Chronic kidney disease activates the HDAC6-inflammatory axis in the heart and contributes to myocardial remodeling in mice: inhibition of HDAC6 alleviates chronic kidney disease-induced myocardial remodeling.

Chronic kidney disease (CKD) adversely affects the heart. The underlying mechanism and the interplay between the kidney and the heart are still obscure. We examined the cardiac effect using the unilateral ureteral obstruction (UUO)-induced CKD pre-clinical model in mice. Echocardiography, histopathology of the heart, myocardial mRNA expression of ANP and BNP, the extent of fibrotic (TGF-ß, α-SMA, and collagen I) and epigenetic (histone deacetylases, namely HDAC3, HDAC4, and HDAC6) proteins, and myocardial inflammatory response were assessed. Six weeks of post-UUO surgery, we observed a compromised left-ventricular wall thickness and signs of cardiac hypertrophy, accumulation of fibrosis associated, and inflammatory proteins in the heart. In addition, we observed a perturbation of epigenetic proteins, especially HDAC3, HDAC4, and HDAC6, in the heart. Pharmacological inhibition of HDAC6 using ricolinostat (RIC) lessened cardiac damage and improved left-ventricular wall thickness. The RIC treatment substantially restored the serum cardiac injury markers, namely creatine kinase-MB and lactate dehydrogenase (LDH) activities, ANP and BNP mRNA expression, and heart histological changes. The extent of myocardial fibrotic proteins, phospho-NF-κB (p65), and pro-inflammatory cytokines (TNF-α, IL-18, and IL-1ß) were significantly decreased in the RIC treatment group. Further findings revealed the CKD-induced infiltration of CD3, CD8a, CD11c, and F4/80 positive inflammatory cells in the heart. Treatment with RIC substantially reduced the myocardial infiltration of these inflammatory cells. From these findings, we believe that CKD-induced myocardial HDAC6 perturbation has a deteriorative effect on the heart, and inhibition of HDAC6 can be a promising approach to alleviate CKD-induced myocardial remodeling.

Exploring the interplay of gut microbiota, inflammation, and LDL-cholesterol: a multiomics Mendelian randomization analysis of their causal relationship in acute pancreatitis and non-alcoholic fatty liver disease.

BACKGROUND: Acute pancreatitis and non-alcoholic fatty liver disease are both serious diseases in the digestive system. The pathogenesis of both diseases is extremely complex closely and it related to gut microbiota, inflammation, and blood fat. There is a close relationship between gut microbiota and blood lipids. METHODS: In this study, we used three types of exposure: 412 gut microbiota, 731 inflammatory cells, and 91 inflammatory proteins (pqtls), with LDL-C as an intermediary and acute pancreatitis and non-alcoholic fatty liver disease as outcomes. We mainly used MR-IVW, co-localization analysis, and reverse MR analysis methods for analysis. RESULTS: 7 gut microbiota, 21 inflammatory cells, and 3 inflammatory proteins can affect LDL-C levels. LDL-C is associated with acute pancreatitis and non-alcoholic fatty liver disease. CONCLUSIONS: Three omics were used: 412 gut microbiota, 731 inflammatory cells, and 91 inflammatory proteins (pqtls). It explains the causal relationship between multiomics, LDL- cholesterol, acute pancreatitis, and non-alcoholic fatty liver disease.

Pedunculagin and tellimagrandin-I stimulate inflammation and angiogenesis and upregulate vascular endothelial growth factor and tumor necrosis factor-alpha in vivo.

Pedunculagin (PD) and tellimagrandin-I (TL), isolated from Myrciaria cauliflora seeds and Eucaliptus microcorys leaves, respectively, have attracted great attention owing to their relevant biological activities, such as antitumor, antioxidant, and hepatoprotective activities. This study investigated the angiogenic potential of PD and TL using a chick embryo chorioallantoic membrane (CAM) assay. Using the CAM assay, our results showed that both PD and TL promoted a significant increase in the number and caliber of blood vessels, the thickness of the CAM, and the presence of fibroblasts and inflammatory cells. Moreover, an increase of tumor necrosis factor-α and vascular endothelial growth factor was observed in the CAM treated with PD and TL, indicating the induction of angiogenic factors. Thus, the remarkable profile of PD and TL in inducing angiogenesis opens up new perspectives for their potential utilization in different therapeutic approaches involving neovascularization.

