Resolution of Cox mediated inflammation by Se supplementation in mouse experimental model of colitis.
Ontology highlight
ABSTRACT:
SUBMITTER: Kaur R
PROVIDER: S-EPMC6067745 | biostudies-other | 2018
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Background & aimsProper resolution of inflammation is essential to maintaining homeostasis, which is important as a dysregulated inflammatory response has adverse consequences, even being regarded as a hallmark of cancer. However, our picture of dynamic changes during inflammation remains far from comprehensive.MethodsHere we used single-cell transcriptomics to elucidate changes in distinct cell types and their interactions in a mouse model of chemically induced colitis.ResultsOur analysis highlights the stromal cell population of the colon functions as a hub with dynamically changing roles over time. Importantly, we found that Serpina3n, a serine protease inhibitor, is specifically expressed in stromal cell clusters as inflammation resolves, interacting with a potential target, elastase. Indeed, genetic ablation of the Serpina3n gene delays resolution of induced inflammation. Furthermore, systemic Serpina3n administration promoted the resolution of inflammation, ameliorating colitis symptoms.ConclusionsThis study provides a comprehensive, single-cell understanding of cell-cell interactions during colorectal inflammation and reveals a potential therapeutic target that leverages inflammation resolution.
| S-EPMC8258998 | biostudies-literature
Project description:GPR4 is a proton-sensing G protein-coupled receptor that can be activated by extracellular acidosis. It has recently been demonstrated that activation of GPR4 by acidosis increases the expression of numerous inflammatory and stress response genes in vascular endothelial cells (ECs) and also augments EC-leukocyte adhesion. Inhibition of GPR4 by siRNA or small molecule inhibitors reduces endothelial cell inflammation. As acidotic tissue microenvironments exist in many types of inflammatory disorders, including inflammatory bowel disease (IBD), we examined the role of GPR4 in intestinal inflammation using a dextran sulfate sodium (DSS)-induced acute colitis mouse model. We observed that GPR4 mRNA expression was increased in mouse and human IBD tissues when compared to control intestinal tissues. To determine the function of GPR4 in intestinal inflammation, wild-type and GPR4-deficient mice were treated with 3% DSS for 7days to induce acute colitis. Our results showed that the severity of colitis was decreased in GPR4-deficient DSS-treated mice in comparison to wild-type DSS-treated mice. Clinical parameters, macroscopic disease indicators, and histopathological features were less severe in the DSS-treated GPR4-deficient mice than the DSS-treated wild-type mice. Endothelial adhesion molecule expression, leukocyte infiltration, and isolated lymphoid follicle (ILF) formation were reduced in intestinal tissues of DSS-treated GPR4-null mice. Collectively, our results suggest GPR4 provides a pro-inflammatory role in the inflamed gut as the absence of GPR4 ameliorates intestinal inflammation in the acute experimental colitis mouse model.
| S-EPMC5222690 | biostudies-literature
Project description:Colonic tissues in Inflammatory Bowel Disease (IBD) patients exhibit oxygen deprivation and activation of hypoxia-inducible factor 1? and 2? (HIF-1? and HIF-2?), which mediate cellular adaptation to hypoxic stress. Notably, macrophages and neutrophils accumulate preferentially in hypoxic regions of the inflamed colon, suggesting that myeloid cell functions in colitis are HIF-dependent. By depleting ARNT (the obligate heterodimeric binding partner for both HIF? subunits) in a murine model, we demonstrate here that myeloid HIF signaling promotes the resolution of acute colitis. Specifically, myeloid pan-HIF deficiency exacerbates infiltration of pro-inflammatory neutrophils and Ly6C+ monocytic cells into diseased tissue. Myeloid HIF ablation also hinders macrophage functional conversion to a protective, pro-resolving phenotype, and elevates gut serum amyloid A levels during the resolution phase of colitis. Therefore, myeloid cell HIF signaling is required for efficient resolution of inflammatory damage in colitis, implicating serum amyloid A in this process.
| S-EPMC6230677 | biostudies-literature
Project description:Expression of IL-22 is induced in several human inflammatory conditions, including inflammatory bowel disease (IBD). Expression of the IL-22 receptor is restricted to innate immune cells; however, the role of IL-22 in colitis has not yet been defined. We developed what we believe to be a novel microinjection-based local gene-delivery system that is capable of targeting the inflamed intestine. Using this approach, we demonstrated a therapeutic potency for IL-22-mediated activation of the innate immune pathway in a mouse model of Th2-mediated colitis that induces disease with characteristics similar to that of IBD ulcerative colitis (UC). IL-22 gene delivery enhanced STAT3 activation specifically within colonic epithelial cells and induced both STAT3-dependent expression of mucus-associated molecules and restitution of mucus-producing goblet cells. Importantly, IL-22 gene delivery led to rapid amelioration of local intestinal inflammation. The amelioration of disease by IL-22 was mediated by enhanced mucus production. In addition, local gene delivery was used to inhibit IL-22 activity through overexpression of IL-22-binding protein. Treatment with IL-22-binding protein suppressed goblet cell restitution during the recovery phase of a dextran sulfate sodium-induced model of acute colitis. These data demonstrate what we believe to be a novel function for IL-22 in the intestine and suggest the potency of a local IL-22 gene-delivery system for treating UC.
