To investigate the pro-phagocytic phenotype of macrophages in SSc and other rheumatic diseases by examining their activation, signalling pathways and treatment responses, with the goal of uncovering mechanisms that drive enhanced phagocytosis.

Single-cell RNA sequencing (scRNA-seq) datasets (GSE138669/GSE212109) from skin and lung macrophages of healthy controls (HC) and SSc patients were analysed. Human monocyte-derived macrophages (hMDMs) were differentiated from CD14+ monocytes from HC, SSc, RA, PsA, and axSpA patients. In selected experiments, hMDMs were pretreated with 0.1 μM nintedanib. Phagocytic activity was quantified using pHrodo bioparticles and flow cytometry. Macrophage surface markers were evaluated by flow cytometry, NF-κB signalling by Western blot and gene expression by RT-qPCR.

Analysis of scRNA-seq datasets revealed a pro-phagocytic signature in SSc-affected organs. SSc macrophages, particularly the FCGR3Ahi cluster in skin, exhibited elevated expression of FCGR genes and enriched FcγR-mediated phagocytosis pathways, accompanied by pro-inflammatory markers. This phenotype extended to FCN1hi lung macrophages in SSc patients with interstitial lung disease, indicating a systemic pro-inflammatory and phagocytic profile. hMDMs from SSc, RA and PsA patients demonstrated enhanced phagocytic activity in vitro. Elevated FcγRI and FcγRII levels were identified as key drivers of increased phagocytic activity and subsequent IL-6-driven inflammation. Nintedanib showed reduction in FcγRI expression, suggesting its potential therapeutic benefit in attenuating the phagocytic process.

This study highlights FcγR-expressing macrophages as drivers of phagocytosis and inflammatory responses in SSc. Dysregulated activation of these macrophages could lead to persistent inflammation and fibrosis in rheumatic diseases, highlighting new potential therapeutic approaches.

Intestinal microbiota is a complex ecosystem of microorganisms that perform diverse metabolic activities to maintain gastrointestinal homeostasis. These microorganisms provide energy and nutrients for growth and reproduction while producing numerous metabolites including lipopolysaccharides (LPS), Bacteroides fragilis toxin (BFT), bile acids (BAs), polyamines (PAs), and short-chain fatty acids (SCFAs). These metabolites are linked to inflammation and various metabolic diseases, such as obesity, type-2 diabetes, non-alcoholic fatty liver disease, cardiometabolic disease, and malnutrition. In addition, they may contribute to tumorigenesis. Evidence suggests that these microbes can increase the susceptibility to certain cancers and affect treatment responses. In this review, we discuss the current knowledge on how the gut microbiome and its metabolites influence tumorigenesis, highlighting the potential molecular mechanisms and prospects for basic and translational research in this emerging field.

Pulmonary tuberculosis (TB) frequently leads to long-term lung complications that contribute to increased mortality. Understanding the pathogenesis of post-TB lung impairments is crucial for improving long-term outcomes in TB patients; yet this area remains poorly researched.

Our study assessed circulatory inflammatory markers in patients who completed TB treatment more than one year before enrolment (population 1) and patients receiving in-hospital treatment for active drug-sensitive TB (population 2).

IL-6 was seven times higher in both populations compared to the normal range. IL-8 was below the limit of detection (LOD) in population 1, while it was approximately 2.5 times higher in population 2 compared to the normal range. TNF-α was 21 times higher in population 1 and 19 times higher in population 2 compared to the normal range. CRP was almost 49 times higher in both populations, and IL-1Ra was below the LOD in population 1, while it was ~1.5 times higher in population 2 compared to the normal range.

These inflammatory biomarkers correlated well with lung function in the post-TB state, and their high levels suggest a persistent pro-inflammatory state post-TB, which may contribute to post-TB lung disease. More research is warranted to better understand this phenomenon, but these findings may highlight a need to consider anti-inflammatory therapy for patients with post-TB lung disease, especially since these high levels of cytokines can directly contribute to lung damage.

To investigate whether gastroesophageal reflux with laryngopharyngeal reflux and aspiration play a role in the pathogenesis of bronchiectasis and Mycobacterium avium complex (MAC) pulmonary infection.

In this prospective case-control study, subjects included 31 patients with bronchiectasis undergoing bronchoscopy to investigate suspected MAC infection and 9 control subjects undergoing bronchoscopy for alternative reasons. Patients drank 45 mL of FD&C Blue #1 mixed with 200 mL of tap water the night prior to bronchoscopy. During bronchoscopy, the bronchial mucosa was inspected for the presence of blue dye staining. Bronchoalveolar lavage (BAL) samples were obtained from the most affected segments on CT scan and were cultured for mycobacteria and assayed for pepsin and bile acids. Gastric aspirate samples were obtained for mycobacterial culture.

93.8% of patients with confirmed pulmonary MAC infection and 91.7% of patients with evidence of bronchiectasis by CT scan, but negative mycobacterial cultures, had blue dye staining of the bronchial mucosa vs. 11.3% of control patients (p < 0.001). Areas of abnormality on CT correlated with airways demonstrating blue staining by bronchoscopy in 100% of MAC patients and 90.9% of patients with bronchiectasis and negative mycobacterial cultures. MAC patients had higher median BAL pepsin levels compared to combined MAC negative patients (subjects with bronchiectasis and negative mycobacterial cultures and true controls), 5.4 ng/mL vs. 3.4 ng/mL (p = 0.019). 78.6% of MAC patients vs. 26.3% of combined MAC negative patients had BAL bile acid concentrations of >/= 0.493 uM (p = 0.005). There was no significant difference in age, supraglottic index, reflux symptoms, gastric pH, or proton pump inhibitor use between the MAC positive vs. MAC negative patients. 42.8% of patients with growth of MAC on BAL also had growth of MAC in the gastric aspirate.

Reflux and aspiration of gastric contents into the airways show a strong association with bronchiectasis and may be associated with MAC pulmonary disease. The novel method introduced in this study of drinking blue dye the evening prior to bronchoscopy should be utilized in the evaluation of infectious and inflammatory lung diseases in which aspiration may play a role.