Vistusertib improves pulmonary inflammation and fibrosis by modulating inflammatory/oxidative stress mediators via suppressing the mTOR signalling.

INTRODUCTION: Inflammation and oxidative stress are key factors in the development of pulmonary fibrosis (PF) by promoting the differentiation of fibroblasts through modulating various pathways including Wnt/ß-catenin, TGF-ß and mTOR signalling. OBJECTIVE AND METHODS: This study aimed to evaluate the effects and elucidate the mechanisms of vistusertib (VSB) in treating pulmonary inflammation/fibrosis, specifically by targeting the mTOR pathway using various in vitro and in vivo models. RESULTS: Lipopolysaccharide (LPS)-induced inflammation model in macrophages (RAW 264.7), epithelial (BEAS-2B) and endothelial (HMVEC-L) cells revealed that treatment with VSB significantly reduced the IL-6, TNF-α, CCL2, and CCL7 expression. TGF-ß induced differentiation was also significantly reduced upon VSB treatment in fibrotic cells (LL29 and DHLF). Further, bleomycin-induced inflammation and fibrosis models demonstrated that treatment with VSB significantly ameliorated the severe inflammation, and lung architectural distortion, by reducing the inflammatory markers expression/levels, inflammatory cells and oxidative stress indicators. Further, fibrosis model results exhibited that, VSB treatment significantly reduced the α-SMA, collagen and TGF-ß expressions, improved the lung architecture and restored lung functions. CONCLUSION: Overall, this study uncovers the anti-inflammatory/anti-fibrotic effects of VSB by modulating the mTOR activation. Although VSB was tested for lung fibrosis, it can be tested for other fibrotic disorders to improve the patient's survival and quality of life.

Inflammatory Cell-Derived MYDGF Attenuates Endothelial LDL Transcytosis to Protect Against Atherogenesis.

BACKGROUND: Inflammation contributes to the pathogenesis of atherosclerosis. But little is known about the potential benefits of inflammatory cells to atherosclerosis. The aim of this study was to investigate the function of inflammatory cells/endothelium axis and determine whether and how inflammatory cell-derived MYDGF (myeloid-derived growth factor) inhibited endothelial LDL (low-density lipoprotein) transcytosis. METHODS: In in vivo experiments, both loss- and gain-of-function strategies were used to evaluate the effect of inflammatory cell-derived MYDGF on LDL transcytosis. We generated monocyte/macrophage-targeted MYDGF-null mice on an Ldlr (LDL receptor)-/- background in the loss-of-function strategy and restored the inflammatory cell-derived MYDGF by bone marrow transplantation and inflammatory cell-specific overexpression of MYDGF mice model in the gain-of-function strategy. In in vitro experiments, coculture experiments between primary mouse aortic endothelial cells and macrophages and mouse aortic endothelial cells supplemented with or without recombinant MYDGF were conducted. RESULTS: Inflammatory cell-derived MYDGF deficiency aggravated endothelial LDL transcytosis, drove LDL uptake by artery wall, and thus exacerbated atherosclerosis in vivo. Inflammatory cell-derived MYDGF restoration by bone marrow transplantation and inflammatory cell MYDGF overexpression alleviated LDL transport across the endothelium, prevented LDL accumulation in the subendothelial space, and subsequently ameliorated atherosclerosis in vivo. Furthermore, in the in vitro study, macrophages isolated from MYDGF+/+ mice and recombinant MYDGF attenuated LDL transcytosis and uptake in mouse aortic endothelial cells. Mechanistically, MYDGF inhibited MAP4K4 (mitogen-activated protein kinase kinase kinase kinase isoform 4) phosphorylation, enhanced activation of Akt (protein kinase B)-1, and diminished the FoxO (forkhead box O) 3a signaling cascade to exert protective effects of MYDGF on LDL transcytosis and atherosclerosis. CONCLUSIONS: The findings support a role for inflammatory cell-derived MYDGF served as a cross talk factor between inflammatory cells and endothelial cells that inhibits LDL transcytosis across endothelium. MYDGF may become a novel therapeutic drug for atherosclerosis, and the beneficial effects of inflammatory cell in atherosclerosis deserve further attention.

The cellular composition of chronic subdural hematoma.

