Fibrotic Group Research Articles

Predictive factors of fibrotic interstitial lung abnormality on high-resolution computed tomography scans: a prospective observational study

BackgroundFibrotic types of interstitial lung abnormalities seen on high-resolution computed tomography scans, characterised by traction bronchiolectasis/bronchiectasis with or without honeycombing, are predictors of progression and poor prognostic factors of interstitial lung abnormalities. There are no reports on the clinical characteristics of fibrotic interstitial lung abnormalities on high-resolution computed tomography scans. Therefore, we aimed to examine these clinical characteristics and clarify the predictive factors of fibrotic interstitial lung abnormalities on high-resolution computed tomography scans.MethodsClinical and paraclinical data of 164 patients enrolled in the initial year of a multicentre prospective observational study (Kumamoto interstitial lung abnormalities study in Japan) involving over 62,000 examinees during routine health examinations were analysed. Clinical laboratory evaluations are expressed as medians and interquartile ranges for each evaluation time point, and boxplots were created for graphical representation. The percentages of abnormal clinical laboratory results were compared between the groups using chi-square or Fisher’s exact tests. Univariate or multivariate logistic regression analyses were performed to analyse the relationship between fibrotic interstitial lung abnormalities and other clinical factors.ResultsFibrotic interstitial lung abnormalities were observed on high-resolution computed tomography scans in 135 (82%) patients at the time of diagnosis. Multivariate analysis showed that older age (Odds ratio, 1.06; 95% confidence interval, 1.01–1.12; p = 0.021), auscultatory fine crackles (Odds ratio, 3.39; 95% confidence interval, 1.33–8.65; p < 0.01), and elevated serum surfactant protein-D (Odds ratio, 2.68; 95% confidence interval, 1.02–8.64; p = 0.045) were independent predictive factors of fibrotic interstitial lung abnormalities. The predicted area under the curve of the fibrotic interstitial lung abnormalities based on these three factors was 0.77 (95% confidence interval, 0.68–0.86). The proportion of undecided diagnoses in the fibrotic interstitial lung abnormalities group (14%) was significantly lower than that in the non-fibrotic interstitial lung abnormalities group (41%) (p = 0.0027).ConclusionsFine crackles on auscultation and elevated serum surfactant protein-D levels are predictors of fibrotic interstitial lung abnormalities in older patients with interstitial lung abnormalities. These findings may assist non-radiological physicians in referring patients to specialists for early intervention in progressive fibrotic interstitial lung diseases.Trial registration number/dateUMIN000045149/2021.12.1.

CD34hi subset of synovial fibroblasts contributes to fibrotic phenotype of human knee osteoarthritis.

Osteoarthritis (OA) shows various clinical manifestations depending on the status of its joint components. We aimed to identify the synovial cell subsets responsible for OA pathophysiology by comprehensive analyses of human synovium samples in single-cell resolution. Two distinct OA synovial tissue groups were classified by gene expression profiles in RNA-Seq: inflammatory and fibrotic. The inflammatory group exhibited high expression of inflammatory cytokines, histologically inflammatory infiltrate, and a more severe pain score. The fibrotic group showed higher expression of fibroblast growth factor (FGFs) and bone morphogenetic proteins (BMPs), showed histologically perivascular fibrosis, and showed a lower pain score. In single-cell RNA-Seq (scRNA-Seq) of synovial cells, MERTKloCD206lo macrophages and CD34hi fibroblasts were associated with the inflammatory and fibrotic groups, respectively. Among the 3 fibroblast subsets, CD34loTHY1lo and CD34loTHY1hi fibroblasts were influenced by synovial immune cells, whereas CD34hi fibroblasts were influenced by mural and endothelial cells. Particularly, in CD34hi fibroblast subsets, CD34hiCD70hi fibroblasts promoted proliferation of Tregs, potentially suppressing synovitis and protecting articular cartilage. Elucidation of the mechanisms underlying the regulation of these synovial cell subsets may lead to novel strategies for OA therapeutics.

Genetics, sex and the use of platelet-rich plasma influence the development of arthrofibrosis after anterior cruciate ligament reconstruction.