Wound healing is a complex and dynamic process of replacing missing cellular structures and tissue layers. Clinical practice includes the application of a sterile bandage to promote healing and to restrain infection, like the commercial nonbiodegradable meshes. However, while inert, nontoxic, and nonimmunogenic, they can cause calcification, fibrosis, and inflammation, potentially hindering the healing process in the long term. To address this challenge and enhance wound healing, we developed a totally biodegradable electrospun poly(d,l-lactide-co-ε-caprolactone) (PDLLCL) drug delivery system that incorporates two already FDA-approved antifibrotics, pirfenidone (PIRF) and triamcinolone acetonide (TA). The PDLLCL meshes, fabricated via electrospinning, exhibited homogeneity and complete degradation after 120 days, consistent with the wound healing process. In vitro, functional analysis on RAW 264.7 macrophages revealed no cytotoxicity and an immunomodulatory effect of PIRF and TA compared with the positive control (lipopolysaccharides, LPS) and the PDLLCL meshes alone. Lastly, subcutaneous in vivo assessment on a rabbit model, following the ISO 10993-6 standard, showed that our tailored made PDLLCL meshes were able to lower both irritation and fibrosis indexes from 2 weeks to 4 weeks of implantation, highlighting the beneficial effect of biodegradable polymers. However, we saw no significant positive effect on the incorporation of antifibrotics in vivo for irritation and fibrosis indexes. This underscores the potential of PDLLCL meshes as a possible alternative for wound healing, reducing the use of intermittent antifibrotic agents during the healing process.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease. Lung cancer (LC) is among the most crucial comorbidity factors in patients with IPF. IPF patients that are diagnosed with LC have a reduced mean survival time. Therapeutic strategies for LC in patients with IPF need to be adapted according to the individual treatment risk. Life-threatening acute exacerbation (AE) of IPF may occur in association with cancer treatment, thereby severely restricting the therapeutic options for IPF-associated LC. Because LC and anticancer treatments can worsen the prognosis of IPF, the prevention of LC is as critical as managing patients with IPF.

The nature of the effector and memory T cell response in the lungs following acute SARS-CoV-2 infections remains largely unknown. To define the pulmonary T-cell response to COVID-19, we compared effector and memory T-cell responses to SARS-CoV-2 and influenza A virus (IAV) in mice. Both viruses elicited potent effector T cell responses in lungs, but memory T cells showed exaggerated contraction in SARS-CoV-2-infected mice. Specifically, unlike the T-bet/EOMES-driven effector transcription program in IAV lungs, SARS-CoV-2-specific CD8 T cells embarked on a STAT-3-centric transcriptional program, a defining characteristic of a pro-fibro-inflammatory program: limited cytotoxicity, diminished expression of tissue-protective inhibitory receptors (PD-1, LAG-3, and TIGIT), and augmented mucosal imprinting (CD103). Circulating CD45RO+HLA-DR+ CD8 T cells in hospitalized COVID-19 patients expressed elevated levels of STAT-3 and low levels of TIGIT. IL-6 blockade experiments implicated IL-6 in STAT-3 induction and downregulation of PD-1 expression on SARS-CoV-2-specific primary effector CD8 T cells. Memory CD8 T cells specific to a single epitope, induced by mucosal vaccination, differentiated into cytotoxic effectors and expressed high levels of CD103, effectively reducing viral burden in lungs following a breakthrough SARS-CoV-2 infection. Our findings have implications for developing targeted immunotherapies to mitigate immunopathology and promote protective T cell immunity to SARS-CoV-2.

The incidence of intestinal fibrosis in Inflammatory bowel disease has increased in recent years, and the repair process is complex, leading to substantial economic and social burdens. Therefore, understanding the pathogenesis of intestinal fibrosis and exploring potential therapeutic agents is crucial.

This article reviews the pathogenesis of IBD-related intestinal fibrosis, potential therapeutic targets, and the progress of research on Traditional Chinese Medicine (TCM) in inhibiting intestinal fibrosis. It also provides foundational data for developing innovative drugs to prevent intestinal fibrosis.

This article reviews the literature from the past decade on advancements in the cellular and molecular mechanisms underlying intestinal fibrosis. Data for this systematic research were obtained from electronic databases including PubMed, CNKI, SciFinder, and Web of Science. Additionally, a comprehensive analysis was conducted on reports regarding the use of TCM for the treatment of intestinal fibrosis. The study synthesizes and summarizes the research findings, presenting key patterns and trends through relevant charts.

This study reviewed recent advancements in understanding the cellular and molecular mechanisms of intestinal fibrosis, the active ingredients of TCM that inhibit intestinal fibrosis, the efficacy of TCM formulae in preventing intestinal fibrosis, and dietary modification that may contribute to the inhibition of intestinal fibrosis.

This article examines the cellular and molecular mechanisms that promote the development of intestinal fibrosis, as well as potential therapeutic targets for its treatment. It also provides a theoretical basis for exploring and utilizing TCM resources in the management of intestinal fibrosis. Through the analysis of various TCM medicines, this article underscores the clinical significance and therapeutic potential of TCM and dietary modifications in treating intestinal fibrosis.

Fibrosis is one of the major outcomes following injury in the heart. Immune response in the injury niche modulates fibrosis, yet little is known about how cell-autonomous immune signaling in adult cardiac fibroblasts regulates fibrosis. Using FACS, single-cell sequencing of cardiac fibroblasts from Collagen1-α1GFP mice and human heart failure patients, we demonstrate that TLR4 is the major immune sensor expressed in cardiac fibroblasts. Inhibition of TLR4 signaling reduces TGF-β induced fibrotic changes such as contractibility and migration of adult human cardiac fibroblasts in TGF-β treated fibrotic conditions. TGF-β treated cardiac fibroblastss show enhanced cytokine expression, and inhibition of TLR4 signaling reduces the expression of cytokines, thereby reducing TGF-β targets such as extracellular matrix genes. Thus, our data demonstrate that TLR4 and other signaling molecules downstream of TLR4 are expressed in cardiac fibroblast, and inhibition of TLR4 modulates fibrotic changes in vitro.

The pathogenesis of biliary atresia (BA) remains elusive. We aimed to investigate the role of long noncoding RNA (lncRNA) MEG9 in BA.

