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The protective effects of HIF-1α activation on sepsis induced intestinal mucosal barrier injury in rats model of sepsis.

ABSTRACT: The integrity of the intestinal barrier is critical for protecting the host against the pathogen. The role of hypoxia-inducible factor-1α (HIF-1α) in the intestinal barrier disfunction related to sepsis remained unclear. The purpose of the present study is to investigate the role of HIF-1α on oxidative damage, the intestinal mucosal permeability, structural and morphological changes during sepsis. Twenty-four Sprague Dawley (SD) rats were randomly divided into four groups of 6 rats each: the sham group (sham), sepsis group (subjected to cecal ligation and perforation, CLP), sepsis + DMOG group (40 mg/kg of DMOG by intraperitoneal injection for 7 consecutive days before CLP), and sepsis + BAY 87-2243 group (9 mg/kg of BAY 87-2243 orally administered for 3 consecutive days before CLP). Sepsis increased plasma levels of inflammatory mediators, oxidative stress markers and HIF-1α expression; caused pathological damage; increased permeability (P < 0.05); and decreased TJ protein expression in the intestinal mucosa of rats with sepsis (P < 0.05). The addition of DMOG up-regulated HIF-1α, then decreased the plasma levels of inflammatory mediators, oxidative stress markers, alleviated pathological damage to the intestinal mucosa and decreased intestinal permeability (P < 0.05); while BAY 87-2243 treatment had the opposite effects. Our findings showed that HIF-1α protects the intestinal barrier function of septic rats by inhibiting intestinal inflammation and oxidative damage, our results provide a novel insight for developing sepsis treatment.

SUBMITTER: Lei X

PROVIDER: S-EPMC9109928 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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The protective effects of HIF-1α activation on sepsis induced intestinal mucosal barrier injury in rats model of sepsis.

Lei Xiuzhen X Teng Wenbin W Fan Ying Y Zhu Yeke Y Yao Liuxu L Li Yuhong Y Zhu Shengmei S

PloS one 20220516 5

The integrity of the intestinal barrier is critical for protecting the host against the pathogen. The role of hypoxia-inducible factor-1α (HIF-1α) in the intestinal barrier disfunction related to sepsis remained unclear. The purpose of the present study is to investigate the role of HIF-1α on oxidative damage, the intestinal mucosal permeability, structural and morphological changes during sepsis. Twenty-four Sprague Dawley (SD) rats were randomly divided into four groups of 6 rats each: the sha ...[more]

PMID: 35576220

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Project description:Background & aimsAlcoholic liver disease (ALD) is characterized by gut dysbiosis and increased gut permeability. Hypoxia inducible factor 1α (HIF-1α) has been implicated in transcriptional regulation of intestinal barrier integrity and inflammation. We aimed to test the hypothesis that HIF-1α plays a critical role in gut microbiota homeostasis and the maintenance of intestinal barrier integrity in a mouse model of ALD.MethodsWild-type (WT) and intestinal epithelial-specific Hif1a knockout mice (IEhif1α-/-) were pair-fed modified Lieber-DeCarli liquid diet containing 5% (w/v) alcohol or isocaloric maltose dextrin for 24 days. Serum levels of alanine aminotransferase and endotoxin were determined. Fecal microbiota were assessed. Liver steatosis and injury, and intestinal barrier integrity were evaluated.ResultsAlcohol feeding increased serum levels of alanine aminotransferase and lipopolysaccharide, hepatic triglyceride concentration, and liver injury in the WT mice. These deleterious effects were exaggerated in IEhif1α-/- mice. Alcohol exposure resulted in greater reduction of the expression of intestinal epithelial tight junction proteins, claudin-1 and occludin, in IEhif1α-/- mice. In addition, cathelicidin-related antimicrobial peptide and intestinal trefoil factor were further decreased by alcohol in IEhif1α-/- mice. Metagenomic analysis showed increased gut dysbiosis and significantly decreased Firmicutes/Bacteroidetes ratio in IEhif1α-/- mice compared to the WT mice exposed to alcohol. An increased abundance of Akkermansia and a decreased level of Lactobacillus in IEhif1α-/- mice were also observed. Non-absorbable antibiotic treatment reversed the liver steatosis in both WT and IEhif1α-/- mice.ConclusionIntestinal HIF-1α is essential for the adaptative response to alcohol-induced changes in intestinal microbiota and barrier function associated with elevated endotoxemia and hepatic steatosis and injury.Lay summaryAlcohol consumption alters gut microbiota and multiple intestinal barrier protecting factors that are regulated by intestinal hypoxia-inducible factor 1α (HIF-1α). Absence of intestinal HIF-1α exacerbates gut leakiness leading to an increased translocation of bacteria and bacterial products to the liver, consequently causing alcoholic liver disease. Intestinal specific upregulation of HIF-1α could be developed as a novel approach for the treatment of alcoholic liver disease.

