Table1.
Intestinal epithelial cell death in the acute and chronic intestinal diseases
| Model | Subjects | Cell death | Findings |
|---|---|---|---|
| A) Sepsis | |||
| Clinical | Patients with sepsis | Apoptosis | Increase in active caspase 3 [39] |
| Clinical | Patients with trauma injuries | Apoptosis | Increase in cytokeratin 18 and active caspase 3 [40] |
| Clinical | Patients with sepsis | Apoptosis | Increase in I-FABP [41] |
| In vivo CLP induced sepsis | Transgenic mice that overexpress Bcl-2 (Fabpl-Bcl-2) | Apoptosis | Decrease in apoptosis and active caspase 3 [44] |
| In vivo pneumonia-induced sepsis | Fabpl-Bcl-2 mice | Apoptosis | Decrease in apoptosis and active caspase 3 [42] |
| In vivo pneumonia-induced sepsis | Fabpl-Bcl-2 mice | Apoptosis | Decrease in apoptosis and active caspase 3 associate with increase in S-phase cells proliferation [43] |
| In vivo MRSA pneumonia-induced sepsis model | Wild-type FVB/N mice | Apoptosis | Increase in Bid and Bax and Bcl-xL in the mitochondrial pathway [45] |
| In vivo MRSA pneumonia-induced sepsis model |
Bid−/− mice Fabpl-Bcl-2 mice |
Apoptosis | Regulate the mitochondrial apoptotic pathway [45] |
| In vivo CLP induced sepsis model | Lacking functional NF-kB in IECs (Vil-Cre/Ikkβf/Δ) | Apoptosis | Increase in mortality, apoptosis with pro-inflammatory cytokines [46] |
| In vivo CLP induced sepsis model | STING-KO mice | Apoptosis | Decrease in apoptosis, inflammation, intestinal permeability and bacterial translocation [47] |
| In vivo LPS induced sepsis model | Tnfr1−/−, Tnfr2−/−, Nfκb1−/−, Nfκb2−/−, mice | Apoptosis | Dependent on NFκB signaling, via NFκB1 favoring cell survival or via NFκB2 favoring apoptosis [8] |
| In vivo LPS induced sepsis model | Co-expressed both Bcl-2 and TAg to Fabpl | Apoptosis | Bi-transgenic animals had reduced crypt apoptosis but had a paradoxical increase in the markers of apoptosis such as caspase 3, BAX and cytochrome c in villus [38] |
| B) Intestinal ischemia/reperfuson (I/R) | |||
| Clinical | Jejunum from patients undergoing pancreaticoduodenectomy | Apoptosis | Increase in apoptosis and I-FABP during ischemia and gradually decrease during reperfusion [51] |
| Clinical | Jejunum from patients undergoing pancreaticoduodenectomy | Apoptosis | Increase in apoptosis and I-FABP associate with inflammatory markers such as C3c complement activation, IL-6, IL-8, and TNFα [52] |
| In vivo I/R rat model | Ischaemia (15–90 min) and ischaemia/reperfusion (15 minutes ischaemia followed by 15–75 min of reperfusion) | Apoptosis, Necrosis | Death cells exhibit apoptosis (80%) and necrosis (20%) characteristics; increase in DNA fragmentation [53] |
| In vivo I/R rat model | Ischemia clamping the SMA (30 or 60 min), after reperfusion various time points up to 4 days. | Apoptosis | Increase in apoptosis and decrease in intestinal ALP and lactase after ischemia, and returned normal with reperfusion [54] |
| In vitro model of ischemia | 2-deoxyglucose and oligomycin-A treated HT-29 and Caco-2 cells | Apoptosis | Greater apoptotic in differentiated cells than undifferentiated cells [54] |
| In vivo I/R rat model | Underwent occlusion of both SMA and PV for 20 minutes followed by 48h of reperfusion | Apoptosis | Increase in apoptosis along with inflammatory markers upregulation of TLR-4, MyD88, and TRAF6 [49] |