INTRODUCTION: The pathophysiology of chronic subdural hematoma (CSDH) remains to be fully understood. Basic knowledge of the composition and features of cells in the CSDH fluid may contribute to the understanding of the seemingly complex processes involved in CSDH formation and recurrence. This study is the first to examine the composition of cells and of cellular features in both systemic blood and subdural fluid from CSDH patients. We hypothesized that the cellular composition and features in the hematoma fluid may be; 1) different from that in the systemic blood; 2) different between patients with and without recurrence; 3) and different between the first and second operation in patients with recurrent CSDH. METHODS: Systemic blood and subdural hematoma fluid were collected from CSDH patients with and without recurrent CSDH at the time of primary and secondary surgery. Analyses of cells and cellular features included total number of white blood cells, erythroblasts, reticulocytes, platelets, neutrophilocytes, lymphocytes, monocytes, eosinophils, basophils, reticulocytes, immature granulocytes, mean corpuscular cell volume (MCV), mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, hemoglobin and hematocrit. RESULTS: Of the 85 included patients, 20 patients were operated for a recurrent CSDH within 90 days follow-up. All cells found in the systemic blood were present in the CSDH fluid, but the composition was different (p < 0.0001). MCV was higher in the hematoma fluid from the primary operation of patients later developing a recurrent CSDH compared to patients not developing recurrence (p = 0.009). Also, the percentage distribution of inflammatory cells in hematoma fluid from patients with recurrent CSDH was different between the first and second operation (p = 0.0017). CONCLUSION: This study is the first to investigate the cellular composition of CSDH fluid. Compared to systemic blood and to a reference distribution, an increased number of immune cells were present in the hematoma fluid, supporting an inflammatory component of the CSDH pathophysiology. MCV was higher in the subdural fluid at time of the first operation of CSDH patients later developing recurrence. CLINICAL TRIAL REGISTRATION: The study was approved by the Scientific Ethical Committee of the Capital Region of Denmark (Journal no. H-20051073.

MicroRNA-223 attenuates hepatocarcinogenesis by blocking hypoxia-driven angiogenesis and immunosuppression.

OBJECTIVE: The current treatment for hepatocellular carcinoma (HCC) to block angiogenesis and immunosuppression provides some benefits only for a subset of patients with HCC, thus optimised therapeutic regimens are unmet needs, which require a thorough understanding of the underlying mechanisms by which tumour cells orchestrate an inflamed tumour microenvironment with significant myeloid cell infiltration. MicroRNA-223 (miR-223) is highly expressed in myeloid cells but its role in regulating tumour microenvironment remains unknown. DESIGN: Wild-type and miR-223 knockout mice were subjected to two mouse models of inflammation-associated HCC induced by injection of diethylnitrosamine (DEN) or orthotopic HCC cell implantation in chronic carbon tetrachloride (CCl4)-treated mice. RESULTS: Genetic deletion of miR-223 markedly exacerbated tumourigenesis in inflammation-associated HCC. Compared with wild-type mice, miR-223 knockout mice had more infiltrated programmed cell death 1 (PD-1+) T cells and programmed cell death ligand 1 (PD-L1+) macrophages after DEN+CCl4 administration. Bioinformatic analyses of RNA sequencing data revealed a strong correlation between miR-223 levels and tumour hypoxia, a condition that is well-documented to regulate PD-1/PD-L1. In vivo and in vitro mechanistic studies demonstrated that miR-223 did not directly target PD-1 and PD-L1 in immune cells rather than indirectly downregulated them by modulating tumour microenvironment via the suppression of hypoxia-inducible factor 1α-driven CD39/CD73-adenosine pathway in HCC. Moreover, gene delivery of miR-223 via adenovirus inhibited angiogenesis and hypoxia-mediated PD-1/PD-L1 activation in both HCC models, thereby hindering HCC progression. CONCLUSION: The miR-223 plays a critical role in modulating hypoxia-induced tumour immunosuppression and angiogenesis, which may serve as a novel therapeutic target for HCC.

Airway inflammatory changes in the lungs of patients with asthma-COPD overlap (ACO): a bronchoscopy endobronchial biopsy study.