LncRNA microarray was conducted to identify differentially expressed lncRNAs in three BA and three para-hepatoblastoma liver tissues. RT-qPCR validated the results. Human intrahepatic bile duct epithelial cells (HIBECs) were stably transfected with lncRNA MEG9 knockdown/overexpression to investigate its cellular localization and function. RNA sequencing (RNA-seq), differentially expressed genes (DEGs) analysis and gene set enrichment analysis were applied to MEG9-overexpresed HIBECs. RNA pull-down and mass spectrometry explored the interacting protein of MEG9, while clinical information was reviewed.

436 differentially expressed lncRNAs were identified, with MEG9 highly upregulated in BA. RT-qPCR further confirmed MEG9's overexpression in BA and diagnostic potential (AUC = 0.9691). MEG9 was predominantly located in the nucleus and significantly promoted cell proliferation and migration. RNA-seq revealed inflammation- and extracellular matrix-related pathways enriched in MEG9-overexpressing HIBECs, with upregulated cytokine genes like CXCL6 and IL6. MMP-7 and collagen I were also overexpressed. Furthermore, 38 proteins were identified to specifically interact with MEG9, and S100A9 was highly expressed in cell models. S100A9 was also significantly upregulated in BA liver tissue and correlated with MEG9 expression (r = 0.313, p < 0.05), albumin level (r = -0.349, p < 0.05), and platelet level (r = -0.324, p < 0.05).

MEG9 influences cholangiocyte proliferation, migration, and cytokine production, potentially regulating BA inflammation and fibrosis via S100A9 interaction.

Long-term exposure of the peritoneum to peritoneal dialysate results in pathophysiological changes in the anatomical organization of the peritoneum and progressive development of peritoneal fibrosis. This leads to a decline in peritoneal function and ultrafiltration failure, ultimately necessitating the discontinuation of peritoneal dialysis, severely limiting the potential for long-term maintenance. Additionally, encapsulating peritoneal sclerosis, a serious consequence of peritoneal fibrosis, resulting in patients discontinuing PD and significant mortality. The causes and mechanisms underlying peritoneal fibrosis in patients undergoing peritoneal dialysis remain unknown, with no definitive treatment available. However, abnormal activation of the immune system appears to be involved in altering the structure of the peritoneum and promoting fibrotic changes. Macrophage infiltration and polarization are key contributors to pathological injury within the peritoneum, showing a strong correlation with the epithelial-to-mesenchymal transition of mesothelial cells and driving the process of fibrosis. This article discusses the role and mechanisms underlying macrophage activation-induced peritoneal fibrosis resulting from PD by analyzing relevant literature from the past decade and provides an overview of recent therapeutic approaches targeting macrophages to treat this condition.

Postoperative scar formation is the primary cause of uncontrolled intraocular pressure following trabeculectomy failure. This study aimed to evaluate the efficacy of zotarolimus as an adjuvant anti-scarring agent in the experimental trabeculectomy.

We performed differential gene and Gene Ontology enrichment analysis on rabbit follicular transcriptome sequencing data (GSE156781). New Zealand white Rabbits were randomly assigned into three groups: Surgery only, Surgery with mitomycin-C treatment, Surgery with zotarolimus treatment. Rabbits were euthanized 3 days or 28 days post-trabeculectomy. Pathological sections were analyzed using immunohistochemistry, immunofluorescence, and Masson staining. In vitro, primary human tenon's capsule fibroblasts (HTFs) were stimulated by transforming growth factor-β1 (TGF-β1) and treated with either mitomycin-C or zotarolimus. Cell proliferation and migration were evaluated using cell counting kit-8, cell cycle, and scratch assays. Mitochondrial membrane potential was detected with the JC-1 probe, and reactive oxygen species were detected using the DCFH-DA probe. RNA and protein expressions were quantified using RT-qPCR and immunofluorescence.

Transcriptome sequencing analysis revealed the involvement of complex immune factors and metabolic disorders in trabeculectomy outcomes. Zotarolimus effectively inhibited fibrosis, reduced proinflammatory factor release and immune cell infiltration, and improved the surgical outcomes of trabeculectomy. In TGF-β1-induced HTFs, zotarolimus reduced fibrosis, proliferation, and migration without cytotoxicity via the dual regulation of the TGF-β1/Smad2/3 and AMPK/AKT/mTOR pathways.

Our study demonstrates that zotarolimus mitigates fibrosis by reducing immune infiltration and correcting metabolic imbalances, offering a potential treatment for improving trabeculectomy surgical outcomes.

The main purpose of this study was to explore the changes of biomarkers in different developmental stages of bleomycin-induced pulmonary fibrosis (PF) in rats via comprehensive pathophysiology, UPLC-QTOF/MS metabonomic technology, and 16S rRNA gene sequencing of intestinal microbiota. The rats were randomly divided into normal control and 1-, 2- and 4-week model group. The rat model of PF was established by one-time intratracheal instillation of bleomycin. The levels of inflammatory and fibrosis-related factors such as hydroxyproline (HYP), type III procollagen (COL-III), type IV collagen (COL-IV), hyaluronidase (HA), laminin (LN), interleukin (IL)-1β, IL-6, malondialdehyde (MDA) increased and superoxide dismutase (SOD) decreased as the PF cycle progressed. In the 1-, 2- and 4-week model group, 2, 19 and 18 potential metabolic biomarkers and 3, 16 and 12 potential microbial biomarkers were detected, respectively, which were significantly correlated. Glycerophospholipid metabolism pathway was observed to be an important pathway affecting PF at 1, 2 and 4 weeks; arginine and proline metabolism pathways significantly affected PF at 2 weeks. Linoleic acid metabolism pathway exhibited clear metabolic abnormalities at 2 and 4 weeks of PF, and alpha-linolenic acid metabolism pathway significantly affected PF at 4 weeks.

Hantaan virus (HTNV) infection in humans can cause hemorrhagic fever and renal syndrome (HFRS). Understanding host responses to HTNV infection is crucial for developing effective disease intervention strategies. Previous RNA-sequencing studies have investigated the role of microRNAs (miRNAs) in the post-transcriptional regulation of host genes in response to HTNV infection. In this study, we demonstrated that HTNV infection induces let-7a expression in human umbilical vein endothelial cells (HUVEC) and that HTNV G protein upregulates the expression of let-7a. miRNA let-7a mimics and inhibitors validated the predicted targets, including cell apoptosis genes (FAS, caspase-8, and caspase-3) and inflammatory factors (IL-6 and its related factors). Modulation of miRNA let-7a levels by miRNA mimics and inhibitors affected HTNV replication, indicating that HTNV modulates host miRNA expression to affect the outcome of the antiviral host response.

