Visceral hypersensitivity in inflammatory bowel diseases and irritable bowel syndrome: The role of proteases

Table 1 Serine protease inhibitors (mammalian): examples of clinical applications in different organ systems

Category	Indication	Serine protease inhibitor (target)	Status	Ref.
Cardiovascular	ACS	Bivalirudin (thrombin)	Approved	[73]
	AF	Rivaroxaban (factor Xa)	Approved	[74]
		Edoxaban (factor Xa)	Approved	[75]
	VTE	Dabigatran (thrombin)	Approved	[76]
Dermatology	Herpes zoster	Argatroban (thrombin)	Clinical - phase II	[77]
	Oral leukoplakia	BBIC (broad specificity)	Clinical - phase II	[78]
Hematology	Heparin-induced thrombocytopenia	Argatroban (thrombin)	Approved	[79]
		Fondaparinux (factor Xa)	Approved
Oncology	Pancreatic cancer: CTx	Upamostat (uPA)	Clinical - phase II	[80]
		Nafamostat mesilate (broad specificity)	Clinical - phase II	[81]
	Lung cancer: RTx	Ulinastatin (broad specificity)	Clinical - phase unknown	[82]
	Colorectal cancer: CTx	Talabostat (fibroblast activating protein)	Clinical - phase II	[83]
	Esophageal cancer: Sx	Ulinastatin (broad specificity)	Clinical - phase unknown	[84]
Pneumology	Asthma	APC 366 (mast cell tryptase)	Clinical - phase II	[85]
	α1 antitrypsin deficiency	α1 antitrypsin (broad specificity)	Approved	[86]
	Cystic fibrosis	α1 antitrypsin (broad specificity)	Clinical - phase II	[87]
Endocrinology	Diabetes	Gliptins (DPP-IV)1	Approved	[88]
Surgery	NA	Aprotinin (broad specificity)	Approved	[89]
		Gabexate mesilate (broad specificity)	Clinical - phase III	[90]
		Nafamostat mesilate (broad specificity)	Clinical - phase IV	[91]
		Sivelestat (neutrophil elastase)	Clinical - phase unknown	[92]

¹DPP-IV is a non-classical serine protease belonging to family S9: prolyl oligopeptidase (novel class). Literature search in Pubmed (last updated Sept 19 2016) with MeSH terms serine protease inhibitor - dpp-4 inhibitor - clinical trials - English - human. ACS: Acute coronary syndrome; A: Atrial fibrillation; BBIC: Bowman Birk inhibitor concentrate; BHR: Bronchial hyperresponsiveness; cf.: Compared to; CTx,: Chemotherapy; DPP-IV: Dipeptidylpeptidase IV; EAR: Early asthmatic response; GP: Glycoprotein IIb/IIIa inhibitor; ICH: Intracranial hemorrhage; LAR: Late asthmatic response; PA: Protease activity; PI: Protease inhibitor; POC: Postoperative complications; RTx: Radiotherapy; SIRS: Systemic inflammatory respiratory syndrome; Sx: Surgery; uPA: Urokinase plasminogen activator; VTE: Venous thromboembolism.

Table 2 Preclinical studies investigating the effects of protease-activated receptor-targeting molecules on visceral hypersensitivity

PAR	Agonist/antagonist	Species (hypersensitivity model)	Study type	Effect	Ref.
PAR-1	Agonist (thrombin, TFLLR-NH2)	Rat (carrageenan)	In vivo	↓ hyperalgesia	[56]
PAR-1	Agonist (TFLLR-NH2)	Mice (capsaicin)	In vivo	↓ hyperalgesia	[55]
PAR-2	Agonist (SLIGRL-NH2)	Mice (PAR2-agonist)	In vivo	↑ hyperalgesia	[59]
PAR-2	Agonist (SLIGRL-NH2, trypsin)	Rat (PAR2-agonist)	In vivo	↑ hyperalgesia	[60]
PAR-2	Agonist (SL-NH2, trypsin, typtase)	Guinea pig submucosal neurons (PAR2-agonist)	Ex vivo	↑ neuron excitability	[61]
PAR-2	Agonist (SLIGRL-NH2, Tc-NH2, trypsin, tryptase)	Mice, rat (PAR2-agonist)	KO	↑ hyperalgesia, absent in KO	[62]
PAR-2	Agonist (2-furoyl-LIGRL-NH2)	Mice (capsaicin)	KO	↑ hyperalgesia, absent in KO	[63]
PAR-2	Antagonist (ENMD-1068)	Mice (IBS-supernatant)	KO	↓ hypersensitivity, absent in KO	[41]
PAR-2	/	Mice DRG (IBS-D supernatant)	KO	↑ neuron excitability, absent in KO	[64]
PAR-4	Agonist (PAR-4-AP, Cat-G)	Mice (IBS-D supernatant)	In vivo	↓ hypersensitivity	[49]
PAR-4	Agonist (AYPGKF-NH2)	Mice (PAR2-agonist, TRPV4-agonist)	In vivo	↓ hypersensitivity	[57]

DRG: Dorsal root ganglia; IBS: Irritable bowel syndrome; KO: Knock-out; PAR: Protease-activated receptor; TRPV: Transient receptor potential vanilloid channels.

Table 3 Serine protease inhibitors investigated in experimental visceral hypersensitivity models

Inhibitor name	Target(s)	Ref.
Aprotinin	Chymotrypsin, elastase, KLK, plasmin, PA, trypsin, urokinase, XIIa	[49]
Bowman-Birk inhibitor	Chymotrypsin, trypsin	[70,71]
Camostat mesilate (FOY-305)	Trypsin, matriptase, prostasin, plasmin, tPA, uPA, Xa, IXa, thrombin, tissue factor, complement factors, tryptase, HNE, KLK	[68,69]
Cathepsin-G inhibitor	Cathepsin G	[49]
Nafamostat mesilate (FUT-175)	Tryptase, trypsin, C1r, C1s, thrombin, kallikrein, plasmin	[37,65-67]
UAMC-0050	Tryptase, matriptase, KLK4, KLK8, uPA	[66,67,93]
Soybean trypsin inhibitor (SBTI)	Trypsin, chymotrypsin, plasmin, kallikrein, Xa	[49]

C1r: Complement component 1r; C1s: Complement component 1s; HNE: 4-hydoxynonenal; KLK: Kallikrein; PA: Plasminogen activator; tPA: Tissue plasminogen activator; uPA: Urokinase plasminogen activator.