To identify genes and patient factors that are related to the development of arthrofibrosis in patients after anterior cruciate ligament (ACL) reconstruction and to develop a prognostic model. The study included patients diagnosed with ACL injury who underwent ACL reconstruction. Patients were enroled consecutively and divided into non-fibrotic (controls) and fibrotic (cases) groups until a balanced sample of matched case-control was achieved. Arthrofibrosis was considered pathological if the range of motion achieved 3 months after surgery decreased by at least 25% compared to its initial full range of motion. Patient variables and saliva samples were collected from each patient to perform a genetic approach by screening a set of candidate genes implicated in arthrofibrosis. Chi-squared was used to analyze the association between the development of arthrofibrosis and different independent variables. Binary logistic regression was used to develop a prognostic algorithm. A total of 45 controls (non-fibrotic patients) (50.1%) and 44 cases (fibrotic patients) (49.9%) were included for analysis. The median age was 34.0 years (95% confidence interval = 29.0-38.0) and the number of women was 32 (35.9%). Seven genetic polymorphisms showed significant association with the development of arthrofibrosis (p < 0.05). After binary regression analysis, the regression model included the polymorphisms rs4343 (ACE), rs1800947 (CRP), rs8032158 (NEDD4) and rs679620 (MMP3). This analysis also indicated that female gender was a risk factor while the use of platelet-rich plasma (PRP) during surgery was a preventive factor (p < 0.05). Genetic alterations involved in inflammation and extracellular matrix turnover predispose to the development of arthrofibrosis after ACL reconstruction. Female sex was a risk factor in the development of this condition, while the application of PRP provided a preventive effect. The combination of patient and genetic variants of a patient allows the development of a prognostic algorithm for the risk of post-surgical arthrofibrosis. level III.

Mutual Amplification of GLI2/Hedgehog and Transcription Factor JUN/AP-1 Signaling in Fibroblasts in Systemic Sclerosis: Potential Implications for Combined Therapies.

Deregulation of the cJUN/AP-1 and hedgehog/GLI2 signaling pathways has been implicated in fibroblast activation in systemic sclerosis (SSc). However, the consequences of their concomitant up-regulation are unknown. Here, we tested the hypothesis that mutual amplification of both pathways might drive persistent fibroblast activation. Cultured fibroblasts and skin sections of patients with diffuse SSc and healthy volunteers were analyzed. cJUN/AP-1 signaling and hedgehog/GLI2 signaling were inhibited using knockdown and pharmacologic approaches. Hedgehog signaling was activated in mice by fibroblast-specific overexpression of constitutively active Smoothened. cJUN and GLI2 are concomitantly up-regulated and colocalize in fibroblasts of patients with SSc compared to healthy controls. Activation of hedgehog/GLI2 signaling induces the expression of cJUN in vitro and in vivo, whereas inactivation of GLI2 inhibits cJUN expression. Likewise, inactivation of cJUN impairs the expression of GLI2. This mutual regulation occurs at the level of transcription with binding of cJUN and GLI2 to specific binding motifs. Interference with this mutual amplification of cJUN signaling and GLI2 signaling inhibits fibroblast activation and collagen release: Inhibition of cJUN/AP-1 signaling ameliorates hedgehog-induced fibroblast activation and skin fibrosis in SmoACT mice with a reduction of skin thickness of 103% (P = 0.0043) in the treatment group compared to the fibrotic control group. Moreover, combined pharmacologic inhibition of cJUN/AP-1 and hedgehog/GLI2 exerts additive antifibrotic effects in a model of TGFβ-driven experimental fibrosis (TBRACT mice). The transcription factors cJUN and GLI2 reinforce each other's activity to promote fibroblast activation in SSc. Interruption of this crosstalk by combined inhibition of both pathways exerts additive antifibrotic effects at well-tolerated doses.

A pilot metabolomics study across the continuum of interstitial lung disease fibrosis severity.

Interstitial lung diseases (ILDs) include a variety of inflammatory and fibrotic pulmonary conditions. This study employs high-resolution metabolomics (HRM) to explore plasma metabolites and pathways across ILD phenotypes, including non-fibrotic ILD, idiopathic pulmonary fibrosis (IPF), and non-IPF fibrotic ILD. The study used 80 plasma samples for HRM, and involved linear trend and group-wise analyses of metabolites altered in ILD phenotypes. We utilized limma one-way ANOVA and mummichog algorithms to identify differences in metabolites and pathways across ILD groups. Then, we focused on metabolites within critical pathways, indicated by high pathway overlap sizes and low p-values, for further analysis. Targeted HRM identified putrescine, hydroxyproline, prolyl-hydroxyproline, aspartate, and glutamate with significant linear increases in more fibrotic ILD phenotypes, suggesting their role in ILD fibrogenesis. Untargeted HRM highlighted pathway alterations in lysine, vitamin D3, tyrosine, and urea cycle metabolism, all associated with pulmonary fibrosis. In addition, methylparaben level had a significantly increasing linear trend and was higher in the IPF than fibrotic and non-ILD groups. This study highlights the importance of specific amino acids, metabolic pathways, and xenobiotics in the progression of pulmonary fibrosis.