| In vivo I/R rat model | Underwent occlusion of both SMA and PV for 20 minutes followed by 24h or 48h of reperfusion | Apoptosis | Increase in apoptosis inversely associate with SHh signaling pathways [50] |
| In vivo I/R rat model | 1hr of ischemia followed by reperfusion | Necroptosis, Necrosis | Increase in necroptotic markers such as RIP-1, -3 and MLKL [19] |
| In vitro model of ischemia | Oxygen and glucose deprivation model in IEC-6 | Necroptosis, Necrosis | Increase in RIP-1, -3 and MLKL together with HMGB1 - TLR4/RAGE signaling [19] |
| In vivo I/R rat model | SMA occlusion (1.5h) of ischemia and 6 h of reperfusion | Necroptosis | RIP1/3 mediated necrosome formation [55] |
| In vivo I/R murine model | IkbkbF/ΔVil-Cre; SMA occlusion for 30 mins followed by reper 】 fusion | Apoptosis | Increase in apoptosis and pro-inflammatory markers such as TNF, IL-1, IL-6 and ICAM. Probably dual function of NFκB signaling [56] |
| In vivo I/R murine model | Fabpl-Bcl-2 mice; SMAO for 20 mins followed by reperfusion | Apoptosis | Decrease in p53-dependent death [57] |
| C) Inflammatory bowel diseases (IBD) | |||
| Clinical | patients with UC | Apoptosis | Increase in apoptosis, active caspase 3 and PUMA expression [59, 62] |
| Clinical; In vivo TNBS induced colitis murine model |
Patients with CD and UC; Wild type balb/c mice | Apoptosis | up-regulation of TRAIL in IEC [60] |
| In vitro model | TRAIL, TNF-α and IFN-γ treatment in HIEC, HT-29 or Caco-2 cells | Apoptosis | NFκB-dependent (TNF-α) or NFκB-independent (IFN-γ) pathway to induce TRAIL mediated apoptosis [60] |
| In vivo DSS or TNBS induced colitis murine model | Wildtype, PUMA−/−, Bid−/−, p53−/− | Apoptosis | PUMA inhibition can provide an efficient way of protecting IEC apoptosis and serve as a new anti-IBD approach [59] |
| In vivo model | TAK1IE-KO mice | Apoptosis | Enhance in cleaved caspase-3 and reduction in claudin-3 and antioxidant- genes and transcription factor Nrf2, and ROS accumulation, like the IBD pathology [61] |
| In vivo anti-CD3 or DSS induced colitis murine model | wild-type, p53−/−, Bid−/−, Bim−/−, Bax3−/−, Bak−/−, PUMA−/−, and Noxa−/− mice | Apoptosis | p53-dependent and - independent mechanisms; PUMA mediated intrinsic apoptosis pathway [62] |
| Clinical; In vivo TNF induced apoptosis model |
Patients with CD and UC; transgenic mice that overexpress A20 in IECs A20-Tg mice | Apoptosis | RIPK1-Dependent IEC Death [63] |
| In vivo DSS induced colitis murine model | Villin kO mice | Apoptosis | Anti-apoptotic function of villin is regulated by PI3-kinase and Akt [64] |
| In vivo DSS induced colitis murine model | TLR4−/−mice | Apoptosis | Increase in apoptosis with reduced Cox-2 and PGE-2 levels [65] |
| In vivo LPS induced injury model | Epithelial cell-specific deletion of Casp8ΔIEC mice TLR stimulation | Necrosis, Necroptosis | Rip3-dependent epithelial necroptosis [66] |
| In vivo spontaneous model | Epithelial cell-specific deletion of FADDΔIEC | Necrosis, Necroptosis | Rip3-dependent epithelial necroptosis [27] |
|
In vivo TNBS induced colitis murine model; In vitro necroptosis model |
Wildtype mice; TNF-α and Z-VAD-fmk induced Caco-2 cells | Necrosis, Necroptosis | Increase in TUNEL-positive, caspase-3 negative cells along with p-RIPK3 [11] |
| Clinical; In vivo model; In vitro model |
Patients with CD; caspase-1/IL-10 double knockout; T84 monolayers | Pyroptosis | Increase in the activated caspase-1[67] |