BACKGROUND: Although asthma and chronic obstructive pulmonary disease (COPD) are two distinct chronic airway inflammatory diseases, they often co-exist in a patient and the condition is referred to as asthma-COPD overlap (ACO). Lack of evidence regarding the inflammatory cells in ACO airways has led to their poor prognosis and treatment. The objective of this endobronchial biopsy (EBB) study was to enumerate inflammatory cellular changes in the airway wall of ACO compared with asthma, COPD current smokers (CS) and ex-smokers (ES), normal lung function smokers (NLFS), and non-smoker controls (HC). METHODS: EBB tissues from 74 patients were immunohistochemically stained for macrophages, mast cells, eosinophils, neutrophils, CD8+ T-cells and CD4+ T-cells. The microscopic images of stained tissues were evaluated in the epithelium, reticular basement membrane (RBM) cells/mm RBM length, and lamina propria (LP) cells/mm2 up to a depth of 120 µM using the image analysis software Image-Pro Plus 7.0. The observer was blinded to the images and disease diagnosis. Statistical analysis was performed using GraphPad Prism v9. RESULTS: The tissue macrophages in ACO were substantially higher in the epithelium and RBM than in HC (P < 0.001 for both), COPD-ES (P < 0.001 for both), and -CS (P < 0.05 and < 0.0001, respectively). The ACO LP macrophages were significantly higher in number than COPD-CS (P < 0.05). The mast cell numbers in ACO were lower than in NLFS (P < 0.05) in the epithelium, lower than COPD (P < 0.05) and NLFS (P < 0.001) in RBM; and lower than  HC (P < 0.05) in LP. We noted lower eosinophils in ACO LP than HC (P < 0.05) and the lowest neutrophils in both ACO and asthma. Furthermore, CD8+ T-cell numbers increased in the ACO RBM than HC (P < 0.05), COPD-ES (P < 0.05), and NLFS (P < 0.01); however, they were similar in number in epithelium and LP across groups. CD4+ T-cells remained lower in number across all regions and groups. CONCLUSION: These results suggest that the ACO airway tissue inflammatory cellular profile differed from the contributing diseases of asthma and COPD with a predominance of macrophages.

Colitis aggravated by Mrgprb2 knockout is associated with altered immune response, intestinal barrier function and gut microbiota.

NEW FINDINGS: What is the central question of this study? What is the role of mas-related G protein-coupled receptor X2 (MRGPRX2/Mrgprb2) in ulcerative colitis in relation to the intestinal flora, intestinal barrier and immune response? What is the main finding and its importance? Knockout of mouse Mrgprb2 aggravates dextran sulfate sodium (DSS)-induced colitis, which is associated with altered gut microbiota and immune response and disruption of the intestinal barrier. MRGPRB2 may have a protective effect on DSS-induced colitis. ABSTRACT: Ulcerative colitis (UC) is a chronic immune-related disease, and changes in the intestinal microbiota and damage to the intestinal barrier contribute to its pathogenesis. Mast cells (MCs) are widely distributed in the gastrointestinal tract and are thought to be related to the pathogenesis of UC. Human mas-related G protein-coupled receptor X2 (MRGPRX2) and its mouse homologue, Mrgprb2, are selectively expressed on MCs to recruit immune cells and modulate host defence against microbial infection. To investigate the role of Mrgprb2 in UC in mice, we compared the differences between Mrgprb2 knockout (b2KO) male mice and wild-type (WT) male mice with dextran sulfate sodium (DSS)-induced colitis in the severity of clinical symptoms, inflammatory cell infiltration, degree of intestinal barrier damage and composition of the intestinal flora. The results showed that weight loss, disease activity index score, colon shortening and colonic pathological damage were significantly increased in b2KO mice while MC activation, cytokine and chemokine secretion, and inflammatory cell infiltration were decreased. In addition, the abundance and diversity of the intestinal microbiota were reduced in b2KO mice. B2KO mice also exhibited a reduction of probiotics such as norank_f_Muribaculaceae and Lactobacillus and increase of harmful bacteria like Escherichia-Shigella. Intestinal mucosal barrier damage of b2KO mice was more severe than that of WT mice due to the attenuated expression of mucin-2 and occludin. These results demonstrated that MRGPRB2 may have a protective effect on DSS-induced colitis by altering the intestinal flora, participating in barrier repair and recruiting inflammatory cells to eliminate pathogens.

