Inflammatory Bowel Disease (IBD) causes significant patient morbidity as a result of local gastrointestinal (GI) and systemic inflammation, as well as GI tract dysfunction. The Vagus nerve plays a critical role in regulating various GI functions. Afferent vagal fibers from the GI tract carry sensory information to the brainstem. There, efferent vagal neurons in the Dorsal Motor Nucleus of the Vagus (DMV) project back to the GI tract to control GI motility and secretory function. Thrombin-induced DMV neuronal damage and resultant vagal dysfunction are postulated to factor in the pathogenesis of IBD. Within the DMV, thrombin binds Protease Activated Receptors (PARs) to initiate signaling cascades within vagal neurons. Thrombin gains access to the DMV neurons via local production and activation of its precursor, prothrombin, as well as by translocation across the blood brain barrier (BBB). Animals with IBD demonstrate increased BBB permeability, thrombin production, and neuronal PAR expression. These findings suggest increased vagal neuron exposure and sensitivity to thrombin in IBD. The character and mechanism of thrombin-induced neuronal damage remain a focus of inquiry. In vitro, thrombin increases neuronal and microglial production of inflammatory cytokines associated with neuronal apoptosis, growth inhibition, and abnormal neuronal response to neurotransmitters. In the DMV, thrombin-induced neuronal apoptosis is mediated by PAR-1, and involves JNK and p38 signaling pathways leading to the activation of caspase-3. IBD is thus associated with excessive central nervous system exposure to thrombin, leading to apoptosis and abnormal neurotransmitter response in DMV vagal neurons. Thrombin and PAR antagonism may represent a potential means of reducing morbidity in patients with IBD.
|Original language||English (US)|
|Title of host publication||Thrombin|
|Subtitle of host publication||Function and Pathophysiology|
|Publisher||Nova Science Publishers, Inc.|
|Number of pages||12|
|State||Published - Dec 1 2012|
ASJC Scopus subject areas