| S-EPMC2157567 | biostudies-literature
Project description:Inflammatory bowel disease (IBD) is characterized by chronic, recurring inflammation of the digestive tract. Current therapeutic approaches are limited and include biologics and steroids such as anti-TNFα monoclonal antibodies and corticosteroids, respectively. Significant adverse drug effects can occur for chronic usage and include increased risk of infection in some patients. GPR4, a pH-sensing G protein-coupled receptor, has recently emerged as a potential therapeutic target for intestinal inflammation. We have assessed the effects of a GPR4 antagonist, 2-(4-((2-Ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)phenyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (GPR4 antagonist 13, also known as NE-52-QQ57) in the dextran sulfate sodium (DSS)-induced acute colitis mouse model. The GPR4 antagonist 13 inhibited intestinal inflammation. The clinical parameters such as body weight loss and fecal score were reduced in the GPR4 antagonist 13 treatment group compared to vehicle control. Macroscopic disease indicators such as colon shortening, splenic expansion, and mesenteric lymph node enlargement were all reduced in severity in the GPR4 antagonist 13 treated mice. Histopathological features of active colitis were alleviated in GPR4 antagonist 13 treatment groups compared to vehicle control. Finally, inflammatory gene expression in the colon tissues and vascular adhesion molecule expression in the intestinal endothelia were attenuated by GPR4 antagonist 13. Our results indicate that GPR4 antagonist 13 provides a protective effect in the DSS-induced acute colitis mouse model, and inhibition of GPR4 can be explored as a novel anti-inflammatory approach.
| S-EPMC6526936 | biostudies-literature
Project description:Previous animal models of acute lung injury (ALI) are limited as they only reproduce part of the complex pathobiology of clinical ALI. Here we develop a translational mouse model of ALI, which not only reflects the major clinical and pathological features but also enables investigation into ALI resolution. Anaesthetised mice underwent orotracheal instillation of hydrochloric acid. During the immediate period after instillation, mice were carefully maintained with supplemental oxygen to avoid mortality. At specified time-points, lung injury was assessed by analysis of blood gases, respiratory mechanics, bronchoalveolar lavage fluid, alveolar fluid clearance and lung histology. Animals exhibited significant weight loss, decreased oxygenation, increased respiratory elastance and pulmonary inflammation (intra-alveolar leukocyte influx/cytokine levels and histological injury scores). Moreover, mice displayed alveolar-capillary barrier dysfunction/epithelial injury as reflected by increased alveolar protein, lung wet/dry weight ratio and soluble receptor for advanced glycation end-products, as well as reduced alveolar fluid clearance. These injury parameters peaked between days 1 and 3, followed by almost complete recovery over days 5-10. Histology showed evidence of fibrosis on day 10. The results indicate that this resolving model of acid aspiration represents a powerful experimental tool to investigate the injurious, inflammatory, fibrotic, and resolving and reparative processes of ALI.
| S-EPMC3568398 | biostudies-literature
Project description:The importance of hypoxia in the pathophysiology of inflammatory bowel disease (IBD) is increasingly being realized; also, hypoxia seems to be an important accelerator of brain inflammation, as has been reported by our group and others. IBD is a chronic intestinal disorder that leads to the development of inflammation, which is related to brain dysfunction. However, no studies have reported whether hypoxia is associated with IBD-induced neuroinflammation. Therefore, the objective of the present study was to determine whether hypoxia augments cerebral inflammation in a DSS-induced colitis mouse model. The mouse model was developed using 3% DSS for five days combined with exposure to hypoxic conditions (6,000 m) for two days. Mice were randomly divided into four groups: control group, DSS group, hypoxia group, and DSS plus hypoxia group. The results demonstrated that DSS combined with hypoxia resulted in up-regulation of colonic and plasmatic proinflammatory cytokines. Meanwhile, DSS plus hypoxia increased expression of Iba1, which is a marker of activated microglia, accompanied by increased expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in the brain. Moreover, the expression of tight junction proteins, such as zonula occludens-1 (ZO-1), occludin, and claudin-5, was markedly downregulated. The current study provides new insight into how hypoxia exposure induces excessive inflammatory responses andpathophysiological consequences in the brain in a DSS-induced colitis model.