Dimethyl Fumarate Used as an Effective Treatment for Granuloma Annulare Disseminatum: An Immunohistochemical Case Study.

This investigation demonstrates the use of dimethyl fumarate (DMF) for the treatment of disseminated granuloma annulare (GAD), a rare and chronic inflammatory skin disease. In this case, progressive GAD was treated with DMF, resulting in significant improvement of skin lesions within 5 weeks and complete healing within 7 months. Clinical response was associated with a reduction in inflammatory cells, including both T cell subsets (CD4+ > CD8+), CD183+/CXCR3+ cells, Langerhans cells (CD1a+), myeloid DCs, M1- and M2-like macrophages and the activation marker HLA-DR in immunohistochemical analysis. These findings support the use of DMF as a promising treatment option for this rare skin condition.

Crosstalk of Inflammatory Cytokines within the Breast Tumor Microenvironment.

Several immune and immunocompetent cells, including dendritic cells, macrophages, adipocytes, natural killer cells, T cells, and B cells, are significantly correlated with the complex discipline of oncology. Cytotoxic innate and adaptive immune cells can block tumor proliferation, and others can prevent the immune system from rejecting malignant cells and provide a favorable environment for tumor progression. These cells communicate with the microenvironment through cytokines, a chemical messenger, in an endocrine, paracrine, or autocrine manner. These cytokines play an important role in health and disease, particularly in host immune responses to infection and inflammation. They include chemokines, interleukins (ILs), adipokines, interferons, colony-stimulating factors (CSFs), and tumor necrosis factor (TNF), which are produced by a wide range of cells, including immune cells, such as macrophages, B-cells, T-cells, and mast cells, as well as endothelial cells, fibroblasts, a variety of stromal cells, and some cancer cells. Cytokines play a crucial role in cancer and cancer-related inflammation, with direct and indirect effects on tumor antagonistic or tumor promoting functions. They have been extensively researched as immunostimulatory mediators to promote the generation, migration and recruitment of immune cells that contribute to an effective antitumor immune response or pro-tumor microenvironment. Thus, in many cancers such as breast cancer, cytokines including leptin, IL-1B, IL-6, IL-8, IL-23, IL-17, and IL-10 stimulate while others including IL-2, IL-12, and IFN-γ, inhibit cancer proliferation and/or invasion and enhance the body's anti-tumor defense. Indeed, the multifactorial functions of cytokines in tumorigenesis will advance our understanding of cytokine crosstalk pathways in the tumor microenvironment, such as JAK/STAT, PI3K, AKT, Rac, MAPK, NF-κB, JunB, cFos, and mTOR, which are involved in angiogenesis, cancer proliferation and metastasis. Accordingly, targeting and blocking tumor-promoting cytokines or activating and amplifying tumor-inhibiting cytokines are considered cancer-directed therapies. Here, we focus on the role of the inflammatory cytokine system in pro- and anti-tumor immune responses, discuss cytokine pathways involved in immune responses to cancer and some anti-cancer therapeutic applications.

Inflammatory Mediators of Axon Regeneration in the Central and Peripheral Nervous Systems.

Although most pathways in the mature central nervous system cannot regenerate when injured, research beginning in the late 20th century has led to discoveries that may help reverse this situation. Here, we highlight research in recent years from our laboratory identifying oncomodulin (Ocm), stromal cell-derived factor (SDF)-1, and chemokine CCL5 as growth factors expressed by cells of the innate immune system that promote axon regeneration in the injured optic nerve and elsewhere in the central and peripheral nervous systems. We also review the role of ArmC10, a newly discovered Ocm receptor, in mediating many of these effects, and the synergy between inflammation-derived growth factors and complementary strategies to promote regeneration, including deleting genes encoding cell-intrinsic suppressors of axon growth, manipulating transcription factors that suppress or promote the expression of growth-related genes, and manipulating cell-extrinsic suppressors of axon growth. In some cases, combinatorial strategies have led to unprecedented levels of nerve regeneration. The identification of some similar mechanisms in human neurons offers hope that key discoveries made in animal models may eventually lead to treatments to improve outcomes after neurological damage in patients.

Early tissue and healing responses after maxillary sinus augmentation using horizontal platelet rich fibrin bone blocks.

