Inflammation Remodeling Research Articles

Early Cyst Formation Leads to the Development of an Inflammatory Microenvironment and Tissue Remodeling in Polycystic Kidney Disease

Early Cyst Formation Leads to the Development of an Inflammatory Microenvironment and Tissue Remodeling in Polycystic Kidney Disease

In Vitro Characterization of a Tissue Renin-Angiotensin System in Human Nucleus Pulposus Cells.

Low back pain is a clinically highly relevant musculoskeletal burden and is associated with inflammatory as well as degenerative processes of the intervertebral disc. However, the pathophysiology and cellular pathways contributing to this devastating condition are still poorly understood. Based on previous evidence, we hypothesize that tissue renin-angiotensin system (tRAS) components, including the SARS-CoV-2 entry receptor angiotensin-converting enzyme 2 (ACE2), are present in human nucleus pulposus (NP) cells and associated with inflammatory and degenerative processes. Experiments were performed with NP cells from four human donors. The existence of angiotensin II, angiotensin II type 1 receptor (AGTR1), AGTR2, MAS-receptor (MasR), and ACE2 in human NP cells was validated with immunofluorescent staining and gene expression analysis. Hereafter, the cell viability was assessed after adding agonists and antagonists of the target receptors as well as angiotensin II in different concentrations for up to 48 h of exposure. A TNF-α-induced inflammatory in vitro model was employed to assess the impact of angiotensin II addition and the stimulation or inhibition of the tRAS receptors on inflammation, tissue remodeling, expression of tRAS markers, and the release of nitric oxide (NO) into the medium. Furthermore, protein levels of IL-6, IL-8, IL-10, and intracellular as well as secreted angiotensin II were assessed after exposing the cells to the substances, and inducible nitric oxide synthase (iNOS) levels were evaluated by utilizing Western blot. The existence of tRAS receptors and angiotensin II were validated in human NP cells. The addition of angiotensin II only showed a mild impact on gene expression markers. However, there was a significant increase in NO secreted by the cells. The gene expression ratios of pro-inflammatory/anti-inflammatory cytokines IL-6/IL-10, IL-8/IL-10, and TNF-α/IL-10 were positively correlated with the AGTR1/AGTR2 and AGTR1/MAS1 ratios, respectively. The stimulation of the AGTR2 MAS-receptor and the inhibition of the AGTR1 receptor revealed beneficial effects on the gene expression of inflammatory and tissue remodeling markers. This finding was also present at the protein level. The current data showed that tRAS components are expressed in human NP cells and are associated with inflammatory and degenerative processes. Further characterization of the associated pathways is warranted. The findings indicate that tRAS modulation might be a novel therapeutic approach to intervertebral disc disease.

Influence of physical loading on behavioral reactions of rats in cerebral hypoperfusion

A number of clinical studies demonstrate that individual characteristics such as stress tolerance and cognitive ability can be considered not only as diagnostic variables but also as risk factors for severe cerebral hypoperfusion. The aim of the study was to identify the typological features of the effect of physical activity on the behavioral reactions of rats during cerebral hypoperfusion. Material and methods. Cerebral hypoperfusion was modeled by bilateral carotid artery ligation. The study involved 280 rats, divided into equal subgroups, according to sex, stress tolerance and learning capacity. Of these, 112 animals were subjected to daily short-term swimming as a rehabilitation model. Before the simulation, and at 6, 8, 14, 21, 28, 35, 60 and 90 days postoperatively, the animals were tested using a Morris water maze and an “open field” test. Results and discussion. The dynamics of stress resistance and learning ability are related to the periodicity of inflammatory, necrotic, circulatory and reparative remodeling in the model used. After 2-3 months of study, cerebral hypoperfusion causes stabilization of indices characterizing stress resistance and cognitive functions below control values. A decrease in stress resistance begins earlier from day 6 of the study, while the index characterizing cognitive functions first decreases significantly after 3 weeks of study. Factors reducing the damaging effects of cerebral hypoperfusion were female gender, high baseline stress tolerance and learning ability. When assessing learning ability under physical load, animals with high baseline cognitive development showed earlier recovery dynamics during urgent adaptation and a significant increase during long-term adaptation.