U-Net-based computed tomography quantification of viral pneumonia can predict fibrotic interstitial lung abnormalities at 3-month follow-up.

Given the high prevalence of fibrotic interstitial lung abnormalities (ILAs) post-COVID-19, this study aims to evaluate the effectiveness of quantitative CT features in predicting fibrotic ILAs at 3-month follow-up. This retrospective study utilized cohorts from distinct clinical settings: the training dataset comprised individuals presenting at the fever clinic and emergency department, while the validation dataset included patients hospitalized with COVID-19 pneumonia. They were classified into fibrotic group and nonfibrotic group based on whether the fibrotic ILAs were present at follow-up. A U-Net-based AI tool was used for quantification of both pneumonia lesions and pulmonary blood volumes. Receiver operating characteristic (ROC) curve analysis and multivariate analysis were used to assess their predictive abilities for fibrotic ILAs. Among the training dataset, 122 patients (mean age of 68 years ±16 [standard deviation], 73 men), 55.74% showed fibrotic ILAs at 3-month follow-up. The multivariate analysis identified the pneumonia volume [PV, odd ratio (OR) 3.28, 95% confidence interval (CI): 1.20-9.31, p = 0.02], consolidation volume (CV, OR 3.77, 95% CI: 1.37-10.75, p = 0.01), ground-glass opacity volume (GV, OR 3.38, 95% CI: 1.26-9.38, p = 0.02), pneumonia mass (PM, OR 3.58, 95% CI: 1.28-10.46, p = 0.02), and the CT score (OR 12.06, 95% CI: 3.15-58.89, p < 0.001) as independent predictors of fibrotic ILAs, and all quantitative parameters were as effective as CT score (all p > 0.05). And the area under the curve (AUC) values were PV (0.79), GV (0.78), PM (0.79), CV (0.80), and the CT score (0.77). The validation dataset, comprising 45 patients (mean age 67.29 ± 14.29 years, 25 males) with 57.78% showing fibrotic ILAs at follow-up, confirmed the predictive validity of these parameters with AUC values for PV (0.86), CV (0.90), GV (0.83), PM (0.88), and the CT score (0.85). Additionally, the percentage of blood volume in vessels <5mm2 relative to the total pulmonary blood volume (BV5%) was significantly lower in patients with fibrotic ILAs (p = 0.048) compared to those without. U-Net based quantification of pneumonia lesion and BV5% on baseline CT scan has the potential to predict fibrotic ILAs at follow-up in COVID-19 patients.

Effect of breathing exercises on patients with interstitial lung disease: A systematic review and meta-analysis.

This study was designed to synthesize the efficacy and safety of breathing exercises in interstitial lung disease (ILD) patients by reviewing the literature and comparing the impact of different control group types, ILD subtypes, breathing exercise action modes or methods, and intervention durations on clinical efficacy. Systematic searches were conducted across 9 electronic databases, including PubMed, to retrieve English and Chinese studies reporting on ILD patients from inception to February 12, 2024. Study selection and data extraction were independently conducted by two researchers. The quality of the included studies was assessed using the Cochrane risk of bias tool. The data were analysed using RevMan 5.4 and STATA 17.0 software. The search identified 25 studies. Compared to the control group, the breathing exercise group exhibited significantly improved lung function (FVC%pred: MD = 3.46, 95%CI = 1.04 to 5.88; DLCO%pred: MD = 3.20, 95% CI = 2.91 to 3.48), dyspnoea (MRC or mMRC scale: MD = -0.50, 95%CI = -0.77 to -0.22), exercise capacity (6MWD: MD = 32.65, 95% CI = 14.77 to 50.53), and HRQoL (SGRQ: MD = -6.53, 95% CI = -8.72 to -4.34) in ILD patients. According to the subgroup analysis, significant improvements consistent with the overall results were observed in the control group with usual treatment. Compared with the control group, breathing exercises had varying degrees of improvement in the mixed diagnostic group, known-cause group, and fibrotic group of ILD patients; breathing exercises alone significantly improved DLCO%pred, MRC (or mMRC), and SGRQ; and the improvement in breathing exercises as part of pulmonary rehabilitation (PR) was more notable. Different durations of breathing exercise could promote the efficacy of different aspects of treatment for ILD patients. Compared with usual treatment, breathing exercises can improve lung function, exercise capacity, and HRQoL in ILD patients, particularly without high requirements for intervention duration. The efficacy of breathing exercises varies for different ILD subtypes, and incorporating breathing exercises as part of PR can be more beneficial for ILD patients. No studies have shown significant risks for ILD patients engaging in breathing exercises.

