Copyright
©The Author(s) 2017.
World J Gastroenterol. Mar 28, 2017; 23(12): 2106-2123
Published online Mar 28, 2017. doi: 10.3748/wjg.v23.i12.2106
Published online Mar 28, 2017. doi: 10.3748/wjg.v23.i12.2106
Protease | Effect | Model | Mechanism of action | Ref. |
Serine proteases | ||||
Matriptase | Protective | ST14 hypomorphic mice | Genetic depletion of matriptase induces an increase in intestinal permeability (decreased TER and increased FITC-dextran flux) | [65, 66] |
Epithelial cell monolayer | Inhibition of matriptase with silencing RNA and the synthetic inhibitor MI-432 increased the intestinal permeability (decreased TER and increased FITC-dextran flux) | [65, 68] | ||
Granzyme M | Protective | GrzM-/- mice | GrzM-/- mice display a permeability increase (FITC-dexran method) | [73] |
Zonulin, Zonula occludens toxin (Zot) | Harmful | Human epithelial cell monolayer | ↑ Permeability after exposure to gliadin (triggers zonulin release; disruption of occludin and ZO-1) | [76] |
Ileal tissue of diabetes prone rats | Zonulin-dependent permeability increase in diabetic rats was abolished after oral treatment with zonulin inhibitor FZI/0 (AT1001/Larazotide) | [82] | ||
PAR2 activation | ||||
Trypsin, tryptase, chymase, synthetic SLIGRL | Harmful | WT mice, WT rats | ↑ Permeability due to PAR2 activation (confirmed by selective PAR2 agonist SLIGRL; increased 51Cr-EDTA flux) | [47, 48, 51] |
PAR4 activation | ||||
Cathepsin G | Harmful | Colonic biopsies from UC and healthy patients | ↑ Permeability in response to UC fecal supernatant was abolished by cathepsin G inhibition | [58] |
PAR1 activation | ||||
Thrombin, synthetic TFLLR-NH2 | Harmful | WT mice, epithelial cell monolayer | ↑ Permeability after PAR1 activation (caspase-3 mediated; disruption of ZO-1) | [62] |
Endogenous inhibitors | ||||
Elafin | Protective | Gluten sensitive mice | ↓ Permeability after elafin delivery by recombinant Lactococcus lactis (51Cr-EDTA flux) | [87] |
Human epithelial cell monolayer | Treatment with elafin normalized the TNF-α-induced increase in paracellular permeability (FITC-dextran method) | [88] | ||
Synthetic inhibitors | ||||
Camostat mesilate | Protective | Rat IBS model | Treatment with camostat mesilate normalized the elevated permeability in the rats (51Cr-EDTA flux and ZO-1 expression) | [89] |
Nafamostat mesilate | Protective | Rectal biopsies from IBS and healthy patients | Nafamostat abolished the trypsin-induced hyperpermeability (macromolecular flux in Ussing chambers) | [94] |
Human epithelial cell monolayer | Treatment with nafamostat normalized the tryptase-induced permeability increase (TER and FITC-dextran method) | [95] | ||
SPI | Protective | IBD mouse model | Treatment with SPI normalized the increased permeability in the T-cell transfer colitis model (FITC-dextran method) | [96] |
Metalloproteases | ||||
Meprin β | Protective | Mep1b-/- mice | Meprin β cleaves MUC2 and alters mucus composition | [128, 129] |
Matrix metalloproteinases | ||||
MMP-2 | Protective | MMP-2-/- mice | ↑ permeability in MMP-2-/- mice (FITC-dextran method) | [111] |
MMP-9 | Harmful | MMP-9-/- mice | = Permeability in MMP-9-/- mice after DSS (FITC-dextran method; no increase in MLCK expression) | [114] |
MMP-9-/- mice | ↑ Goblet cells and MUC2 expression in MMP-9-/- mice | [113] | ||
MMP-9 transgenic mice | ↑ Permeability in mice overexpressing MMP-9 (FITC-dextran method) | [112] | ||
MMP-3, MMP-7 | Harmful | Epithelial cell culture | MMP-7 cleaves E-cadherin | [121] |
ADAM | ||||
TACE/ADAM17 | Harmful | Human and mouse colon samples | ↑ TACE activity in IBD; ↑ TNF-α release; ↑ TNF-α-induced permeability increase | [131, 134, 135] |
Caco-2 | ↓ Permeability after TACE inhibition (by TAPI-2 and GM6001) | [136] | ||
Cysteine proteases | ||||
Caspase-3, caspase-8 | Harmful | Human epithelial cell monolayer | ↓ Cell-cell adhesion (epithelial cell apoptosis; disruption of TJ proteins occludin and claudin-4) | [144] |
Endogenous inhibitor | ||||
Cystatin | No effect | WT mice | No effect on colonic paracellular permeability (51Cr-EDTA flux) | [51] |
Luminal proteases | ||||
Bacteroides fragilis | ||||
Fragilysin | Harmful | Human epithelial cell monolayer | ↑ Permeability (decreased TER and increase in mannitol flux) | [149, 150] |
Entamoeba histolytica | ||||
Cysteine protease | Harmful | Mice transfected with E. histolytica trophozoites | ↑ Permeability (FITC-dextran method) | [151] |
Enterococcus faecalis | ||||
Gelatinases | Harmful | IL10-/- mice | ↑ Permeability (E-cadherin splicing) | [156] |
Epithelial cell monolayers | ↑ Permeability (PAR2 signaling) | [155] | ||
Dermatophagoides pteronyssinus | ||||
Der p 1 | Harmful | Human colonic biopsies | ↑ Permeability (decreased TER in Ussing chambers; disruption of TJ proteins occludin and ZO-1 | [158] |
Kiwifruit cysteine protease | ||||
Act d1 | Harmful | Epithelial cell monolayer | ↑ Permeability (disruption of TJ proteins occludin and ZO-1) | [162] |
WT mice | ↑ Permeability (FITC-dextran method) | [161] | ||
Aspergillus | ||||
Amano SD | Protective | WT rat | Improved mucosal homeostasis through alteration of the microbiome composition and SCFA induction | [163] |
- Citation: Van Spaendonk H, Ceuleers H, Witters L, Patteet E, Joossens J, Augustyns K, Lambeir AM, De Meester I, De Man JG, De Winter BY. Regulation of intestinal permeability: The role of proteases. World J Gastroenterol 2017; 23(12): 2106-2123
- URL: https://www.wjgnet.com/1007-9327/full/v23/i12/2106.htm
- DOI: https://dx.doi.org/10.3748/wjg.v23.i12.2106