A New Model of Acute Exacerbation of Experimental Pulmonary Fibrosis in Mice.

idiopathic pulmonary fibrosis (IPF) is the most severe form of fibrosing interstitial lung disease, characterized by progressive respiratory failure leading to death. IPF's natural history is heterogeneous, and its progression unpredictable. Most patients develop a progressive decline of respiratory function over years; some remain stable, but others present a fast-respiratory deterioration without identifiable cause, classified as acute exacerbation (AE). to develop and characterize an experimental mice model of lung fibrosis AE, mimicking IPF-AE at the functional, histopathological, cellular and molecular levels. we established in C57BL/6 male mice a chronic pulmonary fibrosis using a repetitive low-dose bleomycin (BLM) intratracheal (IT) instillation regimen (four instillations of BLM every 2 weeks), followed by two IT instillations of a simple or double-dose BLM challenge to induce AE. Clinical follow-up and histological and molecular analyses were done for fibrotic and inflammatory lung remodeling analysis. as compared with a low-dose BLM regimen, this AE model induced a late burst of animal mortality, worsened lung fibrosis and remodeling, and superadded histopathological features as observed in humans IPF-AE. This was associated with stronger inflammation, increased macrophage infiltration of lung tissue and increased levels of pro-inflammatory cytokines in lung homogenates. Finally, it induced in the remodeled lung a diffuse expression of hypoxia-inducible factor 1α, a hallmark of tissular hypoxia response and a major player in the progression of IPF. this new model is a promising model of AE in chronic pulmonary fibrosis that could be relevant to mimic IPF-AE in preclinical trials.

Integrative weighted molecular network construction from transcriptomics and genome wide association data to identify shared genetic biomarkers for COPD and lung cancer.

Chronic obstructive pulmonary disease (COPD) is a multifactorial progressive airflow obstruction in the lungs, accounting for high morbidity and mortality across the world. This study aims to identify potential COPD blood-based biomarkers by analyzing the dysregulated gene expression patterns in blood and lung tissues with the help of robust computational approaches. The microarray gene expression datasets from blood (136 COPD and 6 controls) and lung tissues (16 COPD and 19 controls) were analyzed to detect shared differentially expressed genes (DEGs). Then these DEGs were used to construct COPD protein network-clusters and functionally enrich them against gene ontology annotation terms. The hub genes in the COPD network clusters were then queried in GWAS catalog and in several cancer expression databases to explore their pathogenic roles in lung cancers. The comparison of blood and lung tissue datasets revealed 63 shared DEGs. Of these DEGs, 12 COPD hub gene-network clusters (SREK1, TMEM67, IRAK2, MECOM, ASB4, C1QTNF2, CDC42BPA, DPF3, DET1, CCDC74B, KHK, and DDX3Y) connected to dysregulations of protein degradation, inflammatory cytokine production, airway remodeling, and immune cell activity were prioritized with the help of protein interactome and functional enrichment analysis. Interestingly, IRAK2 and MECOM hub genes from these COPD network clusters are known for their involvement in different pulmonary diseases. Additional COPD hub genes like SREK1, TMEM67, CDC42BPA, DPF3, and ASB4 were identified as prognostic markers in lung cancer, which is reported in 1% of COPD patients. This study identified 12 gene network- clusters as potential blood based genetic biomarkers for COPD diagnosis and prognosis.

HDACi promotes inflammatory remodeling of the tumor microenvironment to enhance epitope spreading and antitumor immunity.

Adoptive cell therapy (ACT) with tumor-specific memory T cells has shown increasing efficacy in regressing solid tumors. However, tumor antigen heterogeneity represents a longitudinal challenge for durable clinical responses due to the therapeutic selective pressure for immune escape variants. Here, we demonstrated that delivery of the class I histone deacetylase inhibitor MS-275 promoted sustained tumor regression by synergizing with ACT in a coordinated manner to enhance cellular apoptosis. We found that MS-275 altered the tumor inflammatory landscape to support antitumor immunoactivation through the recruitment and maturation of cross-presenting CD103+ and CD8+ DCs and depletion of Tregs. Activated endogenous CD8+ T cell responses against nontarget tumor antigens were critically required for the prevention of tumor recurrence. Importantly, MS-275 altered the immunodominance hierarchy by directing epitope spreading toward the endogenous retroviral tumor–associated antigen p15E. Our data suggest that MS-275 in combination with ACT multimechanistically enhanced epitope spreading and promoted long-term clearance of solid tumors.