Effects of injury size on local and systemic immune cell dynamics in volumetric muscle loss.

We took a systems approach to the analysis of macrophage phenotype in regenerative and fibrotic volumetric muscle loss outcomes in mice together with analysis of systemic inflammation and of other leukocytes in the muscle, spleen, and bone marrow. Macrophage dysfunction in the fibrotic group occurred as early as day 1, persisted to at least day 28, and was associated with increased numbers of leukocytes in the muscle and bone marrow, increased pro-inflammatory marker expression in splenic macrophages, and changes in the levels of pro-inflammatory cytokines in the blood. The most prominent differences were in muscle neutrophils, which were much more abundant in fibrotic outcomes compared to regenerative outcomes at day 1 after injury. However, neutrophil depletion had little to no effect on macrophage phenotype or on muscle repair outcomes. Together, these results suggest that the entire system of immune cell interactions must be considered to improve muscle repair outcomes.

Role of transforming growth factor beta in assessment of severity of hypersensitivity pneumonitis: a single center study

BackgroundHypersensitivity pneumonitis (HP) is a more frequently diagnosed picture of diffuse parenchymal lung disease. It is an inflammation of the lung tissue, provoked by immune mechanisms, which happens to prone individuals as a reaction to a wide range of antigens. There are different degrees of fibrosis and inflammation. A group of extracellular mediators both proinflammatory and profibrotic claimed to be involved in the pathogenesis of HP. Among these mediators, a significant role is played by transforming growth factor-beta (TGF-β).AimCorrelation between the severity of hypersensitivity pneumonitis and the serum level of TGF beta.Patients and methodsSixty subjects were included in the study who were classified into 30 patients newly diagnosed with hypersensitivity pneumonitis and 30 healthy subjects served as controls. All the participants were subjected to complete history taking, physical examination, spirometry, 6-min walk distance test, HRCT, and serum levels of TGF-β.ResultsThe serum level of TGF beta is elevated in newly diagnosed HP cases (fibrotic and non-fibrotic) in relation to control participants showing statistical significance p value < 0.001, and the serum level of TGF beta in the fibrotic group of HP patients is more than that in non-fibrotic group with statistical significance p value 0.012.ConclusionThe serum level of transforming growth factor can be used in the assessment of the severity of hypersensitivity pneumonitis as regards the intensity of lung parenchymal changes.

Immunological Similarities and Differences between Post-COVID-19 Lung Sequelae and Idiopathic Pulmonary Fibrosis.

Pulmonary fibrosis is an irreversible condition that may be caused by known (including viral triggers such as SARS-CoV-2) and unknown insults. The latter group includes idiopathic pulmonary fibrosis (IPF), which is a chronic, progressive fibrosing interstitial pneumonia of unknown cause. The longer the insult acts on lung tissue, the lower the probability of a complete resolution of the damage. An emerging clinical entity post-COVID-19 is pulmonary fibrosis (PCPF), which shares many pathological, clinical, and immunological features with IPF. The fibrotic response in both diseases-IPF and PCPF-is orchestrated in part by the immune system. An important role regarding the inhibitory or stimulatory effects on immune responses is exerted by the immune checkpoints (ICs). The aim of the present study was to analyse the similarities and differences between CD4+, CD8+, and NK cells in the peripheral blood of patients affected by fibrotic disease, IPF, and PCPF compared with sarcoidosis patients and healthy controls. The second aim was to evaluate the expression and co-expression of PD-1 and TIGIT on CD4, CD8, and NK cells from our patient cohort. One hundred and fifteen patients affected by IPF, PCPF, and sarcoidosis at the rare pulmonary disease centre of the University of Siena were enrolled. Forty-eight patients had an IPF diagnosis, 55 had PCPF, and 12 had sarcoidosis. Further, ten healthy controls were enrolled. PCPF patients were included between 6 and 9 months following hospital discharge for COVID-19. The peripheral blood samples were collected, and through flow cytometric analysis, we analysed the expression of CD4, CD8, NK cells, PD-1, and TIGIT. The results show a greater depletion of CD4 and NK cells in IPF patients compared to other groups (p = 0.003), in contrast with CD8 cells (p < 001). Correlation analysis demonstrated an indirect correlation between CD4 and CD8 cells in IPF and sarcoidosis patients (p < 0.001 = -0.87 and p = 0.042; r = -0.6, respectively). Conversely, PCPF patients revealed a direct correlation between CD4 and CD8 cells (p < 0.001; r = 0.90) accentuating an immune response restoration. The expression of PD-1 and TIGIT was abundant on T and NK cell subsets of the two lung fibrotic groups, IPF and PCPF. Analogously, the co-expression of PD-1 and TIGIT on the surfaces of CD4 and CD8 were increased in such diseases. Conclusions: Our study shines a spotlight on the immune responses involved in the development of pulmonary fibrosis, idiopathic and secondary to SARS-CoV-2 infection. We observed a significant imbalance not only in CD4, CD8, and NK blood percentages in IPF and PCPF patients but also in their functional phenotypes evaluated through the expression of ICs.

