated mice. The treatment of human lung fibroblasts with transforming growth factor-β1 (TGF-β1), a major cytokine elevated in IPF, reduced SLC40A1 mRNA and protein expression. TGF-β1 downregulated SLC40A1 expression via SMAD3 as determined by chromatin immunoprecipitation and luciferase promoter reporter assays. Knockdown of SLC40A1 using lentiviral shRNAs or TGF-β1 treatment induced iron accumulation in human lung fibroblasts as determined by live cell ferrous dye staining using a SiRhoNox-1 probe. Knockdown of SLC40A1 enhanced the iron-induced lung fibroblast activation. In summary, we conclude that the downregulation of SLC40A1 caused by TGF-β1 induces iron accumulation in lung fibroblasts, resulting in fibroblast activation.

  © 2025. The Author(s).

• Dual-functIon Semi-rigid thoraCoscOpy Versus semi-rigid thoracoscopy for the diagnosis of plEuRal diseases: protocol for a multicentre, open-label, randomised controlled trial in China (DISCOVER-I). M. Deng, X. Liu, W. Chen, et al. 2026;27(1). PubMed · Publisher · Free full text

  Abstract

  BACKGROUND: Exudative pleural effusion often presents diagnostic challenges, with up to 25% of cases remaining undiagnosed after thoracentesis or closed pleural biopsy. Semi-rigid thoracoscopy is a widely used minimally invasive diagnostic method. However, its diagnostic yield is limited by small and superficial biopsy samples due to the lack of mechanical power, particularly in cases of thickened pleura or suspected mesothelioma. We had designed and developed a dual-function semi-rigid thoracoscope and semi-rigid forceps to improve sampling quality and depth. However, their diagnostic performance and safety, particularly compared with that of conventional semi-rigid thoracoscopy is still unclear. METHODS: This randomised controlled trial will enrol a total of 522 adults with exudative pleural effusions of unclear aetiology that remain undiagnosed after the initial investigations from 10 sites in China. Participants will be randomised (1:1:1) to undergo thoracoscopy using either a conventional semi-rigid thoracoscope (with flexible forceps) or a novel dual-function semi-rigid thoracoscope (with either semi-rigid forceps alone or a combination of flexible and rigid forceps). The primary outcome is diagnostic yield. Secondary outcomes include the biopsy success rate, incidence of procedure-related complications, biopsy specimen size and depth, histological interpretability, and adequacy of tissue for molecular marker analysis. DISCUSSION: We hypothesize that the dual-function semi-rigid thoracoscopy with semi-rigid forceps will achieve higher diagnostic yield than conventional semi-rigid thoracoscopy due to the larger and deeper sampling. If this hypothesis is validated, dual-function semi-rigid thoracoscopy could be a novel option for performing pleural biopsy for patients with unknown exudative pleural effusion. TRIAL REGISTRATION: This study has been registered at www.clinicaltrials.gov (ID: NCT06744725; Registration Date: 2024-12-19).

• Integrative eQTL and Mendelian randomization analysis reveals key genetic markers in mesothelioma. J. Li, X. Wang, Y. Lin, et al. 2025;26(1):140. PubMed · Publisher · Free full text

  Abstract

  Background: Mesothelioma is a rare cancer that originates from the pleura and peritoneum, with its incidence increasing due to asbestos exposure. Patients are frequently diagnosed at advanced stages, resulting in poor survival rates. Therefore, the identification of molecular markers for early detection and diagnosis is essential.

  Methods: Three mesothelioma datasets were downloaded from the GEO database for differential gene expression analysis. Instrumental variables (IVs) were identified based on expression quantitative trait locus (eQTL) data for Mendelian randomization (MR) analysis using mesothelioma Genome-Wide Association Study (GWAS) data from the FINNGEN database. The intersecting genes from MR-identified risk genes and differentially expressed genes were identified as key co-expressed genes for mesothelioma. Functional enrichment analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), as well as immune cell correlation analysis, were performed to elucidate the roles of key genes in mesothelioma. Additionally, the differential expression of key genes in mesothelioma was validated in independent GEO datasets and TCGA datasets. This integrative research combining multiple databases and analytical methods established a robust model for identifying mesothelioma risk genes.

