Serine proteases excite myenteric neurons through protease-activated receptors in guinea pig small intestine

Gao, Chuanyun; Liu, Sumei; Hu, Hongzhen; Gao, Na; Kim, Gordon Y.; Xia, Yun; Wood, Jackie D.

doi:10.1053/gast.2002.36581

Cited by 95 publications

(80 citation statements)

References 30 publications

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“…In their study, Barbara et al demonstrated that in IBS patients, mast cells lie closer to nerve fibers of the mucosa compared with those in control patients (42). This suggests that once released by degranulating mast cells, tryptase could be in direct contact with enteric or primary afferent nerves, both of which express PAR 2 (5-7, 33, 44, 45), and induce hyperexcitability (34,45).…”

Section: Figurementioning

confidence: 95%

Role for protease activity in visceral pain in irritable bowel syndrome

Cenac¹,

Andrews²,

Holzhausen³

et al. 2007

J. Clin. Invest.

506

551

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Mediators involved in the generation of symptoms in patients with irritable bowel syndrome (IBS) are poorly understood. Here we show that colonic biopsy samples from IBS patients release increased levels of proteolytic activity (arginine cleavage) compared to asymptomatic controls. This was dependent on the activation of NF-κB. In addition, increased proteolytic activity was measured in vivo, in colonic washes from IBS compared with control patients. Trypsin and tryptase expression and release were increased in colonic biopsies from IBS patients compared with control subjects. Biopsies from IBS patients (but not controls) released mediators that sensitized murine sensory neurons in culture. Sensitization was prevented by a serine protease inhibitor and was absent in neurons lacking functional protease-activated receptor-2 (PAR 2 ). Supernatants from colonic biopsies of IBS patients, but not controls, also caused somatic and visceral hyperalgesia and allodynia in mice, when administered into the colon. These pronociceptive effects were inhibited by serine protease inhibitors and a PAR 2 antagonist and were absent in PAR 2 -deficient mice. Our study establishes that proteases are released in IBS and that they can directly stimulate sensory neurons and generate hypersensitivity symptoms through the activation of PAR 2 .

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Section: Figurementioning

confidence: 95%

Role for protease activity in visceral pain in irritable bowel syndrome

Cenac¹,

Andrews²,

Holzhausen³

et al. 2007

J. Clin. Invest.

506

551

View full text Add to dashboard Cite

show abstract

“…49,50 PAR1 and PAR2 expressed on myenteric neurons have been reported to modulate gut motility in different ways, for example, promote con-traction of gastric smooth muscle but reduce contractility of both circular and longitudinal colonic smooth muscles. 51,52 But changed expression ratio of PAR1 to PAR2 in the colon is connected with D-IBS patients, 53 which may partly associated with increased motility. Relatively, MCs have been less extensively studied in patients complaining of constipation, including slow transit constipation and C-IBS patients.…”

Section: Mast Cells Regulate Gastrointestinal Motilitymentioning

confidence: 99%

“…Besides histamine, MC tryptase may stimulate chloride ion secretion via activating PAR2, which is strongly expressed in both basolateral and apical membranes of enterocytes. 52 …”

Section: Mast Cells Regulate Epithelial Secretionmentioning

confidence: 99%

Mast Cells and Irritable Bowel Syndrome: From the Bench to the Bedside

Zhang

Song

Hou

2016

J Neurogastroenterol Motil

109

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Irritable bowel syndrome (IBS) is traditionally defined as a functional disorder since it lacks demonstrable pathological abnormalities. However, in recent years, low grade inflammatory infiltration, often rich in mast cells, in both the small and large bowel, has been observed in some patients with IBS. The close association of mast cells with major intestinal functions, such as epithelial secretion and permeability, neuroimmune interactions, visceral sensation, and peristalsis, makes researchers and gastroenterologists to focus attention on the key roles of mast cells in the pathogenesis of IBS. Numerous studies have been carried out to identify the mechanisms in the development, infiltration, activation, and degranulation of intestinal mast cells, as well as the actions of mast cells in the processes of mucosal barrier disruption, mucosal immune dysregulation, visceral hypersensitivity, dysmotility, and local and central stress in IBS. Moreover, therapies targeting mast cells, such as mast cell stabilizers (cromoglycate and ketotifen) and antagonists of histamine and serotonin receptors, have been tried in IBS patients, and have partially exhibited considerable efficacy. This review focuses on recent advances in the role of mast cells in IBS, with particular emphasis on bridging experimental data with clinical therapeutics for IBS patients.

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“…Activation of PAR 2 on enteric neurons results in depolarization and sustained hyperexcitability (Linden et al, 2001;Gao et al, 2002;Reed et al, 2003). We therefore determined whether PAR 2 activation depolarized small-and medium-diameter DRG neurons in culture and lowered their firing threshold, thereby increasing their excitability to other stimuli, by measuring the rheobase (minimum current to evoke one action potential in the current-clamp mode).…”

Section: Par 2 Agonists Increased Excitability Of Drg Neuronsmentioning

confidence: 99%