The Portal Venous Pulsatility Index and Main Portal Vein Diameter as Surrogate Markers for Liver Fibrosis in Nonalcoholic Fatty Liver Disease and Metabolic-Dysfunction-Associated Steatotic Liver Disease.

(1) Background: Despite numerous noninvasive methods for assessing liver fibrosis, effective ultrasound parameters remain limited. We aimed to identify easily measurable ultrasound parameters capable of predicting liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) and metabolic-dysfunction-associated steatotic liver disease (MASLD); (2) Methods: The data of 994 patients diagnosed with NAFLD via ultrasound at the Armed Forces Goyang Hospital were retrospectively collected from June 2022 to July 2023. A liver stiffness measurement (LSM) ≥ 8.2 kPa was classified as significant fibrosis. Liver steatosis with cardiometabolic risk factors was defined as MASLD. Two ultrasound variables, the portal venous pulsatility index (VPI) and main portal vein diameter (MPVD), were measured; (3) Results: Of 994 patients, 68 had significant fibrosis. Significant differences in VPI (0.27 vs. 0.34, p < 0.001) and MPVD (10.16 mm vs. 8.98 mm, p < 0.001) were observed between the fibrotic and non-fibrotic groups. A logistic analysis adjusted for age and body mass index (BMI) revealed that only VPI (OR of 0.955, p = 0.022, VPI on a 0.01 scale) and MPVD (OR of 1.501, p < 0.001) were significantly associated with significant liver fibrosis. In the MASLD cohort (n = 939), VPI and MPVD were associated with significant fibrosis. To achieve better accuracy in predicting liver fibrosis, we established a nomogram that incorporated MPVD and VPI. The established nomogram was validated in the test cohort, yielding an area under the receiver operating characteristic curve of 0.821 for detecting significant liver fibrosis; (4) Conclusions: VPI and MPVD, as possible surrogate markers, are useful in predicting significant fibrosis in patients with NAFLD and MASLD.

Expression of Matrix Metalloproteinases in Human Cystic Echinococcosis.

Cystic echinococcosis (CE) is a zoonotic disease caused by the Echinococcus granulosus senso lato (E. granulosus s.l.) larval stages. Parasitederived products have been shown to regulate host matrix metalloproteinases (MMPs), contributing to CE pathogenesis and progressive liver fibrosis in intermediate hosts. The current study aimed to investigate the potential role of MMP1, 7, 8, and 13 in E. granulosus s.l-induced liver fibrosis. Thirty CE patients with active, transitional, or inactive hydatid cysts were enrolled in this study to determine the inductive effects of E. granulosus on the expression of MMP-1, MMP-7, MMP-8, and MMP-13 in healthy liver tissue and fibrotic liver tissue using qRT-PCR. According to the WHO-IWGE classification, patients with functional cysts (CE1 and CE2) had the highest percentage (46.6%). MMP-1, MMP-7, MMP-8, and MMP-13 expression levels were significantly higher in fibrotic liver than in normal liver tissue. MMP-13 and MMP-1 had the highest and lowest expression levels among MMPs. Compared to the normal group, the fold change for MMP-13 in the fibrotic group was greater than 12 and had the highest AUC value (AUC= 0.8283). Our findings suggest that E. granulosus-derived products might be involved in regulating host MMPs. Thus, MMPs may be considered potential biomarkers for predicting CE prognosis. Because of the non-normal distribution of our patients' CE types, further research, particularly on circulation MMPs, is needed to confirm the potential role of MMPs in CE pathogenesis and to follow up on CE patients.