Fibroblast activation drives fibrotic diseases such as pulmonary fibrosis. However, the complex interplay of how tissue mechanics and macrophage signals combine to influence fibroblast activation is not well understood. Here, we use hyaluronic acid hydrogels as a tunable cell culture system to mimic lung tissue stiffness and viscoelasticity. We applied this platform to investigate the influence of macrophage signaling on fibroblast activation. Fibroblasts cultured on stiff (50 kPa) hydrogels mimicking fibrotic tissue exhibit increased activation as measured by spreading as well as type I collagen and cadherin-11 expression compared to fibroblasts cultured on soft (1 kPa) viscoelastic hydrogels mimicking normal tissue. These trends were unchanged in fibroblasts cultured with macrophage-conditioned media. However, fibroblasts directly co-cultured with M2 macrophages show increased activation, even on soft viscoelastic hydrogels that normally suppress activation. Inhibition of interleukin 6 (IL6) signaling does not change activation in fibroblast-only cultures but ameliorates the pro-fibrotic effects of M2 macrophage co-culture. These results underscore the ability of direct M2 macrophage co-culture to override hydrogel viscoelasticity to promote fibroblast activation in an IL6-dependent manner. This work also highlights the utility of using hydrogels to deconstruct complex tissue microenvironments to better understand the interplay between microenvironmental mechanical and cellular cues.

Peritoneal inflammation and fibrosis remain major challenges to the long-term maintenance of peritoneal dialysis. Pemafibrate, a selective peroxisome proliferator-activated receptor α (PPARα) modulator, has been implicated in the management of fibrosis-related disorders. We investigated whether pemafibrate ameliorates peritoneal inflammation and fibrosis and explored the underlying mechanisms in mice with methylglyoxal (MGO)-induced peritoneal fibrosis (MGO mice). MGO mice exhibited peritoneal fibrosis with increased expression of mesenchymal markers, transforming growth factor-β1 (TGF-β1), and substantial deposition of extracellular matrix (ECM) proteins. Additionally, MGO mice exhibited peritoneal inflammation as indicated by elevated tumor necrosis factor-α expression and macrophage infiltration in peritoneal tissue. These effects were mitigated by pemafibrate treatment, which also restored peritoneal membrane function. Furthermore, pemafibrate promoted anti-inflammatory macrophage polarization in both mice and THP-1 cells. In human peritoneal mesothelial cells (HPMCs), pemafibrate effectively inhibited interferon-γ-induced production of TGF-β1 and ECM while suppressing the proinflammatory cytokines nuclear factor-κB (NF-κB) and activator protein 1. The NF-κB inhibitory effect of pemafibrate involved stabilization of the NF-κB inhibitory protein IkBα. Notably, pemafibrate hindered activation of the NLR family pyrin domain containing 3/caspase-1 axis in interferon-γ-stimulated THP-1 cells. These findings suggest that pemafibrate ameliorates peritoneal inflammation and fibrosis, making it a promising candidate for peritoneal fibrosis therapy.

In the knee, synovial fibrosis after ligamentous injury is linked to progressive joint pain and stiffness. The objective of this study was to evaluate changes in synovial architecture, mechanical properties, and transcriptional profiles following naturally occurring cruciate ligament injury in canines and to test potential therapeutics that target drivers of synovial inflammation and fibrosis.

Synovia from canines with spontaneous cruciate ligament tears and from healthy knees were assessed via histology (n = 10/group) and micromechanical testing (n = 5/group) to identify changes in tissue architecture and stiffness. Additional samples (n = 5/group) were subjected to RNA-sequencing to define the transcriptional response to injury. Finally, synovial tissue samples from injured animals (n = 6 (IL1) or n = 8 (IL6)/group) were assessed in vitro for response to therapeutic molecules directed against interleukin (IL) signaling (IL1 or IL6).

Cruciate injury resulted in increased synovial fibrosis, vascularity, inflammatory cell infiltration, and intimal hyperplasia. Additionally, the stiffness of both the intima and subintima regions were higher in diseased compared to healthy tissue. Differential gene expression analysis showed that diseased synovium had an upregulation of immune response and cell adhesion pathways and a downregulation of Rho protein transduction pathways. In vitro application of small molecule therapeutics targeting IL1 (anakinra) or IL6 (tocilizumab) dampened expression of inflammatory and matrix deposition mediators.

Spontaneous cruciate ligament injury in canines is associated with synovial inflammation and fibrosis in a relevant model for testing emerging intra-articular treatments. Small molecule therapeutics targeting IL pathways may be ideal interventions for delivery to the joint space after injury.

The aim of this paper is to raise awareness of MC as a clinically significant condition and to highlight its under-recognition, risk factors, diagnosis, management, and complications. This paper underlines the diagnostic and therapeutic challenges associated with the often nonspecific symptoms of MC. In order to create this article, we reviewed available articles found in the PubMed database and searched for articles using the Google Scholar platform. Microscopic colitis (MC) is a chronic inflammatory bowel disease, classified into three types: lymphocytic, collagenous, and unspecified. The average age of onset of MC is around 62-65 years and the disease is more common in women than men (nine times more common). The main symptom of MC is watery diarrhoea without blood, other symptoms include defecatory urgency, faecal incontinence, abdominal pain, nocturnal bowel movements, and weight loss. Once considered a rare disease, MC is now being diagnosed with increasing frequency, but diagnosis remains difficult. To date, a number of causative factors for MC have been identified, including smoking, alcohol consumption, medications (including NSAIDs, PPIs, SSRIs, and ICPIs), genetic factors, autoimmune diseases, bile acid malabsorption, obesity, appendicitis, and intestinal dysbiosis. It may be difficult to recognize and should be differentiated from inflammatory bowel diseases (Crohn's disease and ulcerative colitis), irritable bowel syndrome (IBS), coeliac disease, infectious bowel disease, and others. Diagnosis involves biopsy at colonoscopy and histopathological evaluation of the samples. Treatment consists of budesonide oral (the gold standard) or enema. Alternatives include bile acid sequestrants (cholestyramine, colesevelam, and colestipol), biologics (infliximab, adalimumab, and vedolizumab), thiopurines, methotrexate, and rarely, surgery.