Role of HMGB1 in the formation of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism.

Acute pulmonary embolism (PE) may be a common but fatal condition in several countries; in untreated or inadequately therapeutic PE patients, is a commonly occurring long-term complication affecting patient survival treatment and prognosis, contributing to right heart disease and may even be fatal. To date, the pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) due to acute pulmonary embolism remains unclear; hence, there is an immediate demand for medications that are directly aimed at both preventing and managing the progression of CTEPH. Previous studies have shown that the inflammatory response is associated with thrombosis and the development of pulmonary cardiovascular disease. High-mobility Group B 1 (HMGB1), a damage-associated molecular pattern (DAMP), is involved in deep vein thrombosis and inflammatory reactions, vascular remodeling, and thrombosis in pulmonary hypertension. Therefore, we hypothesized that HMGB1 participates in the process of CTEPH development after acute PE. This paper details the dynamic changes in HMGB1 and the relationship between HMGB1 and the advancement of CTEPH after acute PE to better understand the pathogenic mechanisms and potential clinical applications.

Left ventricular assist device bioinformatics identify possible hubgenes and regulatory networks involved in the myocardium of patients with left ventricular assist device.

ObjectiveThe aim of this study was to clarify the changes of myocardial gene expression profile after left ventricular assist device (LVAD) implantation and the related molecular biological significance.MethodsA thorough bioinformatic analysis to evaluate the changes in gene expression profile in patients pre-LVAD and post-LVAD was conducted. Four relevant gene expression datasets—GSE430, GSE974, GSE21610, and GSE52601 from Gene Expression Omnibus (GEO) database were downloaded. Analysis of GEO2R, Gene Ontology (GO), protein-protein interaction (PPI) were used to determine differentially expressed genes (DEGs) and their function, respectively.ResultsA total of 37 DEGs were identified, including 26 down-regulated and 11 up-regulated genes. The molecular function of DEGs were enriched in “cytokine activity,” “neurotransmitter binding,” “receptor ligand activity.” The gene set enrichment analysis (GSEA) revealed an overall marked increase of neutrophil degranulation signaling, closely correlated with the G protein coupled receptor (GPCR)—ligand binding process after LVAD assistance. 16 hubgenes in these DEGs were further selected and the biological process involved is mainly related to positive regulation of leukocyte chemotaxis mediated by chemokines.ConclusionInflammatory signaling pathway is crucial for the pathophysiology after LVAD implantation. Chemokines mediate cardiac inflammatory response and tissue remodeling after LVAD implantation through GPCR—ligand binding.

Giant Cell Arteritis: Focusing on Current Aspects From the Clinic to Diagnosis and Treatment.

Giant cell arteritis (GCA) is a granulomatous arteritis involving large arteries, particularly the aorta and its major proximal branches, including the carotid and temporal arteries. GCA involves individuals over 50years old. The etiopathogenesis of GCA may involve a genetic background triggered by unknown environmental factors (eg infections), the activation of dendritic cells as well as inflammatory and vascular remodeling. However, its pathogenetic mechanism still remains unclear, although progress has been made in recent years. In the past, inflammatory markers and arterial biopsy were considered as gold standard for the diagnosis of GCA. However, emerging imaging methods have been made more sensitive and specific for the diagnosis of GCA. Treatment includes biological and other modalities including interleukin-6 (IL-6) inhibitors.

