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, acute
intestinal ischemia is a consequence of a sudden decrease in intestinal blood
flow. This can be caused by hypoperfusion of mesenteric vessels or occlusion
which is an interruption of intestinal blood due to embolism or thrombosis. 1
21 Acute intestinal ischemia has a high mortality rate (between 60 to
80%) due to delayed diagnosis and ineffective treatment. 1 21 22


2.3.2 Reperfusion
injury – pathophysiology

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Reperfusion of an ischemic organ is essential to prevent irreversible
tissue injury. However, reperfusion can also aggravate the injury, depending on
the intensity and duration of ischemia, which leads to (further) mucus loss, damage
of enterocytes and Paneth cells eventually inducing severe inflammation.1
23 24 Damage of the
epithelial lining

The role of the epithelial lining is very important as
it functions as the first barrier against pathogens. The integrity of the
crypts is especially important for regeneration and recovery, because the stem
and Paneth cells are located there. 25 The epithelial lining is the first that gets damaged during ischemia
reperfusion. In particular the enterocytes at the villi tips are first
susceptible to ischemia. Prolonged ischemia eventually continues sloughing of the
epithelial cells toward the crypts. 1 26 A study in a human
experimental intestinal IR model shows that during short
periods of small intestinal ischemia (30 minutes) with reperfusion there are
still mechanisms to prevent epithelial lining damage. Namely, a main feature of
short small intestinal ischemia is formation of sub epithelial spaces as a
result of retraction of the basement membrane causing loose epithelial sheets. However,
during reperfusion loose epithelial sheets get pulled together by non-muscle
type myosin fibres. Rapid restoration
of the epithelial lining prevents epithelial wounds and exposure of lamina
propria to intraluminal content.

In contrast to short periods of intestinal ischemia,
45 minutes of ischemia of the small intestine results in disruption of the
epithelial lining. After 30 minutes of reperfusion even more damage of the
villus occurs as apoptosis of enterocytes at the tip of the villi is shown.
Eventually, the damaged epithelial lining causes exposure of PAMPs and DAMPs to
lamina propria immune cells which leads to inflammation. 1 Paneth cell
immunological defence loss

Prolonged IR does not only result in damage of
the epithelial lining at the villi tips, but also induces apoptosis and loss of
Paneth cells in the crypts. 27 Paneth cells together with self-renewing intestinal stem
cells (ISC) are regulators of tissue homeostasis and injury response in the
crypts bottom. 28 Paneth cells excrete factors that constitute the niche for Lgr5 stem cells, which are
important for regeneration of damaged tissue. These factors are, among others,
EGF, Wnt3a and Notch ligand Dll4 which are important signals for stem cell
maintenance in vivo as well as in vitro. 27 28

Paneth cells are also part of the innate immune response
through production of antimicrobial peptides which is important for
immunological barrier. Since Paneth cells have an extensive ER because of producing
and secreting large number of peptides, makes the cells more susceptible to ER
stress. 29 The study of Grootjans, J. et al shows that the
unfolded protein response (UPR) activation in the small intestine, especially
in the Paneth cells, is induced by IR. 30 31 Endoplasmic stress

Inflammation, exposure to microorganisms or hypoxia
can reduce the protein folding capacity and therefore induce ER stress. ER
stress activates UPR which helps the cell to cope with stress. As shown in
figure 3, UPR gets activated by three ER stress sensors, which are PKR-like ER
kinase(PERK), inositol-requiring enzyme 1 (IRE-1) and the activating
transcription factor 6 (ATF6). Normally they are associated with binding
protein (BiP) to maintain an inactive state. However, BiP binds to unfolded
proteins that are present in the ER (due to cell stress) and this activates the
three ER stress sensors since they are not associated with BiP anymore.

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