| S-EPMC7756107 | biostudies-literature
Project description:BackgroundMitoQ is a mitochondria-targeted derivative of the antioxidant ubiquinone, with antioxidant and anti-apoptotic functions. Reactive oxygen species are involved in many inflammatory diseases including inflammatory bowel disease. In this study, we assessed the therapeutic effects of MitoQ in a mouse model of experimental colitis and investigated the possible mechanisms underlying its effects on intestinal inflammation.MethodsReactive oxygen species levels and mitochondrial function were measured in blood mononuclear cells of patients with inflammatory bowel disease. The effects of MitoQ were evaluated in a dextran sulfate sodium-induced colitis mouse model. Clinical and pathological markers of disease severity and oxidative injury, and levels of inflammatory cytokines in mouse colonic tissue were measured. The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed.ResultsCellular and mitochondrial reactive oxygen species levels in mononuclear cells were significantly higher in patients with inflammatory bowel disease (P <0.003, cellular reactive oxygen species; P <0.001, mitochondrial reactive oxygen species). MitoQ significantly ameliorated colitis in the dextran sulfate sodium-induced mouse model in vivo, reduced the increased oxidative stress response (malondialdehyde and 3-nitrotyrosine formation), and suppressed mitochondrial and histopathological injury by decreasing levels of inflammatory cytokines IL-1 beta and IL-18 (P <0.001 and P <0.01 respectively). By decreasing mitochondrial reactive oxygen species, MitoQ also suppressed activation of the NLRP3 inflammasome that was responsible for maturation of IL-1 beta and IL-18. In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells.ConclusionTaken together, our results suggest that MitoQ may have potential as a novel therapeutic agent for the treatment of acute phases of inflammatory bowel disease.
| S-EPMC3750576 | biostudies-literature
Project description:Non-caloric artificial sweeteners are frequently discussed as components of the "Western diet", negatively modulating intestinal homeostasis. Since the artificial sweetener saccharin is known to depict bacteriostatic and microbiome-modulating properties, we hypothesized oral saccharin intake to influence intestinal inflammation and aimed at delineating its effect on acute and chronic colitis activity in mice. In vitro, different bacterial strains were grown in the presence or absence of saccharin. Mice were supplemented with saccharin before or after induction of acute or chronic colitis using dextran sodium sulfate (DSS) and the extent of colitis was assessed. Ex vivo, intestinal inflammation, fecal bacterial load and composition were studied by immunohistochemistry analyses, quantitative PCR, 16 S RNA PCR or next generation sequencing in samples collected from analyzed mice. In vitro, saccharin inhibited bacterial growth in a species-dependent manner. In vivo, oral saccharin intake reduced fecal bacterial load and altered microbiome composition, while the intestinal barrier was not obviously affected. Of note, DSS-induced colitis activity was significantly improved in mice after therapeutic or prophylactic treatment with saccharin. Together, this study demonstrates that oral saccharin intake decreases intestinal bacteria count and hence encompasses the capacity to reduce acute and chronic colitis activity in mice.
| S-EPMC7230785 | biostudies-literature
Project description:Defective apoptosis of eosinophils, the main leukocyte in the pathogenesis of asthma, and delay in its removal lead to lung damage and loss of pulmonary function due to failure in the resolution of inflammation. Here, we investigated the ability of angiotensin-(1-7) [Ang-(1-7)], a pivotal peptide of the renin-angiotensin system, to promote resolution of an allergic lung inflammatory response. Balb/c mice were sensitized and challenged with ovalbumin and treated with Ang-(1-7) at the peak of the inflammatory process. Bronchoalveolar lavage (BAL) fluid and lungs were collected 24?h after treatment. Different lung lobes were processed for histology to evaluate inflammatory cell infiltration, airway and pulmonary remodeling, total collagen staining, and measurements of (i) collagen I and III mRNA expression by qRT-PCR; (ii) ERK1/2, I?B-?, and GATA3 protein levels by Western blotting; and (iii) eosinophilic peroxidase activity. Total number of inflammatory cells, proportion of apoptotic eosinophils and immunofluorescence for caspase 3 and NF-?B in leukocytes were evaluated in the BAL. Mas receptor immunostaining was evaluated in mouse and human eosinophils. Engulfment of human polimorphonuclear cells by macrophages, efferocytosis, was evaluated in vivo. Ang-(1-7) reduced eosinophils in the lung and in the BAL, increased the number of apoptotic eosinophils, shown by histology criteria and by increase in caspase 3 immunostaining. Furthermore, Ang-(1-7) decreased NF-kB immunostaining in eosinophils, reduced GATA3, ERK1/2, and I?B-? expression in the lung and decreased pulmonary remodeling and collagen deposition. Importantly, Ang-(1-7) increased efferocytosis. Our results demonstrate, for the first time, Ang-(1-7) activates events that are crucial for resolution of the inflammatory process of asthma and promotion of the return of lung homeostasis, indicating Ang-(1-7) as novel endogenous inflammation-resolving mediator.
| S-EPMC5797293 | biostudies-literature