Trypsin in pancreatitis: The culprit, a mediator, or epiphenomenon?

Table 1 Trypsinogen activation in hereditary pancreatitis-related genetic mouse models: Representative studies

Genetic mouse model	Genetic modification	Spontaneous pancreatitis	Increase in basal trypsin activity	Effects of pancreatitis inducers	Trypsinogen activation in CER-AP	Ref.
PRSS1R122H	Mutated human PRSS1R122H or WT PRSS1 gene expressed under full-length elastase promoter	No	No	Severity of AP induced with CER, LPS or ethanol increased in the order: WT mouse < PRSS1 < PRSS1R122H	Increased in the order: WT mouse < PRSS1 < PRSS1R122H	[42]
PRSS1
PRSS2	Transgenic mice similarly expressing human PRSS2 gene	Focal areas (< 10% of total pancreas)	ND	CER-AP was more severe in PRSS2 expressing mice	ND	[44]
PRSS1/PRSS2	Compound mice co-expressing WT PRSS1 and PRSS2 or PRSS1R122H and PRSS2 from their native promoters	Yes, in homozygous PRSS1R122H/PRSS2 mice, but not in PRSS1/PRSS2 mice	ND	One i.p. injection of low-dose CER induced pancreatitis in PRSS1R122H/PRSS2 but not in PRSS1/PRSS2 mice	ND	[46]
PRSS1R122H/PRSS2
PRSS1/PRSS2+ PRSS2	Compound PRSS1/PRSS2 or PRSS1R122H/PRSS2 mice were further crossed with mice expressing WT PRSS2	Yes, in PRSS1R122H/PRSS2+ PRSS2 mice, but not in PRSS1/PRSS2+ PRSS2 mice	ND	ND	ND	[46]
PRSS1R122H/PRSS2+ PRSS2
T7D23A knock-in	Heterozygous p.D23A mutation in the TAP part of T7 trypsinogen gene	Yes	Yes	ND	ND	[38]
T7K24R knock-in	Heterozygous p.K23R mutation in the TAP part of T7 trypsinogen gene	No	No	CER-AP was aggravated	Increased	[43]
Ctrb1-del	Mice deficient in CTRB1 chymotrypsin that promotes trypsinogen degradation	No	No	CER-AP was aggravated	Increased	[39,49]
T7K24R×Ctrb1-del	Compound mice carrying both the trypsinogen mutant T724KR and chymotrypsin Ctrb1 deletion alleles	Yes	ND	ND	ND	[49]

CER: Cerulein; LPS: Lipopolysaccharide; ND: Not determined; TAP: Trypsinogen activation peptide.

Table 2 Trypsinogen activation in experimental AP models: Representative studies

Experimental pancreatitis induced by	Trypsin activity measured in tissue or acinar cells (ex-vivo models)	Ref.
Cerulein	Rat pancreas	[21,28,53-55,58,59,62]
	Mouse pancreas	[60,62,74,88,112,135,143,201]
Taurocholate or TLCS	Rat pancreas	[56,61]
	Mouse pancreas	[68,70]
L-arginine	Rat pancreas	[65]
	Mouse pancreas	[66,78]
L-ornithine, L-lysine	Rat pancreas	[69,71]
CDE diet	Mouse pancreas	[51,52]
EtOH + low-dose cerulein	Mouse pancreas	[72]
EtOH + POA	Mouse pancreas	[73]
CCK/cerulein	Rat and mouse acinar cells	[21,24,64,74,129,131,136,143]
TLCS	Rat, mouse, and human acinar cells	[32,67,75]
EtOH + low-dose CCK	Rat and mouse acinar cells	[72,76]
NNK (tobacco compound)	Rat acinar cells	[75]
Agonist of the mechano receptor Piezzo1	Mouse acinar cells	[77]

TLCS: Taurolithocholic acid sulfate; CDE: Choline-deficient, ethionine supplemented (diet); EtOH: Ethanol; POA: Palmitoleic acid; CCK: Cholecystokinin; NNK: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

Table 3 Genetic autophagy blockade increases the basal trypsin activity in the pancreas

Knockout mouse	Function of ablated protein	Effect of the knockout on autophagy	Fold increase in trypsin activity	Ref.
Atg7Δpan	Key mediators of autophagosome formation	Blockade of autophagosome formation and autophagy	2.5	[186]
Atg5Δpan			2.0	[187]
VMP1Δac			3.5	[188]
LAMP2 KO	Major lysosomal membrane protein	Lysosomal dysfunction. Autophagy blockade	3.0	[135]
GNPTAB KO	Mediator of hydrolase delivery to lysosomes	Lysosomal and endosomal dysfunction. Autophagy blockade	8.0	[143]
TfebΔac; Tfe3-/-	Transcriptional regulator of lysosomal biogenesis, autophagy	Autophagy blockade	2.5	[140,146]