  Results: The research conducted in our study identified 1608 genes that were expressed differentially in mesothelioma GEO datasets. By combining these genes with 192 genes from MR analysis, we identified 14 key genes. Notably, MPZL1, SOAT1, TACC3, and CYBRD1 are linked to a high risk of mesothelioma, while TGFBR3, NDRG2, EPAS1, CPA3, MNDA, PRKCD, MTUS1, ALOX15, LRRN3, and ITGAM are associated with a lower risk. These genes were found to be enriched in pathways associated with superoxide metabolism, cell cycle regulation, and proteasome function, all of which are linked to the development of mesothelioma. Noteworthy observations included a significant infiltration of M1 macrophages and CD4 + T cells in mesothelioma, with genes SOAT1, MNDA, and ITGAM showing a positive correlation with the level of M1 macrophage infiltration. Furthermore, the differential expression analyses conducted on the GEO validation set and TCGA data confirmed the significance of the identified key genes.

  Conclusion: This integrative eQTL and Mendelian randomization analysis provides evidence of a positive causal association between 14 key co-expressed genes and mesothelioma genetically. These disease critical genes are implicated in correlations with biological processes and infiltrated immune cells related to mesothelioma. Moreover, our study lays a theoretical foundation for further research into the mechanisms of mesothelioma and potential clinical applications.

  © 2025. The Author(s).

• Role of the occupational disease consultant in the multidisciplinary discussion of interstitial lung diseases. S. Carlier, M. Nasser, E. Fort, et al. 2022;23(1):332. PubMed · Publisher · Free full text

  Abstract

  Background: Diffuse interstitial lung diseases (ILD) constitute a heterogeneous group of conditions with complex etiological diagnoses requiring a multidisciplinary approach. Much is still unknown about them, particularly their relationship with occupational exposures. The primary objective of this study was to investigate the distribution of occupational exposures according to type of ILD. The secondary objectives were to estimate the proportion of ILDs possibly related to occupational exposure and to evaluate the added value of the participation of an occupational disease consultant in ILD multidisciplinary discussions (MDD).

  Methods: From May to December 2020, all consecutive patients with ILD whose cases were reviewed during a MDD in a referral centre for ILD were prospectively offered a consultation with an occupational disease consultant.

  Results: Of the 156 patients with ILD whose cases were reviewed in MDD during the study period, 141 patients attended an occupational exposure consultation. Occupational exposure was identified in 97 patients. Occupational exposure to asbestos was found in 12/31 (38.7%) patients with idiopathic pulmonary fibrosis (IPF) and in 9/18 (50.0%) patients with unclassifiable fibrosis. Occupational exposure to metal dust was found in 13/31 (41.9%) patients with IPFs and 10/18 (55.6%) patients with unclassifiable fibrosis. Silica exposure was found in 12/50 (24.0%) patients with autoimmune ILD. The link between occupational exposure and ILD was confirmed for 41 patients after the specialist occupational consultation. The occupational origin had not been considered (n = 9) or had been excluded or neglected (n = 4) by the MDD before the specialised consultation. A total of 24 (17%) patients were advised to apply for occupational disease compensation, including 22 (15.6%) following the consultation. In addition, a diagnosis different from the one proposed by the MDD was proposed for 18/141 (12.8%) patients.

  Conclusions: In our study, we found a high prevalence of occupational respiratory exposure with a potential causal link in patients with ILD. We suggest that a systematic specialised consultation in occupational medicine could be beneficial in the ILD diagnostic approach.

  © 2022. The Author(s).

• Safety and tolerability of pirfenidone in asbestosis: a prospective multicenter study. J.R. Miedema, C.C. Moor, M. Veltkamp, et al. 2022;23(1):139. PubMed · Publisher · Free full text

  Abstract

  Background: Pirfenidone slows down disease progression in idiopathic pulmonary fibrosis (IPF). Recent studies suggest a treatment effect in progressive pulmonary fibrosis other than IPF. However, the safety and effectiveness of pirfenidone in asbestosis patients remain unclear. In this study, we aimed to investigate the safety, tolerability and efficacy of pirfenidone in asbestosis patients with a progressive phenotype.