Epithelial ovarian cancer (EOC) is often diagnosed in advanced stage with peritoneal dissemination. Recent studies indicate that aberrant accumulation of collagen fibers in tumor stroma has a variety of effects on tumor progression. We refer to remodeled fibrous stroma with altered expression of collagen molecules, increased stiffness, and highly oriented collagen fibers as tumor-associated fibrosis (TAF). TAF contributes to EOC cell invasion and metastasis in the intraperitoneal cavity. However, an understanding of molecular events involved is only just beginning to emerge. Further development in this field will lead to new strategies to treat EOC. In this review, we focus on the recent findings on how the TAF contributes to EOC malignancy. Furthermore, we will review the recent initiatives and future therapeutic strategies for targeting TAF in EOC.

Pulmonary fibrosis (PF) is a chronic, irreversible interstitial lung disease. The pathogenesis of PF remains unclear, and there are currently no effective treatments or drugs that can completely cure PF. The primary cause of PF is an imbalance of inflammatory response and inappropriate repair following lung injury. Dendritic cells (DCs), as one of the immune cells in the body, play an important role in regulating immune response, immune tolerance, and promoting tissue repair following lung injury. However, the role of DCs in the PF process is ambiguous or even contradictory in the existing literature. On the one hand, DCs can secrete transforming growth factor β(TGF-β), stimulate Th17 cell differentiation, stimulate fibroblast proliferation, and promote the generation of inflammatory factors interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α), thereby promoting PF. On the other hand, DCs suppress PF through mechanisms including the secretion of IL-10 to inhibit effector T cell activity in the lungs and promote the function of regulatory T cells (Tregs), as well as by expressing matrix metalloproteinases (MMPs) which facilitate the degradation of the extracellular matrix (ECM). This article will infer possible reasons for the different roles of DCs in PF and analyze possible reasons for the functional imbalance of DCs in pulmonary fibrosis from the complexity and changes of the pulmonary microenvironment, autophagy defects of DCs, and changes in the pulmonary physical environment.

Transplantation of bone marrow mesenchymal stem cells (BMSCs) has demonstrated promising clinical utility in the treatment of endometrial injury and the restoration of fertility. However, since the efficacy of BMSCs after transplantation is not stable, it is very important to find effective ways to enhance the utilisation of BMSCs. Electroacupuncture (EA) has some positive effects on the chemotaxis of stem cells and diseases related to uterine injury. In this study, we established the intrauterine adhesion (IUA) model of the Sprague-Dawley rat using lipopolysaccharide infection and mechanical scratching. Phosphate-buffered saline, BMSCs alone, and BMSCs combined with EA were randomly administered to the rats. Fluorescent cell labelling showed the migration of transplanted BMSCs. H&E staining, Masson staining, Western blot, immunohistochemistry, ELISA, and qRT-PCR were utilised to detect changes in endometrial morphology and expressions of endometrial receptivity-related factors, endometrial pro-inflammatory factors, and fibrosis factors. Finally, we conducted a fertility test to measure the recovery of uterine function. The results showed that EA promoted transplanted BMSCs to migrate into the injured uterus by activating the SDF-1/CXCR4 axis. Endometrial morphology showed the most significant improvement in the BMSC + EA group. The expressions of endometrial pro-inflammatory factors and fibrosis indexes in the BMSC + EA group were lower than those in the model and BMSC groups. Further studies revealed that the expression of endometrial receptivity-related factors and the number of embryos implanted on day 8 of gestation increased in the BMSC + EA group compared with the model group and the BMSC group.

Capsular contracture is attributed to an exaggerated fibrosis response within the capsule and is partly associated with bacterial contamination in situ. However, the cellular mechanisms that initiate this response are unclear.

The authors developed a mouse model of capsular contracture by repeated injection of 10 μg/mL lipoteichoic acid (LTA). The histological changes in the capsule tissue were measured by hematoxylin and eosin, Masson trichrome, and immunohistochemical staining. The expression of cytokines was measured by quantitative reverse transcription polymerase chain reaction. The authors also used pharmacological methods to verify the roles of macrophages and toll-like receptor 2 (TLR2) signaling in this pathological process.

The authors discovered that repeated LTA injection, at a low concentration, could induce thickening of the capsule tissue. Macrophage infiltration and TLR2/nuclear factor-κB signaling activated in this process could be suppressed by macrophage depletion or TLR2 receptor inhibition.

As TLR2 signal activation was found to cause capsular contracture by inducing macrophage infiltration as a consequence of trace amounts of LTA contamination in situ, this target is helpful for understanding that chronic or repeated subclinical infection can activate capsular contracture.

This finding is of significant importance for understanding that chronic or repeated subclinical infection could activate a persistent immune response and capsular contracture, and provides novel strategies to interfere with the formation of capsular contracture.

Galectin-3 is a pro-fibrotic β-galactoside binding lectin highly expressed in fibrotic liver and implicated in hepatic fibrosis. Selvigaltin (previously known as GB1211) is a novel orally active galectin-3 small molecule inhibitor that has high affinity for galectin-3 (human KD = 25 nM; rabbit KD = 12 nM) and high oral bioavailability in rabbits and man. In this study the efficacy of selvigaltin was investigated in a high fat diet (HFD) rabbit model of metabolic-associated steatohepatitis (MASH).

Male New Zealand White rabbits were individually caged under standard conditions in a temperature and humidity-controlled room on a 12 h light/darkness cycle. After 1 week of regular diet (RD), rabbits were randomly assigned for 8 or 12 weeks to different groups: RD/vehicle, RD/selvigaltin, HFD (8 weeks), HFD/vehicle and HFD/selvigaltin (0.3, 1.0, 5.0 or 30 mg/kg selvigaltin with vehicle/selvigaltin p.o. dosed therapeutically q.d. 5 days per week from week 9 or 12). Liver inflammation, steatosis, ballooning, and fibrosis was measured via blood metabolic markers, histomorphological evaluation [Oil Red O, Giemsa, Masson's trichome, picrosirius red (PSR) and second harmonic generation (SHG)], and mRNA and protein expression.