| Clinical | Patients with CD | Ferroptosis | Reduction in GPx4 levels [37] |
| D) Necrotizing enterocolitis (NEC) | |||
| Clinical | Infants with NEC | Apoptosis | Increase in NO and apoptosis through peroxynitrite formation [70] |
| In vivo NEC model | formula feeding, and cold/asphyxia stress induced neonatal rat | Apoptosis | Increase in caspase 3 and DNA fragmentation [71] |
| In vitro NEC model | H2O2 induced rat IECs (RIE)-1 | Apoptosis | Increase in intracellular ROS generation activates PI3-k pathway [72] |
|
In vivo; In vitro NEC model |
formula feeding/hypoxia followed by Enterobacter sakazakii (ES) mediated NEC; ES administration to IEC-6 in vitro | Apoptosis | Increase in active caspase-3 and pro-inflammatory cytokines such as IL-6 [73] |
|
In vivo; In vitro NEC model |
formula feeding/hypoxia followed by Cronobacter sakazakii (CS) mediated NEC; CS administration to HT-29 in vitro | Pyroptosis, Apoptosis | Increase in NLRP3 inflammasome, caspase-3 and caspase-1 levels [74] |
|
In vivo; In vitro NEC model |
Rat pups collected by caesarian section, followed by hand fed; TNF-α and IFN-γ induced IEC-6 cells | Apoptosis | Increase in Bax/Bcl-w ratio, cleaved caspase-3 and COX-2 levels; these events were reverted by Bifidobacterium bifidum [75] |
| In vivo NEC model | NEC induced by asphyxia and cold stress, and followed by hand fed milk | Apoptosis | Increase in pro-apoptotic Bax, cleaved caspase-3, and decrease in anti-apoptotic Bcl-2; this effect was attenuated by EGF administration [76] |
| In vivo NEC model | NEC induced by hypoxia, hypothermia, hypertonic formula feeding plus enteral administration of LPS | Apoptosis | Increase in TUNEL and active caspase 3 levels; these changes were inhibited by HB-EGF [77] |
I-FABP, Intestinal fatty acid-binding protein; CLP, Cecal ligation and puncture; MRSA, Methicillin-resistant Staphylococcus aureus; Bcl-2, B-cell lymphoma 2; Bid, BH3 Interacting Domain Death Agonist; Bax, BCL2 Associated X, Apoptosis Regulator; Bcl-xL, B-cell lymphoma-extra-large; IKK, the inhibitor of I-κB kinase; NFκB, nuclear factor kappa B; STING, Stimulator of interferon genes; LPS, lipo-polysaccharides; TAg, viral protein large T-antigen; TNF, tumor necrosis factor; IL, interleukin; IR, ischaemia/reperfusion; SMA, superior mesenteric artery; PV, portal vein; SHh, sonic hedgehog; TLR, Toll-like receptor; TRAF6, Tumor necrosis factor receptor (TNFR)-associated factor 6; MyD88, Myeloid differentiation factor 88; RIPK, receptor-interacting serine/threonine-protein kinase; MLKL, Mixed lineage kinase domain-like pseudokinase; RAGE, Receptor for advanced glycosylation end product; ICAM, Intercellular Adhesion Molecule; UC, Ulcerative colitis; CD, Crohn’s disease; PUMA, p53 upregulated modulator of apoptosis; TRAIL, TNF-related apoptosis-inducing ligand; TNBS, 2,4,6-trinitrobenzene sulfonic acid; IFN, Interferon; HIEC, human intestinal epithelial cells; IBD, Inflammatory bowel disease; DSS, Dextran sodium sulfate; TAG1, TGF-β activated kinase 1; COX-2, cyclooxygenase-2; PGE2, prostaglandin E2; FADD, Fas-associated death domain; TUNEL, Terminal deoxynucleotidyl transferase dUTP nick end labeling; NEC, Necrotizing enterocolitis; ROS, reactive oxygen species; NO, Nitric oxide; NLRs, Nucleotide-binding oligomerization domain-like receptors; NLRP3, NLR Family Pyrin Domain Containing 3; EGF, epidermal growth factor; HB-EGF, Heparin Binding EGF Like Growth Factor.