Inflammatory macrophages interrupt osteocyte maturation and mineralization via regulating the Notch signaling pathway

BackgroundIt is well-known that both macrophages and osteocytes are critical regulators of osteogenesis and osteoclastogenesis, yet there is limited understanding of the macrophage-osteocyte interaction, and how their crosstalk could affect bone homeostasis and mineralization. This research therefore aims to investigate the effects of macrophage polarization on osteocyte maturation and mineralization process.MethodsA macrophage-derived conditioned medium based osteocyte culture was set up to investigate the impact of macrophages on osteocyte maturation and terminal mineralization. Surgically induced osteoarthritis (OA) rat model was used to further investigate the macrophage-osteocyte interaction in inflammatory bone remodeling, as well as the involvement of the Notch signaling pathway in the mineralization process.ResultsOur results identified that osteocytes were confined in an immature stage after the M1 macrophage stimulation, showing a more rounded morphology, higher expression of early osteocyte marker E11, and significantly lower expression of mature osteocyte marker DMP1. Immature osteocytes were also found in inflammatory bone remodeling areas, showing altered morphology and mineralized structures similar to those observed under the stimulation of M1 macrophages in vitro, suggesting that M1 macrophages negatively affect osteocyte maturation, leading to abnormal mineralization. The Notch signaling pathway was found to be down regulated in M1 macrophage-stimulated osteocytes as well as osteocytes in inflammatory bone. Overexpression of the Notch signaling pathway in osteocytes showed a significant circumvention on the negative effects from M1 macrophage.ConclusionTaken together, our findings provide valuable insights into the mechanisms involved in abnormal bone mineralization under inflammatory conditions.

Circ_0040929 Serves as Promising Biomarker and Potential Target for Chronic Obstructive Pulmonary Disease.

BackgroundCircular RNAs (circRNAs) can act as essential regulators in many diseases, including chronic obstructive pulmonary disease (COPD). We aimed to explore the role and underlying mechanism of circ_0040929 in COPD.MethodsA cellular model of COPD was constructed by treating human bronchial epithelial cells (16HBE) with cigarette smoke extract (CSE). The levels of circ_0040929, microRNA-515-5p (miR-515-5p) and insulin-like growth factor-binding protein 3 (IGFBP3) were measured by quantitative real-time PCR. Cell proliferation was assessed by Cell Counting Kit-8 and 5-ethynyl-2’-deoxyuridine assays. Cell apoptosis was evaluated by flow cytometry. Protein expression was measured using Western blot assay. The levels of inflammatory factors and airway remodeling were assayed via enzyme-linked immunosorbent assay. The interaction between miR-515-5p and circ_0040929/IGFBP3 was confirmed by dual-luciferase reporter, RNA pull-down and RNA immunoprecipitation assays. Exosomes were detected using transmission electron microscopy.ResultsCirc_0040929 expression and IGFBP3 expression were upregulated in the serum of smokers (n = 22) compared to non-smokers (n = 22) and more significantly upregulated in the serum of COPD patients (n = 22). However, miR-515-5p expression was decreased in the serum of smokers compared to non-smokers and further reduced in the serum of COPD. Circ_0040929 knockdown attenuated CSE-induced cell injury by increasing proliferation and reducing apoptosis, inflammation, and airway remodeling in 16HBE cells. MiR-515-5p was a direct target of circ_0040929, and miR-515-5p inhibition reversed the effect of circ_0040929 knockdown in CSE-treated 16HBE cells. IGFBP3 was a direct target of miR-515-5p, and miR-515-5p overexpression alleviated CSE-induced cell injury via targeting IGFBP3. Moreover, circ_0040929 regulated IGFBP3 expression by targeting miR-515-5p. Importantly, circ_0040929 was upregulated in serum exosomes from COPD patients.ConclusionCirc_0040929 played a promoting role in CSE-induced COPD by regulating miR-515-5p/IGFBP3 axis, suggesting that it might be a novel potential target for COPD treatment.

Biologics and airway remodeling in severe asthma.

Asthma is a chronic inflammatory airway disease resulting in airflow obstruction, which in part can become irreversible to conventional therapies, defining the concept of airway remodeling. The introduction of biologics in severe asthma has led in some patients to the complete normalization of previously considered irreversible airflow obstruction. This highlights the need to distinguish a "fixed" airflow obstruction due to structural changes unresponsive to current therapies, from a "reversible" one as demonstrated by lung function normalization during biological therapies not previously obtained even with high-dose systemic glucocorticoids. The mechanisms by which exposure to environmental factors initiates the inflammatory responses that trigger airway remodeling are still incompletely understood. Alarmins represent epithelial-derived cytokines that initiate immunologic events leading to inflammatory airway remodeling. Biological therapies can improve airflow obstruction by addressing these airway inflammatory changes. In addition, biologics might prevent and possibly even revert "fixed" remodeling due to structural changes. Hence, it appears clinically important to separate the therapeutic effects (early and late) of biologics as a new paradigm to evaluate the effects of these drugs and future treatments on airway remodeling in severe asthma.