Steatosis, inflammation, ballooning, and fibrosis were all increased from RD to HFD/vehicle groups. Selvigaltin demonstrated target engagement by significantly decreasing galectin-3 levels in the liver as measured via immunohistochemistry and mRNA analysis. Selvigaltin dose-dependently reduced biomarkers of liver function (AST, ALT, bilirubin), inflammation (cells foci), and fibrosis (PSR, SHG), as well as decreasing the mRNA and protein expression of several key inflammation and fibrosis biomarkers (e.g., IL6, TGFβ3, SNAI2, collagen). Doses of 1.0 or 5.0 mg/kg demonstrated consistent efficacy across most biological endpoints supporting the current clinical doses of selvigaltin being investigated in liver disease.

Selvigaltin significantly reduced hepatic inflammation and fibrosis in an HFD rabbit model of MASH following therapeutic dosing for 4 weeks in a dose-dependent manner. These data support the human selvigaltin dose of 100 mg b.i.d. that has been shown to reduce key liver biomarkers during a clinical study in liver cirrhosis.

Fibrosis is a common pathological process that can affect virtually all the organs, but there are hardly any effective therapeutic options. This has led to an intense search for antifibrotic therapies over the last decades, with a great number of clinical assays currently underway. We have systematically reviewed all current and recently finished clinical trials involved in the development of new antifibrotic drugs, and the preclinical studies analyzing the relevance of each of these pharmacological strategies in fibrotic processes affecting tissues beyond those being clinically studied. We analyze and discuss this information with the aim of determining the most promising options and the feasibility of extending their therapeutic value as antifibrotic agents to other fibrotic conditions.

Granulomatous tubulointerstitial nephritis (GTIN) attributed to early onset sarcoidosis is an ultrarare finding in an allograft kidney biopsy. We present the case of a young man with allograft dysfunction who had GTIN upon biopsy. We performed a thorough case review based on recovered records from early childhood and reassessed genetic testing results. We revised his underlying diagnosis from cryopyrin-associated periodic syndrome to early-onset sarcoidosis with wild-type NOD2 and established a rationale to use the interleukin-6 (IL-6) receptor blocker tocilizumab (TCZ). This suppressed his inflammatory disease and stabilised kidney function. We performed a literature review related to the emerging role of IL-6 pathway blockade in kidney transplantation. We identified 18 reports with 417 unique patients treated with TCZ for indications including HLA-desensitisation, transplant immunosuppression induction, treatment of chronic antibody-mediated rejection, and treatment of subclinical rejection. Both TCZ and the direct IL-6 inhibitor clazakizumab are being studied in ongoing randomised control trials.

Peritoneal dialysis is a widely used method for treating kidney failure. However, over time, the peritoneal structure and function can deteriorate, leading to the failure of this therapy. This deterioration is primarily caused by infectious and sterile inflammation. Sterile inflammation, which is inflammation without infection, is particularly concerning as it can be subtle and often goes unnoticed. The onset of sterile inflammation involves various pathological processes. Peritoneal cells detect signals that promote inflammation and release substances that attract immune cells from the bloodstream. These immune cells contribute to the initiation and escalation of the inflammatory response. The existing literature extensively covers the involvement of different cell types in the sterile inflammation, including mesothelial cells, fibroblasts, endothelial cells, and adipocytes, as well as immune cells such as macrophages, lymphocytes, and mast cells. These cells work together to promote the occurrence and progression of sterile inflammation, although the exact mechanisms are not fully understood. This review aims to provide a comprehensive overview of the signals from both stromal cells and components of immune system, as well as the reciprocal interactions between cellular components, during the initiation of sterile inflammation. By understanding the cellular and molecular mechanisms underlying sterile inflammation, we may potentially develop therapeutic interventions to counteract peritoneal membrane damage and restore normal function.

Pulmonary hypertension (PH) pathogenesis is driven by inflammatory and metabolic derangements as well as glycolytic reprogramming. Induction of both interleukin 6 (IL6) and transglutaminase 2 (TG2) expression participates in human and experimental cardiovascular diseases. However, little is known about the role of TG2 in these pathologic processes. The current study aimed to investigate the molecular interactions between TG2 and IL6 in mediation of tissue remodeling in PH. A lung-specific IL6 over-expressing transgenic mouse strain showed elevated right ventricular (RV) systolic pressure as well as increased wet and dry tissue weights and tissue fibrosis in both lungs and RVs compared to age-matched wild-type littermates. In addition, IL6 over-expression induced the glycolytic and fibrogenic markers, hypoxia-inducible factor 1α, pyruvate kinase M2 (PKM2), and TG2. Consistent with these findings, IL6 induced the expression of both glycolytic and pro-fibrogenic markers in cultured lung fibroblasts. IL6 also induced TG2 activation and the accumulation of TG2 in the extracellular matrix. Pharmacologic inhibition of the glycolytic enzyme, PKM2 significantly attenuated IL6-induced TG2 activity and fibrogenesis. Thus, we conclude that IL6-induced TG2 activity and cardiopulmonary remodeling associated with tissue fibrosis are under regulatory control of the glycolytic enzyme, PKM2.

Arthrofibrosis is a joint disorder characterized by excessive scar formation in the joint tissues. Vitamin E is an antioxidant with potential anti-fibroblastic effect. The aim of this study was to establish an arthrofibrosis rat model after joint replacement and assess the effects of vitamin E supplementation on joint fibrosis.

We simulated knee replacement in 16 male Sprague-Dawley rats. We immobilized the surgical leg with a suture in full flexion. The control groups were killed at 2 and 12 weeks (n = 5 per group), and the test group was supplemented daily with vitamin E (0.2 mg/mL) in their drinking water for 12 weeks (n = 6). We performed histological staining to investigate the presence and severity of arthrofibrosis. Immunofluorescent staining and α2-macroglobulin (α2M) enzyme-linked immunosorbent assay (ELISA) were used to assess local and systemic inflammation. Static weight bearing (total internal reflection) and range of motion (ROM) were collected for functional assessment.