  Methods: This was a multicenter prospective study in asbestosis patients with progressive lung function decline. After a 12-week observational period, patients were treated with pirfenidone 801 mg three times a day. Symptoms and adverse events were evaluated weekly and patients completed online patient-reported outcomes measures. At baseline, start of therapy, 12 and 24 weeks, in hospital measurement of lung function and a 6 min walking test were performed. Additionally, patients performed daily home spirometry measurements.

  Results: In total, 10 patients were included of whom 6 patients (66.7%) experienced any adverse events during the study period. Most frequently reported adverse events were fatigue, rash, anorexia and cough, which mostly occurred intermittently and were reported as not very bothersome. No significant changes in hospital pulmonary function (forced vital capacity (FVC), diffusion capacity of the lung for carbon monoxide (DLCO), 6 min walking test or patient-reported outcomes measures before and after start of pirfenidone were found. Home spirometry demonstrated a FVC decline in 12 weeks before start of pirfenidone, while FVC did not decline during the 24 week treatment phase, but this difference was not statistically significant.

  Conclusions: Treatment with pirfenidone in asbestosis has an acceptable safety and tolerability profile and home spirometry data suggest this antifibrotic treatment might attenuate FVC decline in progressive asbestosis. Trial registration MEC-2018-1392; EudraCT number: 2018-001781-41.

  © 2022. The Author(s).

• Possible reversibility between epithelioid and sarcomatoid types of mesothelioma is independent of ERC/mesothelin expression. M. Kojima, K. Kajino, S. Momose, et al. 2020;21(1):187. PubMed · Publisher · Free full text

  Abstract

  Background: Mesothelioma is histologically divided into three subgroups: epithelioid, sarcomatoid, and biphasic types. The epithelioid or sarcomatoid type is morphologically defined by polygonal or spindle-like forms of cells, respectively. The biphasic type consists of both components. It is not yet understood how histological differentiation of mesothelioma is regulated. ERC/mesothelin is expressed in most cases of the epithelioid type, but not in the sarcomatoid type of mesothelioma. Consequently, its expression is well correlated to the histological subtype. We hypothesized that ERC/mesothelin expression influences the histological differentiation of mesothelioma, and tested this hypothesis.

  Methods: We performed studies using the overexpression or knockdown of ERC/mesothelin in mesothelioma cells to examine its effect on cellular morphology, growth kinetics, or migration/invasion activity, in vitro. We then transplanted ERC/mesothelin-overexpressing and control cells into the intraperitoneal space of mice. We examined the effect of ERC/mesothelin overexpression on mouse survival and tumor phenotype.

  Results: In vitro cell culture manipulations of ERC/mesothelin expression did not affect cellular morphology or proliferation, although its overexpression enhanced cellular adhesion and the migration/invasion activity of mesothelioma cells. The survival rate of mice following intraperitoneal transplantation of ERC/mesothelin-overexpressing mesothelioma cells was significantly lower than that of mice with control cells. The histological evaluation of the tumors, however, did not show any morphological difference between two groups, and our hypothesis was not validated. Unexpectedly, both groups (ERC/mesothelin-overexpressing and control) of mesothelioma cells that were morphologically monophasic and spindle-like in vitro differentiated into a biphasic type consisting of polygonal and spindle-like components in the transplanted tumor, irrespective of ERC/mesothelin expression.

  Conclusions: These results suggested that the histological transition of mesothelioma between epithelioid and sarcomatoid types may be reversible and regulated not by ERC/mesothelin, but by other unknown mechanisms.

2010s

• CD44 and its ligand hyaluronan as potential biomarkers in malignant pleural mesothelioma: evidence and perspectives. L. Cortes-Dericks, R.A. Schmid. 2017;18(1):58. Review PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is a rare and highly drug resistant tumor arising from the mesothelial surfaces of the lung pleura. The standard method to confirm MPM is the tedious, time-consuming cytological examination of cancer biopsy. Biomarkers that are detectable in pleural effusion or patient serum are reasonable options to provide a faster and noninvasive diagnostic approach. As yet, the current biomarkers for MPM lack specificity and sensitivity to discriminate this neoplasm from other lung tumors. CD44, a multifunctional surface receptor has been implicated in tumor progression in different cancers including MPM. The interaction of CD44 with its ligand, hyaluronan (HA) has demonstrated an important role in modulating cell proliferation and invasiveness in MPM. In particular, the high expression levels of these molecules have shown diagnostic relevance in MPM. This review will summarize the biology and diagnostic implication of CD44 and HA as well as the interaction of both molecules in MPM that will demonstrate their potential as biomarkers. Augmentation of the current markers in MPM may lead to an earlier diagnosis and management of this disease.