Exploring the Mechanism of Aspirin in the Treatment of Kawasaki Disease Based on Molecular Docking and Molecular Dynamics.

Purpose The research aims to investigate the mechanism of action of aspirin in the treatment of Kawasaki disease. Methods We predicted the targets of aspirin with the help of the Drugbank and PharmMapper databases, the target genes of Kawasaki disease were mined in the GeneCards and Disgenet databases, the intersection targets were processed in the Venny database, and the gene expression differences were observed in the GEO database. The Drugbank and PharmMapper databases were used to predict the target of aspirin, and the target genes of Kawasaki disease were explored in the GeneCards and Disgenet databases, and the Venny was used for intersection processing. We observed the gene expression differences in the GEO database. The disease-core gene target-drug network was established and molecular docking was used for verification. Molecular dynamics simulation verification was carried out to combine the active ingredient and the target with a stable combination. The supercomputer platform was used to measure and analyze the binding free energy, the number of hydrogen bonds, the stability of the protein target at the residue level, the radius of gyration, and the solvent accessible surface area. Results Aspirin had 294 gene targets, Kawasaki disease had 416 gene targets, 42 intersecting targets were obtained, we screened 13 core targets by PPI; In the GO analysis, we learned that the biological process of Kawasaki disease involved the positive regulation of chemokine biosynthesis and inflammatory response; pathway enrichment involved PI3K-AKT signaling pathway, tumor necrosis factor signaling pathway, etc. After molecular docking, the data showed that CTSG, ELANE, and FGF1 had the best binding degree to aspirin. Molecular dynamics was used to prove and analyze the binding stability of active ingredients and protein targets, and Aspirin/ELANE combination has the strongest binding energy. Conclusion In the treatment of Kawasaki disease, aspirin may regulate inflammatory response and vascular remodeling through CTSG, ELANE, and FGF1.

Abdominal Aortic Calcification Volume Is Associated with Wall Enhancement of Unruptured Intracranial Aneurysm

Inflammatory atherosclerotic remodeling of unruptured intracranial aneurysms (UIAs) wall, which could be detected as aneurysm wall enhancement (AWE) in MR vessel wall imaging (VWI), plays a pivotal role in pathophysiology of progression to rupture. On the other hand, abdominal aortic calcification reflects the extent of systemic atherosclerosis, which in turn predicts the risk of atherosclerotic cardiovascular as well as cerebrovascular diseases. This study sought to investigate whether the abdominal aortic calcification was associated with increased wall enhancement of UIAs in VWI. This retrospective study reviewed subjects who underwent evaluation using 3T MR-VWI of UIAs and abdominal CT before endovascular treatments for UIAs between 2018 to 2020. Abdominal aortic calcification volume (ACV) was quantitatively measured from abdominal CT scans between renal arteries and bifurcation. The presence of AWE was correlated with patient profile, aneurysm morphology, and the ACV. A total of 42 patients with 50 UIAs were included. AWE was detected in 19 (38.0%) UIAs. Maximum diameter (9.2 ± 5.0 mm vs 5.3 ± 1.5 mm, P < 0.01) and the ACV (8.2 ± 6.0 mL vs 4.7 ± 4.6 mL, P= 0.038) were significantly higher in UIAs with AWE than those without AWE. The ACV was significantly associated with increased wall enhancement of UIAs. Systemic atherosclerosis might be a risk factor for the instability of UIAs. Future studies examining the effect of medications for systemic atherosclerosis on the extent of AWE in UIAs is warranted.