The ROM and weight-bearing symmetry decreased after the procedure and recovered slowly with still significant deficit at the end of the study for both groups. Histological analysis confirmed fibrosis in both lateral and posterior periarticular tissue. Vitamin E supplementation showed a moderate anti-inflammatory effect on the local and systemic levels. The vitamin E group exhibited significant improvement in ROM and weight-bearing symmetry at day 84 compared to the control group.

This model is viable for simulating arthrofibrosis after joint replacement. Vitamin E may benefit postsurgical arthrofibrosis, and further studies are needed for dosing requirements.

Fibrosis-related diseases (FRD) include conditions like myocardial fibrosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, and others. The impact of fibrosis can be severe, causing organ dysfunction, reduced functionality, and even organ failure, leading to significant health issues. Currently, there is a lack of effective modern anti-fibrosis drugs in clinical practice. However, Chinese medicine has a certain beneficial effect on the treatment of such diseases. Angelica sinensis, with its considerable medicinal value, has garnered attention for its anti-fibrosis properties in recent investigations. In the past few years, there has been a growing number of experimental inquiries into the impact of angelica polysaccharide (ASP), angelica water extract, angelica injection, and angelica compound preparation on fibrosis-associated ailments, piquing the interest of researchers. This paper aims to consolidate recent advances in the study of Angelica sinensis for the treatment of fibrosis-related disorders, offering insights for prospective investigations. Literature retrieval included core electronic databases, including Baidu Literature, CNKI, Google-Scholar, PubMed, and Web of Science. The applied search utilized specified keywords to extract relevant information on the pharmacological and phytochemical attributes of plants. The investigation revealed that Angelica sinensis has the potential to impede the advancement of fibrotic diseases by modulating inflammation, oxidative stress, immune responses, and metabolism. ASP, Angelica sinensis extract, Angelica sinensis injection, and Angelica sinensis compound preparation were extensively examined and discussed. These constituents demonstrated significant anti-fibrosis activity. In essence, this review seeks to gain a profound understanding of the role of Angelica sinensis in treating fiber-related diseases. Organ fibrosis manifests in nearly all tissues and organs, posing a critical challenge to global public health due to its widespread occurrence, challenging early diagnosis, and unfavorable prognosis. Despite its prevalence, therapeutic options are limited, and their efficacy is constrained. Over the past few years, numerous studies have explored the protective effects of traditional Chinese medicine on organ fibrosis, with Angelica sinensis standing out as a multifunctional natural remedy. This paper provides a review of organ fibrosis pathogenesis and summarizes the recent two decades' progress in treating fibrosis in various organs such as the liver, lung, kidney, and heart. The review highlights the modulation of relevant signaling pathways through multiple targets and channels by the effective components of Angelica sinensis, whether used as a single medicine or in compound prescriptions.

Tissue damage elicits a wound healing response of inflammation and remodeling aimed at restoring homeostasis. Dysregulation of wound healing leads to accumulation of effector cells and extracellular matrix (ECM) components, collectively termed fibrosis, which impairs organ functions. Fibrosis of the central nervous system, neurofibrosis, is a major contributor to the lack of neural regeneration and it involves fibroblasts, microglia/macrophages and astrocytes, and their deposited ECM. Neurofibrosis occurs commonly across neurological conditions. This review describes processes of wound healing and fibrosis in tissues in general, and in multiple sclerosis in particular, and considers approaches to ameliorate neurofibrosis to enhance neural recovery.

Dermatomyositis (DM)/polymyositis (PM) is a systemic autoimmune disease characterized by proximal limb muscle with high morbidity and mortality and poor prognosis mediated by immune dysfunction; its etiology is unknown. DM/PM patients are at excessive risk of interstitial lung disease (ILD) and a higher risk of death. However, the role of circulating lymphocyte subsets, which play a pivotal role in occurrence and progression of DM/PM and ILD, respectively, remains unclear in DM/PM patients with ILD.

Demographic characteristics, general data, and peripheral lymphocyte levels measured by flow cytometry were collected and analyzed in 47 DM/PM patients with ILD, 65 patients without ILD, and 105 healthy controls (HCs).

The most important first symptom of DM/PM patients is rash. Compared with non-ILD patients, the levels of neutrophil/lymphocyte ratio (NLR), systemic inflammatory response index (SIRI) were significantly higher and the levels of C reactive protein (CRP) were significantly lower in patients with ILD. Compared with HCs, DM/PM patients, with or without ILD, had decreased absolute counts of T, CD4 + T, CD8 + T, natural killer (NK), helper T (Th) 1, Th2, Th17, and regulatory T (Treg)cells. The fewest Th1 and Treg cells and the the lowest CD8 + T and Th1 cells percentages were seen in peripheral blood of patients with ILD. Longer duration, decreased lymphocyte/monocyte ratio (LMR)levels and CD8 + T and Th1 cells proportions, and fewer circulating Treg cells were independent risk factors for DM/PM with ILD.

The identification of peripheral blood T lymphocyte subsets, especially Treg cells, and blood count in DM/PM appears to be useful in the comprehensive assessment of clinical lung involvement.

The impact of fibroblasts on the immune system provides insight into the function of fibroblasts. In various tissue microenvironments, multiple fibroblast subtypes interact with immunocytes by secreting growth factors, cytokines, and chemokines, leading to wound healing, fibrosis, and escape of cancer immune surveillance. However, the specific mechanisms involved in the fibroblast-immunocyte interaction network have not yet been fully elucidated.

Therefore, we systematically reviewed the molecular mechanisms of fibroblast-immunocyte interactions in fibrosis, from the history of cellular evolution and cell subtype divisions to the regulatory networks between fibroblasts and immunocytes. We also discuss how these communications function in different tissue and organ statuses, as well as potential therapies targeting the reciprocal fibroblast-immunocyte interplay in fibrosis. A comprehensive understanding of these functional cells under pathophysiological conditions and the mechanisms by which they communicate may lead to the development of effective and specific therapies targeting fibrosis.