• Dibutyryl-cAMP attenuates pulmonary fibrosis by blocking myofibroblast differentiation via PKA/CREB/CBP signaling in rats with silicosis. Y. Liu, H. Xu, Y. Geng, et al. 2017;18(1):38. PubMed · Publisher · Free full text

  Abstract

  Background: Myofibroblasts play a major role in the synthesis of extracellular matrix (ECM) and the stimulation of these cells is thought to play an important role in the development of silicosis. The present study was undertaken to investigate the anti-fibrotic effects of dibutyryl-cAMP (db-cAMP) on rats induced by silica.

  Methods: A HOPE MED 8050 exposure control apparatus was used to create the silicosis model. Rats were randomly divided into 4 groups: 1)controls for 16 w; 2)silicosis for 16 w; 3)db-cAMP pre-treatment; 4) db-cAMP post-treatment. Rat pulmonary fibroblasts were cultured in vitro and divided into 4 groups as follows: 1) controls; 2) 10-7mol/L angiotensin II (Ang II); 3) Ang II +10-4 mol/L db-cAMP; and 4) Ang II + db-cAMP+ 10-6 mol/L H89. Hematoxylin-eosin (HE), Van Gieson staining and immunohistochemistry (IHC) were performed to observe the histomorphology of lung tissue. The levels of cAMP were detected by enzyme immunoassay. Double-labeling for α-SMA with Gαi3, protein kinase A (PKA), phosphorylated cAMP-response element-binding protein (p-CREB), and p-Smad2/3 was identified by immunofluorescence staining. Protein levels were detected by Western blot analysis. The interaction between CREB-binding protein (CBP) and Smad2/3 and p-CREB were measured by co-immunoprecipitation (Co-IP).

  Results: Db-cAMP treatment reduced the number and size of silicosis nodules, inhibited myofibroblast differentiation, and extracellular matrix deposition in vitro and in vivo. In addition, db-cAMP regulated Gαs protein and inhibited expression of Gαi protein, which increased endogenous cAMP. Db-cAMP increased phosphorylated cAMP-response element-binding protein (p-CREB) via protein kinase A (PKA) signaling, and decreased nuclear p-Smad2/3 binding with CREB binding protein (CBP), which reduced activation of p-Smads in fibroblasts induced by Ang II.

  Conclusions: This study showed an anti-silicotic effect of db-cAMP that was mediated via PKA/p-CREB/CBP signaling. Furthermore, the findings offer novel insight into the potential use of cAMP signaling for therapeutic strategies to treat silicosis.

• Growth suppressive effect of pegylated arginase in malignant pleural mesothelioma xenografts. S.K. Lam, Y.Y. Li, S. Xu, et al. 2017;18(1):80. PubMed · Publisher · Free full text

  Abstract

  Background: Malignant pleural mesothelioma (MPM) is a difficult-to-treat global disease. Pegylated arginase (BCT-100) has recently shown anti-tumor effects in hepatocellular carcinoma, acute myeloid leukemia and melanoma. This study aims to investigate the effects of PEG-BCT-100 in MPM.

  Methods: A panel of 5 mesothelioma cell lines (H28, 211H, H226, H2052 and H2452) was used to study the in vitro effects of BCT-100 by crystal violet staining. The in vivo effects of BCT-100 were studied using 211H and H226 nude mice xenografts. Protein expression (argininosuccinate synthetase, ornithine transcarbamylase, cleaved PARP, cleaved caspase 3, cyclins (A2, D3, E1 and H), CDK4 and Ki67) and arginine concentration were evaluated by Western blot and ELISA respectively. Cellular localization of BCT-100 was detected by immunohistochemistry and immunoflorescence. TUNEL assay was used to identify cellular apoptotic events.

