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Paneth cell-mediated multiorgan dysfunction after acute kidney injury.

ABSTRACT: Acute kidney injury (AKI) is frequently complicated by extrarenal multiorgan injury, including intestinal and hepatic dysfunction. In this study, we hypothesized that a discrete intestinal source of proinflammatory mediators drives multiorgan injury in response to AKI. After induction of AKI in mice by renal ischemia-reperfusion or bilateral nephrectomy, small intestinal Paneth cells increased the synthesis and release of IL-17A in conjunction with severe intestinal apoptosis and inflammation. We also detected significantly increased IL-17A in portal and systemic circulation after AKI. Intestinal macrophages appear to transport released Paneth cell granule constituents induced by AKI, away from the base of the crypts into the liver. Genetic or pharmacologic depletion of Paneth cells decreased small intestinal IL-17A secretion and plasma IL-17A levels significantly and attenuated intestinal, hepatic, and renal injury after AKI. Similarly, portal delivery of IL-17A in macrophage-depleted mice decreased markedly. In addition, intestinal, hepatic, and renal injury following AKI was attenuated without affecting intestinal IL-17A generation. In conclusion, AKI induces IL-17A synthesis and secretion by Paneth cells to initiate intestinal and hepatic injury by hepatic and systemic delivery of IL-17A by macrophages. Modulation of Paneth cell dysregulation may have therapeutic implications by reducing systemic complications arising from AKI.

SUBMITTER: Park SW

PROVIDER: S-EPMC3504173 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Paneth cell-mediated multiorgan dysfunction after acute kidney injury.

Park Sang Won SW Kim Mihwa M Kim Joo Yun JY Ham Ahrom A Brown Kevin M KM Mori-Akiyama Yuko Y Ouellette André J AJ D'Agati Vivette D VD Lee H Thomas HT

Journal of immunology (Baltimore, Md. : 1950) 20121029 11

Acute kidney injury (AKI) is frequently complicated by extrarenal multiorgan injury, including intestinal and hepatic dysfunction. In this study, we hypothesized that a discrete intestinal source of proinflammatory mediators drives multiorgan injury in response to AKI. After induction of AKI in mice by renal ischemia-reperfusion or bilateral nephrectomy, small intestinal Paneth cells increased the synthesis and release of IL-17A in conjunction with severe intestinal apoptosis and inflammation. W ...[more]

PMID: 23109723

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Project description:Background and Objectives: Critically ill surgical patients are susceptible to various postoperative complications, including acute kidney injury (AKI) and multiorgan distress syndrome (MODS). These complications intensify patient suffering and significantly increase morbidity and mortality rates. This study aimed to identify the biomarkers for predicting AKI and MODS in critically ill surgical patients. Materials and Methods: We prospectively enrolled critically ill surgical patients admitted to the intensive care unit via the emergency department between July 2022 and July 2023. A total of 83 patients were recruited, and their data were used to analyze MODS. Three patients who showed decreased creatinine clearance at the initial presentation were excluded from the analysis for AKI. Patient characteristics and laboratory parameters including white blood cell (WBC) count, neutrophil count, delta neutrophil index, urine and serum β2-microglobulin, and urine serum mitochondrial DNA copy number (mtDNAcn) were analyzed to determine the reliable biomarker to predict AKI and MODS. Results: The following parameters were independently correlated with MODS: systolic blood pressure (SBP), initial neutrophil count, and platelet count, according to a logistic regression model. The optimal cut-off values for SBP, initial neutrophil count, and platelet count were 113 mmHg (sensitivity 66.7%; specificity 73.9%), 8.65 (X3) (109/L) (sensitivity 72.2%; specificity 64.6%), and 195.0 (X3) (109/L) (sensitivity 66.7%; specificity 81.5%), respectively. According to the logistic regression model, diastolic blood pressure (DBP) and initial urine mtDNAcn were independently correlated with AKI. The optimal cut-off value for DBP and initial urine mtDNAcn were 68.5 mmHg (sensitivity 61.1%; specificity 79.5%) and 1225.6 copies/μL (sensitivity 55.6%; specificity 95.5%), respectively. Conclusions: SBP, initial neutrophil count, and platelet count were independent predictors of MODS in critically ill patients undergoing surgery. DBP and initial urine mtDNAcn levels were independent predictors of AKI in critically ill surgical patients. Large-scale multicenter prospective studies are needed to confirm our results.

Project description:IntroductionThe mechanism underlying radiation-induced gut microbiota dysbiosis is undefined. This study examined the effect of radiation on the intestinal Paneth cell α-defensin expression and its impact on microbiota composition and mucosal tissue injury and evaluated the radio-mitigative effect of human α-defensin 5 (HD5).MethodsAdult mice were subjected to total body irradiation, and Paneth cell α-defensin expression was evaluated by measuring α-defensin mRNA by RT-PCR and α-defensin peptide levels by mass spectrometry. Vascular-to-luminal flux of FITC-inulin was measured to evaluate intestinal mucosal permeability and endotoxemia by measuring plasma lipopolysaccharide. HD5 was administered in a liquid diet 24 hours before or after irradiation. Gut microbiota was analyzed by 16S rRNA sequencing. Intestinal epithelial junctions were analyzed by immunofluorescence confocal microscopy and mucosal inflammatory response by cytokine expression. Systemic inflammation was evaluated by measuring plasma cytokine levels.ResultsIonizing radiation reduced the Paneth cell α-defensin expression and depleted α-defensin peptides in the intestinal lumen. α-Defensin down-regulation was associated with the time-dependent alteration of gut microbiota composition, increased gut permeability, and endotoxemia. Administration of human α-defensin 5 (HD5) in the diet 24 hours before irradiation (prophylactic) significantly blocked radiation-induced gut microbiota dysbiosis, disruption of intestinal epithelial tight junction and adherens junction, mucosal barrier dysfunction, and mucosal inflammatory response. HD5, administered 24 hours after irradiation (treatment), reversed radiation-induced microbiota dysbiosis, tight junction and adherens junction disruption, and barrier dysfunction. Furthermore, HD5 treatment also prevents and reverses radiation-induced endotoxemia and systemic inflammation.ConclusionThese data demonstrate that radiation induces Paneth cell dysfunction in the intestine, and HD5 feeding prevents and mitigates radiation-induced intestinal mucosal injury, endotoxemia, and systemic inflammation.

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Paneth cell-mediated multiorgan dysfunction after acute kidney injury.

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Paneth cell-mediated multiorgan dysfunction after acute kidney injury.

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