Intestinal damage of enterocytes and Paneth cells eventually inducing

Intestinal ischemia can be of chronic or acute nature. Chronic ischemia,which can be caused by atherosclerosis, is more common. In contrast, acuteintestinal ischemia is a consequence of a sudden decrease in intestinal bloodflow. This can be caused by hypoperfusion of mesenteric vessels or occlusionwhich is an interruption of intestinal blood due to embolism or thrombosis. 121 Acute intestinal ischemia has a high mortality rate (between 60 to80%) due to delayed diagnosis and ineffective treatment.

1 21 22  2.3.2 Reperfusioninjury – pathophysiologyReperfusion of an ischemic organ is essential to prevent irreversibletissue injury. However, reperfusion can also aggravate the injury, depending onthe intensity and duration of ischemia, which leads to (further) mucus loss, damageof enterocytes and Paneth cells eventually inducing severe inflammation.123 24 2.3.2.1 Damage of theepithelial liningThe role of the epithelial lining is very important asit functions as the first barrier against pathogens.

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The integrity of thecrypts is especially important for regeneration and recovery, because the stemand Paneth cells are located there. 25 The epithelial lining is the first that gets damaged during ischemiareperfusion. In particular the enterocytes at the villi tips are firstsusceptible to ischemia. Prolonged ischemia eventually continues sloughing of theepithelial cells toward the crypts. 1 26 A study in a humanexperimental intestinal IR model shows that during shortperiods of small intestinal ischemia (30 minutes) with reperfusion there arestill mechanisms to prevent epithelial lining damage.

Namely, a main feature ofshort small intestinal ischemia is formation of sub epithelial spaces as aresult of retraction of the basement membrane causing loose epithelial sheets. However,during reperfusion loose epithelial sheets get pulled together by non-muscletype myosin fibres. Rapid restorationof the epithelial lining prevents epithelial wounds and exposure of laminapropria to intraluminal content.In contrast to short periods of intestinal ischemia,45 minutes of ischemia of the small intestine results in disruption of theepithelial lining.

After 30 minutes of reperfusion even more damage of thevillus occurs as apoptosis of enterocytes at the tip of the villi is shown.Eventually, the damaged epithelial lining causes exposure of PAMPs and DAMPs tolamina propria immune cells which leads to inflammation. 1 2.3.2.

2 Paneth cellimmunological defence lossProlonged IR does not only result in damage ofthe epithelial lining at the villi tips, but also induces apoptosis and loss ofPaneth cells in the crypts. 27 Paneth cells together with self-renewing intestinal stemcells (ISC) are regulators of tissue homeostasis and injury response in thecrypts bottom. 28 Paneth cells excrete factors that constitute the niche for Lgr5 stem cells, which areimportant for regeneration of damaged tissue. These factors are, among others,EGF, Wnt3a and Notch ligand Dll4 which are important signals for stem cellmaintenance in vivo as well as in vitro. 27 28Paneth cells are also part of the innate immune responsethrough production of antimicrobial peptides which is important forimmunological barrier. Since Paneth cells have an extensive ER because of producingand secreting large number of peptides, makes the cells more susceptible to ERstress.

29 The study of Grootjans, J. et al shows that theunfolded protein response (UPR) activation in the small intestine, especiallyin the Paneth cells, is induced by IR. 30 31 2.3.2.3 Endoplasmic stressInflammation, exposure to microorganisms or hypoxiacan reduce the protein folding capacity and therefore induce ER stress.

ERstress activates UPR which helps the cell to cope with stress. As shown infigure 3, UPR gets activated by three ER stress sensors, which are PKR-like ERkinase(PERK), inositol-requiring enzyme 1 (IRE-1) and the activatingtranscription factor 6 (ATF6). Normally they are associated with bindingprotein (BiP) to maintain an inactive state. However, BiP binds to unfoldedproteins that are present in the ER (due to cell stress) and this activates thethree ER stress sensors since they are not associated with BiP anymore.

Dissociation of BiP from IRE-1 also induces splicingof X-box binding protein 1 (XBP1) mRNA leading to functional XBP1 proteinproduction. XBP1 protein plays an important role in cellular survival in theintestine. However, prolonged and severe ER stress will lead to proapoptoticsignalling, instead of pro-survival. Further, PERK activation inducesphosphorylation of eIF2? which modulates ER protein syntheses, but prolonged ERstress provokes stimulation of CHOP by eIF2? initiating apoptosis, as shown infigure 3. 18 32 33