BACKGROUND: The effects of horizontal platelet-rich fibrin (H-PRF) bone block on the healing and immune response during sinus augmentation have not been fully investigated histologically at early time points. METHODS: Eighteenth male New Zealand white rabbits underwent bilateral sinus augmentation and were divided into two groups: deproteinized bovine bone mineral (DBBM) alone and H-PRF + DBBM (H-PRF bone block) group. Maxilla samples were collected at 3, 7 and 14 days post sinus augmentation procedures and analyzed using histological staining for the number of inflammatory cells, new blood vessels and evidence for early osteoclast bone turnover/remodeling. Furthermore, the effects of H-PRF bone blocks on the migration of osteoblasts and THP-1 macrophages were evaluated using a Transwell assay in vitro. RESULTS: A higher number of immune cells were found in the H-PRF bone block group at 3 and 7 days post-surgery when compared to the DBBM alone group,most notably in the regions close to the mucosal lining and bone plates. Furthermore, a significantly greater number of new blood vessel formations and early signs of osteoclast development were found in the H-PRF bone block group at 14 days. The in vitro transwell assay further confirmed that culture medium from H-PRF bone block markedly promote the migration of osteoblasts and THP-1 macrophages. CONCLUSIONS: The findings from this study have shown that H-PRF bone block is capable of increasing early immune cell infiltration leading to the acceleration of neovascularization and speeding the process of bone metabolism in vivo following maxillary sinus grafting with DBBM.

Role of ceRNA network in inflammatory cells of rheumatoid arthritis. / CeRNAç½‘ç»œåœ¨ç±»é£Žæ¹¿å ³èŠ‚ç‚Žçš„ç‚Žç—‡ç»†èƒžä¸­çš„ä½œç”¨.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease caused by inflammatory cells. Various inflammatory cells involved in RA include fibroblast-like synoviocytes, macrophages, CD4+T-lymphocytes, B lymphocytes, osteoclasts and chondrocytes. The close interaction between various inflammatory cells leads to imbalance of immune response and disorder of the expression of mRNA in inflammatory cells. It helps to drive production of pro-inflammatory cytokines and stimulate specific antigen-specific T- and B-lymphocytes to produce autoantibodies which is an important pathogenic factor for RA. Competing endogenous RNA (ceRNA) can regulate the expression of mRNA by competitively binding to miRNA. The related ceRNA network is a new regulatory mechanism for RNA interaction. It has been found to be involved in the regulation of abnormal biological processes such as proliferation, apoptosis, invasion and release of inflammatory factors of RA inflammatory cells. Understanding the ceRNA network in 6 kinds of RA common inflammatory cells provides a new idea for further elucidating the pathogenesis of RA, and provides a theoretical basis for the discovery of new biomarkers and effective therapeutic targets.

Cell-Mediated Glomerulonephritis Without Immune Complexes in Native Kidney Biopsies: A Report of 7 Cases.

We report 7 native kidney biopsies with diffuse endocapillary hypercellularity without immune deposits, affecting 5 women and 2 men aged 52-85 years. All patients had acute kidney injury, and 4 had nephrotic-range proteinuria. Comorbidities included breast cancer in 2, pancreatitis in 1, and para-aortic lymphadenopathy and bilateral carpal tunnel syndrome in 1. Kidney biopsies were characterized by predominant T-cell and CD68-positive macrophage infiltration in glomerular capillaries without deposits. Coexisting lesions included small cellular crescents in 5, mild peritubular capillaritis in 1, mononuclear cell intimal arteritis in 1, acute tubulointerstitial nephritis in 4, and mild arteriolosclerosis in 1. During the mean follow-up duration of 24.8 months, 4 patients showed partial or complete initial remission in response to immunosuppression. However, 2 deteriorated when prednisone was rapidly tapered (1 of them achieved subsequent remission with increased prednisone). Three patients developed kidney failure. We propose that this unusual pattern of injury is mediated by abnormal cell-mediated immune response. The underlying causes and pathogenesis of this cell-mediated glomerulonephritis will require further study.

Bronchial eosinophils, neutrophils, and CD8 + T cells influence asthma control and lung function in schoolchildren and adolescents with severe treatment-resistant asthma.