Abstract P1133: Association Of Mesenchymal Stem Cells Therapy And An Agonist Of Adenosine Receptor On Monocrotaline-induced Pulmonary Arterial Hypertension In Rats

Introduction: Pulmonary arterial hypertension (PAH) is characterized by an intense inflammatory component leading to vascular remodeling, increasing the pulmonary artery pressure, eventually resulting in right ventricular dysfunction. Hypothesis: Association of human mesenchymal stem cells (hMSC) therapy and LASSBio-1860 (agonist of adenosine receptors) would reduce the inflammatory response and vascular remodeling, decreasing the vascular resistance and pulmonary artery pressure, improving right ventricle function and reducing hypertrophy. Methods: Protocols were approved by Animal Care and Use Committee at Universidade Federal do Rio de Janeiro. PAH was induced in male Wistar rats by injection of monocrotaline (MCT; 60 mg/kg, i.p.) and confirmed within 14 days by transthoracic echocardiography. Groups were orally treated daily during 14 days with vehicle, LASSBio-1860 (180 μmol/kg) after a single intravenous injection of 10 5 hMSC At the end of protocol, tissues were collected and processed to evaluate expression of proteins using immunohistochemical and western-blotting analysis. Results: Mean pulmonary artery acceleration time (PAAT) was reduced in MCT-induced PAH group compared to the control group from 31.0 ± 1.5 to 21.9 ± 1.3 ms. In contrast, the association of LASSBio-1860 and hMSC has recovered the PAAT to 31.0 ± 2.0 ms, which effect was not observed in isolated treatment either with LASSBio-1860 or hMSC (23.5 ± 2.1 and 22.2 ± 2.2 ms). Table 1 shows hemodynamic, molecular and immunohistochemical parameters. In conclusion, the association of LASSBio-1860 and hMSC improved hemodynamic, morphologic and inflammatory parameters in an MCT-induced model of PAH.

Bone disturbances and progression of atherosclerosis in ApoE knockout mice.

Epidemiological evidence supports a link between atherosclerosis and osteoporosis. These conditions might share common pathophysiological mechanisms, with inflammation being one of the hypotheses.Apolipoprotein E deficient mice (ApoE-/-) develop atherosclerotic lesions spontaneously, further aggravated by a high-fat diet. Their bone remodelling is also disturbed. We hypothesised that a proinflammatory state could be a common contributive factor for vessel and bone disturbances observed in this animal model. We evaluated vessels and bones of ApoE-/- and control C57BL/6 (B6) female mice fed a high-fat diet in five time-points (8, 16, 20, 24 and 28 weeks of age) and quantified the development of atherosclerotic lesions, analysed gene expression of inflammatory and bone remodelling proteins (IL-1β, IL-6, IL-17A, TNF, RANKL, and OPG), measured serum bone turnover markers (P1NP and CTX-I), performed bone (L3-L4 vertebras) histomorphometric analysis and evaluated biomechanical properties of bones. We compared the outcomes of B6 and ApoE-/- groups at each time-point and, within each group, over time. Atherosclerotic lesions developed as previously described for ApoE-/- mice, but no significant differences were found in bone histomorphometry or biomechanical properties between ApoE-/- and B6 mice. Also, gene expression (either in bones or aortas) and serum biomarkers were similar in both groups. When considering over time evaluations we found that bone histomorphometry changes were similar between ApoE-/- and B6 mice, but CTX-I/P1NP ratio was significantly increased (meaning higher resorption than bone formation) in ApoE-/- as compared to B6 mice. Our study suggests that inflammation is not the principal driver for atherosclerosis progression and bone disturbances in this animal model.

Label-free analysis of inflammatory tissue remodeling in murine lung tissue based on multiphoton microscopy, Raman spectroscopy and machine learning.

Inflammatory fibrotic tissue remodeling can lead to severe morbidity. Histopathology grading requires extraction of biopsies and elaborate tissue processing. Label-free optical technologies can provide diagnostic readout without preparation and artificial stainings and show potential for in vivo applications. Here, we present an integration of Raman spectroscopy (RS) and multiphoton microscopy for joint investigation of the bio-chemical composition and morphological features related to cellular components and connective tissue. Both modalities show that collagen signatures were significantly increased in a murine fibrosis model. Furthermore, autofluorescence signatures assigned to immune cells show high correlation with disease severity. RS indicates increased levels of elastin and lipids. Further, we investigated the effect of joint data sets on prediction performance in machine learning models. Although binary classification did not benefit from adding more features, multi-class classification was improved by integrated data sets.

