Level of activation of the unfolded protein response correlates with paneth cell apoptosis in human small intestine exposed to ischemia/reperfusion.

J. Grootjans, C.M.I. Hodin, J. de Haan, J.P.M. Derikx, K.M.A. Rouschop, F.K. Verheyen, R.M. van Dam, C.H.C. Dejong, W.A. Buurman, K. Lenaerts

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND & AIMS: In the intestine, Paneth cells participate in the innate immune response. Their highly secretory function makes them susceptible to environmental conditions that cause endoplasmic reticulum (ER) stress. We investigated whether intestinal ischemia/reperfusion (I/R) induces ER stress, thereby activating the unfolded protein response (UPR), and whether excessive UPR activation affects Paneth cells. In addition, we investigated the consequences of Paneth cell compromise during physical barrier damage. METHODS: Jejunal I/R was studied using a human experimental model (n = 30 patients). Activation of the UPR was assessed using immunofluorescence for binding protein and quantitative polymerase chain reaction analyses for C/EBP homologous protein (CHOP), growth arrest and DNA-damage inducible protein 34 (GADD34), and X-box binding protein 1 (XBP1) splicing. Paneth cell apoptosis was assessed by double staining for lysozyme and M30. Male Sprague-Dawley rats underwent either intestinal I/R to investigate UPR activation and Paneth cell apoptosis, or hemorrhagic shock with or without intraperitoneal administration of dithizone, to study consequences of Paneth cell compromise during physical intestinal damage. In these animals, bacterial translocation and circulating tumor necrosis factor-alpha and interleukin-6 levels were assessed. RESULTS: In jejunum samples from humans and rats, I/R activated the UPR and resulted in Paneth cell apoptosis. Apoptotic Paneth cells showed signs of ER stress, and Paneth cell apoptosis correlated with the extent of ER stress. Apoptotic Paneth cells were shed into the crypt lumen, significantly lowering their numbers. In rats, Paneth cell compromise increased bacterial translocation and inflammation during physical intestinal damage. CONCLUSIONS: ER stress-induced Paneth cell apoptosis contributes to intestinal I/R-induced bacterial translocation and systemic inflammation.

Original languageEnglish
Pages (from-to)529-539
Number of pages14
JournalGastroenterology
Volume140
Issue number2
DOIs
Publication statusPublished - Feb 2011

Keywords

  • DDIT3
  • Ischemic Damage
  • Intestinal Microbiota
  • Inflammatory Bowel Disease
  • ENDOPLASMIC-RETICULUM STRESS
  • INFLAMMATORY-BOWEL-DISEASE
  • HEMORRHAGIC-SHOCK
  • REPERFUSION
  • DEFENSINS
  • ISCHEMIA
  • ALPHA
  • PERMEABILITY
  • DYSFUNCTION
  • EXPRESSION

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