Sulforaphane (Sul) reduces renal interstitial fibrosis (RIF) by controlling the inflammation and TGF-β/Smad signaling pathway

All chronic renal disorders eventually lead to renal interstitial fibrosis (RIF). Chronic inflammation and pro-fibrotic substances are familiar companions of the fibrotic process. The Sulforaphane (Sul) molecule is particularly useful in protecting the liver from oxidative damage. To investigate the Sul effects on fibrosis markers and inflammatory proteins in the kidney of NRK52E cell line and rats and clarify the mechanism of TGF-β/Smad signaling pathway in a rat model of RIF were developed in the present study. Sul (50, 100, and 200 ng/ml) remarkably reduced the gene expressions of tumor necrosis factor (TNF-α), interleukin-6 (IL-6), interleukin (IL)-1β, collagen 3 (COL3A1), collagen 1 (COL1A1), and α-smooth muscle actin (α-SMA) in fibrotic NRK52E cells compared with those in cells inspired by transforming growth factor-α (TGF-α). Histopathological investigations showed that Sul administration retained renal tissue structure and decreased kidney tissue fibrosis in rats subjected to unilateral ureteral blockage (UUO). The expression level of TNF-α, IL-6, IL-1β, COL3A1, COL1A1, and α-SMA in the rats’ kidneys exposed to UUO was also suppressed by the treatment of Sul. In the present study, western blot analysis showed that Sul upregulated the expressions of fibrotic NRK52E cells Smad7 and rat model UUO groups while simultaneously decreasing the stimulation of Smad2/3 and the expressions of cyclooxygenase-2, NF-κB, Smad4, activator protein-1, and high-mobility group protein B1. Ultimately, Sul’s ability to inhibit the TGF-β/Smad pathway and the development of inflammation factors may mitigate RIF.

The Role of Zinc on Liver Fibrosis by Modulating ZIP14 Expression Throughout Epigenetic Regulatory Mechanisms

Zinc plays a pivotal role in tissue regeneration and maintenance being as a central cofactor in a plethora of enzymatic activities. Hypozincemia is commonly seen with chronic liver disease and is associated with an increased risk of liver fibrosis development and hepatocellular carcinoma. Previously favorable effects of zinc supplementation on liver fibrosis have been shown. However, the underlying mechanism of this effect is not elucidated. Liver fibrosis was induced in mice by using CCl4 injection, followed by treatment with zinc chloride (ZnCl2) both at fibrotic and sham groups, and their hepatocytes were isolated. Our results showed that the administration of ZnCl2 restored the depleted cytosolic zinc levels in the hepatocytes isolated from the fibrotic group. Also, alpha-smooth muscle actin (αSMA) expression in hepatocytes was decreased, indicating a reversal of the fibrotic process. Notably, ZIP14 expression significantly increased in the fibrotic group following ZnCl2 treatment, whereas in the sham group ZIP14 expression decreased. Chromatin immunoprecipitation (ChIP) experiments revealed an increased binding percentage of Metal-regulatory transcription factor 1 (MTF1) on ZIP14 promoter in the hepatocytes isolated from fibrotic mice compared to the sham group after ZnCl2 administration. In the same group, the binding percentage of the histone deacetylase HDAC4 on ZIP14 promoter decreased. Our results suggest that the ZnCl2 treatment ameliorates liver fibrosis by elevating intracellular zinc levels through MTF1-mediated regulation of ZIP14 expression and the reduction of ZIP14 deacetylation via HDAC4. The restoration of intracellular zinc concentrations and the modulation of ZIP14 expression by zinc orchestrated through MTF1 and HDAC4, appear to be essential determinants of the therapeutic response in hepatic fibrosis. These findings pave the way for potential novel interventions targeting zinc-related pathways for the treatment of liver fibrosis and associated conditions.

Can TERT rs2853669 polymorphysm indicate fibrosis in sarcoidosis?

Sarcoidosis is a systemic inflammatory disease of unknown cause, characterized by the presence of non-caseating granulomas, which can affect all organs in the body, especially the lung. The fibrotic stage 4 of sarcoidosis usually does not respond adequately to treatment and may cause respiratory distress in the patient. Some telomerase gene polymorphisms have been significantly associated with lung cancer and idiopathic pulmonary fibrosis. In our study, we aimed to investigate the relationship between telomerase mutation and progression to fibrosis in patients with sarcoidosis. A total of 93 patients, including 18 males and 73 females, who were clinically and histopathologically diagnosed with sarcoidosis were included in the study. The 78 patients included in the study were classified as non-fibrotic and 15 as fibrotic sarcoidosis. In telomerase rs2853669 single nucleotide polymorphism, three genotypes, homozygous TT, homozygous CC and heterozygous TC, were determined as the genotypes of the patients. When non-fibrotic and fibrotic sarcoidosis groups were compared, no significant difference was found in terms of genotypes (p=0.76). The FEV1 (forced expiratory volume in the first second) % of the CC genotype was lower than that of the other genotypes (p=0.01). In sarcoidosis patients, telomerase rs2853669 polymorphism does not indicate progression to fibrosis, but since FEV1% was found to be lower in individuals with homozygous CC polymorphism, it is thought that it may predict loss of respiratory function. Further studies are needed to evaluate the association of telomerase polymorphisms with fibrosis in sarcoidosis.