BACKGROUND: Studies in adult severe treatment-resistant asthma (STRA) have demonstrated heterogeneous pathophysiology. Studies in the pediatric age group are still scarce, and few include bronchial tissue analysis. OBJECTIVE: We investigated 6-18-year-old patients diagnosed with STRA in Sao Paulo, Brazil, by characterizing the different lung compartments and their correlations with asthma control and lung function. METHODS: Inflammatory profiles of 13 patients with a confirmed diagnosis of STRA were analyzed using blood, induced sputum, bronchoalveolar lavage, viral and bacterial screens and endobronchial biopsy. Inflammatory cells, cytokines, and basement membrane thickening were tested for correlations with the asthma control test (ACT) and spirometry and plethysmography parameters. RESULTS: Endobronchial biopsy specimens from 11 patients were viable for analysis. All biopsies showed eosinophilic infiltration. Submucosal (SM) eosinophils and neutrophils were correlated with worse lung function (pre-BD FEV1), and SM neutrophils were correlated with fixed obstruction (post-BD FEV1). Intraepithelial (IE) neutrophils were positively correlated with lung function (pre-BD sGaw). CD8 + T cells had the highest density in the IE and SM layers and were positively correlated with ACT and negatively correlated with the cytokines IL1ß, IL2, IL5, IL7, IL10, IL12, IL17, GCSF, MCP-1, INF-δ, and TNFα in sputum supernatant. The ASM chymase + mast cell density correlated positively with quality-of-life score (pAQLQ) and ACT. CONCLUSION: Eosinophils and SM neutrophils correlated with worse lung function, while IE neutrophils correlated with better lung function. Most importantly, CD8 + T cells were abundant in bronchial biopsies of STRA patients and showed protective associations, as did chymase + mast cells.

Duodenal mast cells and eosinophils in children with celiac disease: occurrence and distribution pattern.

OBJECTIVE: The aim of this study was to characterize duodenal mast cell (MC) and eosinophil (EO) numbers, their distribution within the lamina propria and possible impact on disease severity of paediatric celiac patients compared to children without celiac disease (CD). METHODS: We analysed duodenal samples of 215 children (109 CD, 106 controls) who underwent esophagogastroduodenoscopy from 2010 to 2018. After immunohistochemical staining, average MC and EO counts were histologically examined in ten high-power-fields. Additionally, cell-distribution within the lamina propria was analysed. Possible influence of relevant clinical parameters was evaluated. STATISTICS: Student's-t-test, Mann-Whitney U-test, Chi-square-test, ANOVA, significance-level <.05. Trial registration-number: DRKS00024669. RESULTS: MC-density was higher in CD-patients compared to the control-group (23.7 (±12.1)/HPF versus 19.7 (±9.1)/HPF; p = .008), varying in number interindividually. Eosinophils were also increased in the duodenum of celiac patients (23.3 (±9.3)/HPF versus 12.2 (±6.3)/HPF; p= <.001). MCs were distributed more often homogenously in all parts of CD lamina propria (44 biopsies (40.4%), residing more distant from the intestinal lumen in controls (0 biopsies with homogenous distribution-pattern (0%); p= <.001). Regarding EOs no polarity was observable. Atopic diseases did not occur significantly more often in patients with elevated EO-counts. CONCLUSION: MC- and EO-numbers were increased in the duodenum of CD-patients and MCs showed a different distribution-pattern in the lamina propria of celiac patients. These findings support the concept that both cell-types contribute to disease-pathogenesis. However, functional studies highlighting both cell-types' and their mediators' role regarding mucosal alterations during the course of the inflammatory process in celiac patients are needed. TRIAL REGISTRATION NUMBER AND URL: DRKS00024669; https://www.drks.de/drks_web/.

Impacts of eosinophil percentage on prognosis acute type A aortic dissection patients.