  Results: Argininosuccinate synthetase was expressed in H28, H226, and H2452 cells as well as 211H and H266 xenografts. Ornithine transcarbamylase was undetectable in all cell lines and xenograft models. BCT-100 reduced in vitro cell viability (IC50 values at 13-24 mU/ml, 72 h) across different cell lines and suppressed tumor growth in both 211H and H226 xenograft models. BCT-100 (60 mg/kg) significantly suppressed tumor growth (p < 0.01) with prolonged median survival (p < 0.01) in both xenograft models. Combining BCT-100 with pemetrexed or cisplatin conferred no additional benefits over single agents. Serum and intratumoral arginine levels were effectively decreased by BCT-100, associated with cytosolic accumulation of BCT-100 within tumor cells. Apoptosis (PARP cleavage in 211H xenografts; Bcl-2 downregulation, and cleavage of PARP and caspase 3 in H226 xenografts; positive TUNEL staining in both) and G1 arrest (downregulation of cyclin A2, D3, E1 and CDK4 in 211H xenografts; suppression of cyclin A2, E1, H and CDK4 in H226 xenografts) were evident with BCT-100 treatment. Furthermore, proliferative factor Ki67 was downregulated in BCT-100 treatments arms.

  Conclusions: BCT-100 suppressed tumor growth with prolonged median survival partially mediated by intratumoral arginine depletion resulting in apoptosis and G1 arrest in mesothelioma xenograft models. The findings provide scientific evidence to support further clinical development of BCT-100 in treatment of MPM.

• Overexpression or absence of calretinin in mouse primary mesothelial cells inversely affects proliferation and cell migration. W. Blum, L. Pecze, E. Felley-Bosco, et al. 2015;16:153. PubMed · Publisher · Free full text

  Abstract

  Background: The Ca(2+)-binding protein calretinin is currently used as a positive marker for identifying epithelioid malignant mesothelioma (MM) and reactive mesothelium, but calretinin's likely role in mesotheliomagenesis remains unclear. Calretinin protects immortalized mesothelial cells in vitro from asbestos-induced cytotoxicity and thus might be implicated in mesothelioma formation. To further investigate calretinin's putative role in the early steps of MM generation, primary mesothelial cells from calretinin knockout (CR-/-) and wildtype (WT) mice were compared.

  Methods: Primary mouse mesothelial cells from WT and CR-/- mice were investigated with respect to morphology, marker proteins, proliferation, cell cycle parameters and mobility in vitro. Overexpression of calretinin or a nuclear-targeted variant was achieved by a lentiviral expression system.

  Results: CR-/- mice have a normal mesothelium and no striking morphological abnormalities compared to WT animals were noted. Primary mouse mesothelial cells from both genotypes show a typical "cobblestone-like" morphology and express mesothelial markers including mesothelin. In cells from CR-/- mice in vitro, we observed more giant cells and a significantly decreased proliferation rate. Up-regulation of calretinin in mesothelial cells of both genotypes increases the proliferation rate and induces a cobblestone-like epithelial morphology. The length of the S/G2/M phase is unchanged, however the G1 phase is clearly prolonged in CR-/- cells. They are also much slower to close a scratch in a confluent cell layer (2D-wound assay). In addition to a change in cell morphology, an increase in proliferation and mobility is observed, if calretinin overexpression is targeted to the nucleus. Thus, both calretinin and nuclear-targeted calretinin increase mesothelial cell proliferation and consequently, speed up the scratch-closure time. The increased rate of scratch closure in WT cells is the result of two processes: an increased proliferation rate and augmented cell mobility of the border cells migrating towards the empty space.

  Conclusions: We hypothesize that the differences in proliferation and mobility between WT and CR-/- mesothelial cells are the likely result from differences in their developmental trajectories. The mechanistic understanding of the function of calretinin and its putative implication in signaling pathways in normal mesothelial cells may help understanding its role during the processes that lead to mesothelioma formation and could possibly open new avenues for mesothelioma therapy, either by directly targeting calretinin expression or indirectly by targeting calretinin-mediated downstream signaling.

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