Identification of Fibroinflammatory and Fibrotic Transcriptomic Subsets of Human Cutaneous Sclerotic Chronic Graft-Versus-Host Disease

Cutaneous sclerotic chronic graft-versus-host disease (cGVHD) is a common and highly morbid complication of allogeneic hematopoietic stem cell transplantation (HSCT). Our goals were to identify signals active in the skin of sclerotic cGVHD patients in an effort to better understand how to treat this manifestation and to explore the heterogeneity of the disease. We identified genes that are significantly upregulated in the skin of sclerotic cGVHD patients (n = 17) compared to HSCT patients without cutaneous cGVHD (n = 9) by bulk RNA sequencing. Sclerotic cGVHD was most associated with Th1, phagocytic, and fibrotic pathways. Additionally, different transcriptomic groups of affected patients were discovered: those with fibrotic and inflammatory/Th1 gene expression (the fibroinflammatory group) and those with predominantly fibrotic/TGFβ-associated expression (the fibrotic group). Further study will help elucidate if these gene expression findings can be used to tailor treatment decisions. Multiple proteins encoded by highly-induced genes in the skin (SFRP4, SERPINE2, COMP) were also highly induced in the plasma of sclerotic cGVHD patients (n = 16) compared to control HSCT patients without sclerotic cGVHD (n = 17), suggesting these TGFβ and Wnt pathway mediators as candidate blood biomarkers of disease.

Targeted changes in blood lipids improves fibrosis in renal allografts

BackgroundChronic interstitial fibrosis is the primary barrier against the long-term survival of transplanted kidneys. Extending the lifespan of allografts is vital for ensuring the long-term health of patients undergoing kidney transplants. However, few targets and their clinical applications have been identified. Moreover, whether dyslipidemia facilitates fibrosis in renal allograft remains unclear.MethodsBlood samples were collected from patients who underwent kidney transplantation. Correlation analyses were conducted between the Banff score and body mass index, and serum levels of triacylglycerol, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. A rat model of renal transplantation was treated with the lipid-lowering drug, fenofibrate, and kidney fibrosis levels were determined by histochemical staining. Targeted metabolomic detection was conducted in blood samples from patients who underwent kidney transplantation and were divided into fibrotic and non-fibrotic groups. Rats undergoing renal transplantation were fed either an n-3 or n-6 polyunsaturated fatty acid (PUFA)-enriched diet. Immunohistochemical and Masson’s trichrome staining were used to determine the degree of fibrosis.ResultsHyperlipidemia was associated with fibrosis development. Treatment with fenofibrate contributed to improve fibrosis in a rat model of renal transplantation. Moreover, n-3 PUFAs from fibrotic group showed significant downregulation compared to patients without fibrotic renal allografts, and n-3 PUFAs-enriched diet contributed to delayed fibrosis in a rat model of renal transplantation.ConclusionsThis study suggests that hyperlipidemia facilitates fibrosis of renal allografts. Importantly, a new therapeutic approach was provided that may delay chronic interstitial fibrosis in transplanted kidneys by augmenting the n-3 PUFA content in the diet.

Occupational quantitative exposure to crystalline silica, solvents and pesticides and risk of clinical forms of systemic sclerosis