BACKGROUND: Eosinophils are pro-inflammatory cells involved in thrombosis and have been proposed as a prognosis marker in acute ischemic stroke and ST-elevation myocardial Infarction. Here, we sought to clarify the prognostic value of eosinophil percentage (EOS%) in patients with acute type A aortic dissection (AAAD). METHODS: We examined 183 consecutive AAAD patients. Based on the optimum cut-off value of EOS% determined by X-tile software, patients were classified into the low EOS% (EOS% ≤ 0.1) and high EOS% groups (EOS% > 0.1). We performed multivariate regression analysis and Kaplan-Meier (KM) survival curves to assess the association between EOS% and mortality. Eosinophil accumulation in aortic dissection intraluminal thrombus was confirmed using hematoxylin-eosin (H&E) staining. An external cohort from Medical Information Mart for Intensive Care IV was performed to validate the results. RESULTS: Relative to surviving patients, those who died during hospitalization had significantly lower EOS% (p = 0.001) but significantly higher WBC (p = 0.002) and neutrophil (p = 0.001) counts. Multivariate regression analysis identified EOS% as an independent predictor of in-hospital and 1-year mortality. KM curves revealed that 1-year cumulative mortality was significantly higher in the low EOS% group, although it was mainly attributed to the higher 30-day mortality. H&E staining revealed massive infiltration of eosinophils in all 20 thrombus specimens. The external validation confirmed that relative to survivors, patients with in-hospital mortality (p = 0.010) had significantly lower EOS%. Moreover, multivariate regression analyses identified that decreased EOS% was independently significantly associated with in-hospital mortality. CONCLUSIONS: Low EOS% is significantly related to increased mortality rates in AAAD patients.

Relationship between inflammatory cells level and longer duration of hypertension in Chinese community residents.

BACKGROUND: To explore the relationship between duration of hypertension and inflammatory cell levels and to assess whether long duration might aggravate these inflammatory cells among Chinese urban community residents. METHODS: A cross-sectional study of 5199 hypertensive and 2675 no-hypertensive participants who registered in community health service centers for physical examination was performed in Tianjin, China. Data of blood pressure and inflammatory cells were collected. Binary logistic regression was performed to assess the effect of hypertensive duration on the level of inflammatory cells before and after adjustment for the potential confounding factors. RESULTS: Individuals with hypertension had significantly higher level of leukocyte count, neutrophil proportion, neutrophil-to-lymphocyte ratio (NLR), and lower level of lymphocyte proportion than those without hypertension. Two-way ANOVA showed that hypertension duration, rather than blood pressure control or their interaction, had significant influence on the levels of neutrophil proportion, lymphocyte proportion, and NLR. With the prolongation of the duration of hypertension, the level of neutrophil proportion and NLR increased, and the level of lymphocyte proportion decreased. Long hypertension duration (>10 years) was significantly associated with high level of neutrophil proportion (OR = 1.48, 95% CI: 1.25, 1.75), high level of NLR (OR = 1.53, 95% CI: 1.29, 1.81), and low level of lymphocyte proportion (OR = 1.54, 95% CI: 1.30, 1.82) in comparison with short duration (<5 years) after adjustment for confounding factors. CONCLUSION: Hypertensive patients had higher level of leukocyte count, neutrophil proportion, NLR, and lower level of lymphocyte proportion than normotensive ones. Long duration of hypertension was associated with aggravated inflammatory biomarkers.

Relationship between the expression levels of CD4+ T cells, IL-6, IL-8 and IL-33 in the liver of biliary atresia and postoperative cholangitis, operative age and early jaundice clearance.

OBJECTIVE: To investigate the expression levels of CD4+ T cells, IL-6, IL-8 and IL-33 in liver tissue of BA, and the relationship with postoperative cholangitis, operative age and early jaundice clearance. METHODS: 45 cases of jaundice treated in the hospital from June 2018 to May 2020 were analyzed retrospectively. The expression and distribution of these factors were detected by HE staining and immunohistochemistry, the total bilirubin level and the incidence of cholangitis were recorded, and the relationship between liver inflammation level and the postoperative incidence of cholangitis, age of operation and early jaundice clearance were compared. RESULTS: Immunohistochemistry showed that the expression of CD4+ T cells, IL-6, IL-8 and IL-33 in the BA group were higher than those in the CBD group. ROC curve analysis showed the AUC of CD4+ T cells, IL-6 and IL-8 were 0.869, 0.886 and 0.838, respectively. The expression level of CD4+ T cells was negatively correlated with the decline rate of TBIL 3 months after operation, and the expressions of IL-8 and IL-33 were negatively correlated with the decline rate of TBIL 1 week after operation. CONCLUSION: The high expression of CD4+ T cells, IL-6, IL-8 and IL-33 in the BA liver tissue may lead to cholangitis and can be used as a predictor of early jaundice clearance. The degree of liver inflammation infiltration had nothing to do with the age of operation and is not a risk factor for postoperative cholangitis.