Project description:BackgroundLeakage of the intestinal mucosal barrier may cause translocation of bacteria, then leading to multiorgan failure. This study hypothesized that rhubarb monomers might protect the gut mucosal barrier in sepsis through junction proteins.MethodsHealthy male Sprague-Dawley rats (weighing 230-250 g) under anesthesia and sedation were subjected to cecal ligation and perforation (CLP). After surgical preparation, rats were randomly assigned to eight groups (n = 6 or 8 each group): sham group (Group A: normal saline gavage); sepsis group (Group B: normal saline gavage); Group C (intraperitoneally, dexamethasone 0.5 mg/kg) immediately after CLP surgery; and rhubarb monomer (100 mg/kg in normal saline)-treated groups (Group D: rhein; Group E: emodin; Group F: 3,8-dihydroxy-1-methyl-anthraquinone-2-carboxylic acid; Group G: 1-O-caffeoyl-2-(4-hydroxy-O-cinnamoyl)-D-glucose; and Group H: daucosterol linoleate). Animals were sacrificed after 24 h. Intestinal histology, lactulose, mannitol concentrations were measured, and zonula occludens (ZO)-1, occludin and claudin-5 transcription (polymerase chain reaction), translation (by Western blot analysis), and expression (by immunohistochemistry) were also measured.ResultsIntestinal histology revealed injury to intestinal mucosal villi induced by sepsis in Group B, compared with Group A. Compared with Group A (0.17 ± 0.41), the pathological scores in Groups B (2.83 ± 0.41, P < 0.001), C (1.83 ± 0.41, P < 0.001), D (2.00 ± 0.63, P < 0.001), E (1.83 ± 0.41, P < 0.001), F (1.83 ± 0.75, P < 0.001), G (2.17 ± 0.41, P < 0.001),and H (1.83 ± 0.41, P < 0.001) were significantly increased. Lactulose/mannitol (L/M) ratio in Group B (0.046 ± 0.003) was significantly higher than in Group A (0.013 ± 0.001, P< 0.001) while L/M ratios in Groups C (0.028 ± 0.002, P< 0.001), D (0.029 ± 0.003, P< 0.001), E (0.026 ± 0.003, P< 0.001), F (0.027 ± 0.003, P< 0.001), G (0.030 ± 0.005, P< 0.001), and H (0.026 ± 0.002, P< 0.001) were significantly lower than that in Group B. ZO-1, occludin and claudin-5 transcription, translation, and expression in Group B were significantly lower than that in Group A (P < 0.001), but they were significantly higher in Groups C, D, E, F, G, and H than those in Group B (P < 0.05).ConclusionRhubarb monomer treatment ameliorated mucosal damage in sepsis via enhanced transcription, translation, and expression of junction proteins.

Project description:BackgroundVentricular remodeling is the adaptive process in which the heart undergoes changes due to stress, leading to heart failure (HF). The progressive decline in cardiac function is considered to contribute to intestinal barrier impairment. LuQi Formula (LQF) is a traditional Chinese medicine preparation widely used in the treatment of ventricular remodeling and HF. However, the role of LQF in the impairment of intestinal barrier function induced by ventricular remodeling remains unclear.Materials and methodsVentricular remodeling was induced in rats by permanently ligating the left anterior descending branch coronary artery, and cardiac function indexes were assessed using echocardiography. Heart and colon tissue morphology were observed by hematoxylin-eosin, Masson's trichrome and Alcian Blue Periodic acid Schiff staining. Myocardial cell apoptosis was detected using TUNEL and immunohistochemistry. Circulatory levels of brain natriuretic peptide (BNP), intestinal permeability markers endotoxin, D-lactate and zonulin, as well as inflammatory cytokines tumor necrosis factor alpha and interleukin-1 beta were measured by Enzyme-linked immunosorbent assay. Expression levels of tight junction (TJ) proteins and hypoxia-inducible factor-1 alpha (HIF-1α) in colon tissue were detected by immunofluorescence, immunohistochemistry and western blotting. Cardiac function indexes and intestinal permeability markers of patients with HF were analyzed before and after 2-4 months of LQF treatment.ResultsLQF protected cardiac function and alleviated myocardial fibrosis and apoptosis in rats with ventricular remodeling. LQF protected the intestinal barrier integrity in ventricular remodeling rats, including maintaining colonic tissue morphology, preserving the number of goblet cells and normal expression of TJ proteins. Furthermore, LQF upregulated the expression of HIF-1α protein in colon tissue. Intervention with a HIF-1α inhibitor weakened the protective effect of LQF on intestinal barrier integrity. Moreover, a reduction of HIF-1α aggravated ventricular remodeling, which could be alleviated by LQF. Correspondingly, the circulating levels of intestinal permeability markers and BNP in HF patients were significantly decreased, and cardiac function markedly improved following LQF treatment.ConclusionsWe demonstrated that LQF effectively protected cardiac function by preserving intestinal barrier integrity caused by ventricular remodeling, at least partially through upregulating HIF-1α expression.

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The protective effects of HIF-1α activation on sepsis induced intestinal mucosal barrier injury in rats model of sepsis.

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The protective effects of HIF-1α activation on sepsis induced intestinal mucosal barrier injury in rats model of sepsis.

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