Abstract Objectives To estimate the association between SSc clinical phenotypes and quantitative occupational exposure to crystalline silica, chlorinated solvents, trichloroethylene and pesticides using job-exposure matrices. Methods In the VISS-EXPOSITION transversal study, data on declarative occupational exposure to crystalline silica, solvents and pesticides were retrieved. In parallel, the lifetime occupational history was evaluated using a questionnaire and cursus laboris for SSc patients followed at Bordeaux University Hospital (France). Using job-exposure matrices, we assessed patients’ occupational exposure in relation to relevant clinical phenotypic forms of the disease. Results Toxic exposure to crystalline silica and pesticides is underestimated by patients. Non-biased job-exposure matrices retrieved more exposed patients than the declarative assessment (10.1% of patients by job-exposure matrices vs 6.3% by declaration for crystalline silica and 25.9% vs 12.2% for pesticides). Patients overestimate their solvent exposure (7.9% for chlorinated solvents and 4.8% for trichlorethylene assessed by job-exposure matrices and 24.4% declarative exposure to solvents at large). Clinical form evaluation revealed a non-significant trend toward an increased risk of crystalline silica occupational exposure in the pulmonary fibrotic group of SSc patients [odds ratio (OR) 3.12 (95% CI 0.80, 12.15)]. We also observed a non-significant trend toward an elevated OR ([2.89 (95% CI 0.93, 8.95)] for chlorinated solvent occupational exposure and the vascular phenotype of SSc. Of note, pesticide occupational exposure evaluation represents one of the largest to date in SSc patients. Conclusion This study emphasizes that many exposed SSc patients are unaware of their occupational exposure. Job-exposure matrices allow better exposure screening for SSc secondary prevention and occupational exposure compensation. Clinical trial registration clinicaltrials.gov (https://www.clinicaltrials.gov), NCT03543956

Arsenic exposure was associated with lung fibrotic changes in individuals living near a petrochemical complex.

Individuals residing near petrochemical complexes have been found to have increasing the risk of respiratory distress and diseases. On visit 1 in 2016, all participants underwent urinary arsenic measurement and low-dose computed tomography (LDCT). The same participants had LDCT performed at visit 2 in 2018. Our study revealed that individuals with lung fibrotic changes had significantly higher levels of urinary arsenic compared to the non-lung fibrotic changes group. Moreover, we found that participants with urinary arsenic levels in the highest sextile (> 209.7 μg/g creatinine) had a significantly increased risk of lung fibrotic changes in both visit 1 (OR = 1.87; 95% CI= 1.16-3.02; P = 0.010) and visit 2 (OR = 1.74; 95% CI = 1.06-2.84; P = 0.028) compared to those in the lowest sextile (≤ 41.4 μg/g creatinine). We also observed a significantly increasing trend across urinary arsenic sextile in both visits (Ptrend = 0.015 in visit 1 and Ptrend = 0.026 in visit 2). Furthermore, participants with urinary arsenic levels in the highest sextile had a significantly increased risk of lung fibrotic positive to positive (OR = 2.18; 95% CI: 1.24, 3.82; P = 0.007) compared to the lowest sextile (reference category: lung fibrotic negative to negative). Our findings provide support for the hypothesis that arsenic exposure is significantly associated with an increased risk of lung fibrotic changes. It is advisable to reduce the levels of arsenic exposure for those residing near such petrochemical complexes.

Evaluation of the flavonol-rich fraction of Rosa damascena in an animal model of liver fibrosis by targeting the expression of fibrotic cytokines, antioxidant/oxidant ratio and collagen cross-linking

IntroductionThe flavonoid-rich fraction of Rosa damascena (FRFRD) contains antioxidant and active compounds. Therefore, this study aimed to investigate the role of FRFRD, rich in quercetin and kaempferol, in liver fibrosis induced by CCl4. Materials and methodsThe FRFRD fraction was separated and standardized by High-Performance Liquid Chromatography (HPLC) based on the levels of quercetin and kaempferol. Liver fibrosis was induced over CCl4 over 12 weeks in 30 male Wistar rats, and three concentrations of FRFRD were administered to them during the last four weeks. Subsequently, after evaluation of liver serum markers and fibrotic parameters, the relative expression of transforming growth factor-beta-1 (TGF-β1), platelet-derived growth factor (PDGF), and lysyl oxidase homolog 2 (Loxl2) genes were assessed, along with the measurement of lysyl oxidase activity and oxidative markers. ResultsFibrotic markers demonstrated progressive recovery of liver damage in the treated group compared to the non-treatment group (p < 0.01). These results were accompanied by a significant decrease in the expression of TGF-β1, PDGF, and Loxl2 genes, as well as, a reduction in lysyl oxidase activity (p < 0.001). The antioxidant effects of the treatment were observed through a significant decrease in malondialdehyde (MDA) levels and an increase in catalase enzyme (CAT) and glutathione peroxidase (GPx) activity in the treatment group compared to the fibrotic group (p < 0.01). ConclusionThe flavonoid-rich fraction of Rosa damascena ameliorates liver damage by affecting collagen cross-linking and lowering oxidative and inflammatory levels.