Studies have suggested that the progress of most kidney diseases from occurrence to course and subsequent related complications are closely related to inflammatory reaction. Increased common leukocytes count in the family (neutrophils, eosinophils, basophils, lymphocytes, etc.) are also involved in the tissue damage of kidney diseases. However, these studies are only traditional observational studies, which cannot prove whether there is a causal relationship between these four kinds of leukocytes count and kidney diseases. We aim to explore the causal relationship between these four kinds of leukocytes count and kidney diseases by Mendelian randomization (MR). Large sample size of the genome-wide association database of four cell traits (neutrophil, basophil, lymphocyte, and eosinophil cell counts) in the leukocyte family were used as exposure variables. The outcome variables were various renal diseases (including chronic renal failure, acute renal failure, hypertensive heart or/and kidney disease, hypertensive renal disease, disorders resulting from impaired renal tubular function, and type 1 diabetes with renal complications). The covariates used in multivariable MR are also four cell traits related to blood cells (neutrophil, basophil, lymphocyte, and eosinophil cell counts). Instrumental variables and single nucleotide polymorphic loci were identified (P < 5 × 10-8. Linkage disequilibrium R2 < 0.001). The causal relationships were studied by inverse variance weighted (IVW), weighted median, and MR-Egger regression. Sensitivity analysis was also performed. In our study, IVW analysis results showed that increased neutrophil cell count was a risk factor for chronic renal failure (OR = 2.0245861, 95% CI = 1.1231207-3.649606, P = 0.01896524), increased basophil cell count was a risk factor for chronic renal failure (OR = 3.975935, 95% CI = 1.4871198-10.62998, P = 0.005942755). Basophil cell count was not a risk factor for acute renal failure (OR = 1.160434, 95% CI = 0.9455132-1.424207, P = 0.15448828). Increased basophil cell count was a protective factor for hypertensive heart and/or renal disease (OR = 0.7716065, 95% CI = 0.6484979-0.9180856, P = 0.003458707). Increased basophil cell count was a risk factor for disorders resulting from impaired renal tubular function (OR = 1.648131, 95% CI = 1.010116-2.689133, P = 0.04546835). Increased lymphocyte cell count was a risk factor for hypertensive renal disease (OR = 1.372961, 95% CI = 1.0189772-1.849915, P = 0.03719874). Increased eosinophil cell count was a risk factor for type 1 diabetes with renal complications (OR = 1.516454, 95% CI = 1.1826453-1.944482, P = 0.001028964). Macrophage inflammatory protein 1b levels was a protective factor for renal failure (OR = 0.9381862, 95% CI = 0.8860402-0.9934013, P = 0.02874872). After multivariable MR was used to correct covariates (neutrophil, basophil, and lymphocyte cell counts), the correlation effect between increased eosinophil cell counts and type 1 diabetes with renal complications was still statistically significant (P = 0.02201152). After adjusting covariates (neutrophil, basophil, and eosinophil cell counts) with multivariable MR, the correlation effect between increased lymphocyte cell counts and hypertensive renal disease was still statistically significant (P = 0.02050226). This study shows that increased basophils can increase the relative risk of chronic renal failure and renal tubular dysfunction, and reduce the risk of hypertensive heart disease and/or hypertensive nephropathy, while increased basophil cell count will not increase the relative risk of acute renal failure, increased neutrophil cell count can increase the risk of chronic renal failure, increased lymphocyte cell count can increase the relative risk of hypertensive nephropathy, and increased eosinophil cell count can increase the relative risk of type 1 diabetes with renal complications. Macrophage inflammatory protein 1b levels was a protective factor for renal failure.

» Arthrofibrosis after total knee arthroplasty (TKA) is the new formation of excessive scar tissue that results in limited ROM, pain, and functional deficits.» The diagnosis of arthrofibrosis is based on the patient's history, clinical examination, absence of alternative diagnoses from diagnostic testing, and operative findings. Imaging is helpful in ruling out specific causes of stiffness after TKA. A biopsy is not indicated, and no biomarkers of arthrofibrosis exist.» Arthrofibrosis pathophysiology is multifactorial and related to aberrant activation and proliferation of myofibroblasts that primarily deposit type I collagen in response to a proinflammatory environment. Transforming growth factor-beta signaling is the best established pathway involved in arthrofibrosis after TKA.» Management includes both nonoperative and operative modalities. Physical therapy is most used while revision arthroplasty is typically reserved as a last resort. Additional investigation into specific pathophysiologic mechanisms can better inform targeted therapeutics.

Objective: This study aimed to investigate the effects of stevioside (STE) on pulmonary fibrosis (PF) and the potential mechanisms. Methods: In this study, a mouse model of PF was established by a single intratracheal injection of bleomycin (BLM, 3 mg/kg). The experiment consisted of four groups: control group, BLM group, and STE treatment groups (STE 50 and 100 mg/kg). ELISA and biochemical tests were conducted to determine the levels of TNF-α, IL-1β, IL-6, NO, hydroxyproline (HYP), SOD, GSH, and MDA. Histopathological changes and collagen deposition in lung tissues were observed by HE and Masson staining. Immunohistochemistry was performed to determine the levels of collagen I-, collagen III-, TGF-β1- and p-Smad2/3-positive cells. Western blot analysis was used to measure the expression of epithelial-mesenchymal transition (EMT) markers, including α-SMA, vimentin, E-cadherin, and ZO-1, as well as proteins related to the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, nuclear transcription factor-κB (NF-κB) pathway, and TGF-β1/Smad2/3 pathway in lung tissues. Results: STE significantly alleviated BLM-induced body weight loss and lung injury in mice, decreased HYP levels, and reduced the levels of collagen I- and collagen III-positive cells, thereby decreasing extracellular matrix (ECM) deposition. Moreover, STE markedly improved oxidative stress (MDA levels were decreased, while SOD and GSH activity were enhanced), the inflammatory response (the levels of TNF-α, IL-1β, IL-6, and NO were reduced), and EMT (the expression of α-SMA and vimentin was downregulated, and the expression of E-cadherin and ZO-1 was upregulated). Further mechanistic analysis revealed that STE could activate the Nrf2 pathway and inhibit the NF-κB and TGF-β1/Smad2/3 pathways. Conclusion: STE may alleviate oxidative stress by activating the Nrf2 pathway, suppress the inflammatory response by downregulating the NF-κB pathway, and inhibit EMT progression by blocking the TGF-β1/Smad2/3 pathway, thereby improving BLM-induced PF.