Serological biomarkers for management of primary sclerosing cholangitis.

Clinical manifestations and progression of primary sclerosing cholangitis (PSC) are heterogeneous, and its pathogenesis is poorly understood. The importance of gut-liver interactions in the pathogenesis has been clinically confirmed and highlighted in different theories. Recent advances regarding biomarkers of biliary-gut crosstalk may help to identify clinically relevant PSC subgroups assisting everyday clinical work-up (e.g., diagnosis, disease stratification, or surveillance) and the exploration of potential therapeutic targets. Alkaline phosphatase produced by the biliary epithelium is consistently associated with prognosis. However, its level shows natural fluctuation limiting its use in individual patients. Inflammatory, cell activation, and tissue remodeling markers have been reported to predict clinical outcome. Elevated immunoglobulin (Ig) G4 level is associated with a shorter transplantation-free survival. IgG type atypical perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCAs) are non-specific markers of various autoimmune liver diseases and may reflect an abnormal B-cell response to gut microbial antigens. IgG type atypical P-ANCA identifies PSC patients with particular clinical and genetic (for human leukocyte antigens) characteristics. The presence of IgA type anti-F-actin antibody (AAA) may predict a progressive disease course, and it is associated with enhanced mucosal immune response to various microbial antigens and enterocyte damage. IgA type anti-glycoprotein 2 (GP2) antibodies identify patients with a severe disease phenotype and poor survival due to enhanced fibrogenesis or development of cholangiocarcinoma. Elevated soluble vascular adhesion protein-1 (sVAP-1) level is associated with adverse disease outcomes in PSC. High sVAP-1 levels correlate with mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression in the liver that contributes to gut activated T-cell homing to the hepatobiliary tract. In the present paper, we review the evidence on these possible serological markers that could potentially help address the unmet clinical needs in PSC.

Neuroinflammation and galectins: a key relationship in neurodegenerative diseases.

Neurodegeneration is a pathological condition that is associated with the loss of neuronal function and structure. In neurodegenerative diseases, mounting evidence indicates that neuroinflammation is a common factor that contributes to neuronal damage and neurodegeneration. Neuroinflammation is characterized by the activation of microglia, the neuroimmune cells of the central nervous system (CNS), which have been implicated as active contributors to neuronal damage. Glycan structure modification is defining the outcome of neuroinflammation and neuronal regeneration; moreover, the expression of galectins, a group of lectins that specifically recognize β-galactosides, has been proposed as a key factor in neuronal regeneration and modulation of the inflammatory response. Of the different galectins identified, galectin-1 stimulates the secretion of neurotrophic factors in astrocytes and promotes neuronal regeneration, whereas galectin-3 induces the proliferation of microglial cells and modulates cell apoptosis. Galectin-8 emerged as a neuroprotective factor, which, in addition to its immunosuppressive function, could generate a neuroprotective environment in the brain. This review describes the role of galectins in the activation and modulation of astrocytes and microglia and their anti- and proinflammatory functions within the context of neuroinflammation. Furthermore, it discusses the potential use of galectins as a therapeutic target for the inflammatory response and remodeling in damaged tissues in the central nervous system.

Role of Hepatic Macrophages in Acute and Chronic Injury and Repair

Under optimal physiologic conditions, liver resident macrophages, such as Kupffer cells, are abundant in maintaining homeostasis. They orchestrate postinjury inflammatory tissue remodeling, surveil malignant microbial organisms, and remove toxins. Nevertheless, during chronic inflammation and wound healing in the liver, hepatic infiltration of immune cells from the bone marrow, peritoneum, and lymph nodes can promote the maintenance of macrophages subsets that exacerbate liver injury. Depending on the span of the inflammation and the extent of the damage, the liver can undergo acute liver injury or chronic liver injury. In this review, we explain the role of macrophages in the innate immune system, specifically discussing the role of the immune innate system and the description of Kupffer cells. The review also discusses macrophage activity in acute and chronic liver diseases, such as acetaminophen-induced injury, nonalcoholic steatohepatitis/nonalcoholic fatty liver disease, and alcoholic liver disease. Finally, the review also discuss Kupffer cell mechanisms for liver repair and regeneration.