Biomedical subjects

Willemijntje A Hoogerwerf

Publications and source records attributed to Willemijntje A Hoogerwerf.

6 recordsLinked to original sources

PubMed2006

Biologic clocks and the gut.

The gastrointestinal tract displays biologic rhythms in basal gastric acid output, epithelial cell proliferation, gastrointestinal motility, and appetite regulation. Furthermore, the development of gastrointestinal complications after administration of aspirin and after chemo- and radiotherapy for metastatic colon cancer depends on the time of administration. Biologic rhythms are driven by so-called clock genes. Thus, it is conceivable that subsets of genes in the gastrointestinal tract are under clock gene control as well. The purpose of this article is to discuss basic concepts in the studies of biologic rhythms, to review examples of biologic rhythms in the gastrointestinal tract, and to discuss examples of gastrointestinal diseases in which alterations in biologic rhythms may play a pathogenetic role.

Animals↗

PubMed2006

Tachykinin receptors as drug targets for motility disorders.

The tachykinins and their receptors are strategically distributed within the gut wall, spinal cord, and central nervous system to be potential targets of therapeutic agents for gastrointestinal motility disorders. However, the development of effective tachykinin receptor agonists or antagonists to treat these disorders has had very limited success so far. This is, in part, due to the complex and multilevel of regulation of gastrointestinal motility function and the challenges faced in targeting the specific type of gut contraction to normalize function in disease state.

Animals↗

PubMed2005

Pharmacological management of pancreatitis.

Pancreatitis is a common disease with substantial morbidity and mortality. Pharmacological therapy for the prevention and treatment of pancreatitis is an intense subject of investigation. The use of proteinase inhibitors such as gabexate mesylate in the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis (ERCP) has been disappointing. Initial studies using ulinastatin are promising but additional dose-response studies are needed. Somatostatin, but not octreotide, is likely to be effective in the prevention of post-ERCP pancreatitis. Rectal diclofenac might provide a simple, cheap alternative but large-scale studies are again needed. New insights into the role of proteinase-activated receptor-2 in the pancreas add to the complexity of the mechanisms involved in the pathophysiology of pancreatitis, and the development of specific agonists and antagonists of this receptor is necessary to assess their therapeutic potential in the prevention and management of pancreatitis.

Animals↗

PubMed2005

The role of mast cells in the pathogenesis of pain in chronic pancreatitis.

BACKGROUND: The biological basis of pain in chronic pancreatitis is poorly understood. Mast cells have been implicated in the pathogenesis of pain in other conditions. We hypothesized that mast cells play a role in the pain of chronic pancreatitis. We examined the association of pain with mast cells in autopsy specimens of patients with painful chronic pancreatitis. We explored our hypothesis further using an experimental model of trinitrobenzene sulfonic acid (TNBS) -induced chronic pancreatitis in both wild type (WT) and mast cell deficient mice (MCDM). METHODS: Archival tissues with histological diagnoses of chronic pancreatitis were identified and clinical records reviewed for presence or absence of reported pain in humans. Mast cells were counted. The presence of pain was assessed using von Frey Filaments (VFF) to measure abdominal withdrawal responses in both WT and MCDM mice with and without chronic pancreatitis. RESULTS: Humans with painful chronic pancreatitis demonstrated a 3.5-fold increase in pancreatic mast cells as compared with those with painless chronic pancreatitis.WT mice with chronic pancreatitis were significantly more sensitive as assessed by VFF pain testing of the abdomen when compared with MCDM. CONCLUSION: Humans with painful chronic pancreatitis have an increased number of pancreatic mast cells as compared with those with painless chronic pancreatitis. MCDM are less sensitive to mechanical stimulation of the abdomen after induction of chronic pancreatitis as compared with WT. Mast cells may play an important role in the pathogenesis of pain in chronic pancreatitis.

Abdomen↗

PubMed2004

Trypsin mediates nociception via the proteinase-activated receptor 2: a potentially novel role in pancreatic pain.

BACKGROUND & AIMS: The pathogenesis of pain in pancreatitis remains poorly understood. We hypothesized that trypsin, a key inflammatory mediator in this condition, can also activate nociceptive neurons via the proteinase-activated receptor 2. METHODS: Double immunohistochemical staining of T8 to T12 dorsal root ganglia sections was performed with antibodies against proteinase-activated receptor 2 and vanilloid receptor 1, a marker for primary nociceptive neurons. In vivo nociceptive activity was measured by FOS immunoreactivity in thoracic spinal dorsal horn segments after intrapancreatic administration of proteinase-activated receptor 2 agonists. Pain behavior was assessed by visceromotor reflex activity in response to noxious stimulation of the pancreas with proteinase-activated receptor 2 agonists. RESULTS: Proteinase-activated receptor 2 was expressed by virtually all nociceptive neurons in thoracic dorsal root ganglia. Intraductal trypsin, in subinflammatory concentrations, activated spinal dorsal horn neurons in a dose-dependent manner, as measured by FOS expression. Both trypsin and a proteinase-activated receptor 2-specific peptide agonist induced a behavioral pain response when infused into the pancreatic duct of awake rats. Preinfusion of the pancreatic duct with proteinase-activated receptor 2-specific activating peptide desensitized the response to trypsin. CONCLUSIONS: Our findings suggest a novel proteinase-activated receptor 2-mediated role for trypsin in the pathogenesis of pancreatic pain and one that is independent of its inflammatory effect.

Animals↗

PubMed2002

Molecular cloning of the rat proteinase-activated receptor 4 (PAR4).

BACKGROUND: The proteinase-activated receptor 4 (PAR4) is a G-protein-coupled receptor activated by proteases such as thrombin and trypsin. Although activation of PAR4 has been shown to modulate rat gastrointestinal motility, the rat PAR4 sequence was unknown until now. This study aimed to identify the rat PAR4 cDNA. RESULTS: The cDNA coding for the rat PAR4 homologue was cloned from the duodenum. Northern blots demonstrated a 3.0 kb transcript in the duodenum. Protein homology with mouse and human counterparts was 90% and 75% respectively. PAR4 is expressed predominantly in the esophagus, stomach, duodenum and the spleen. When expressed in COS cells, PAR4 is activated by trypsin (1 nM), thrombin (50 nM), mouse PAR4 specific peptide (500 microM) and a putative rat PAR4 specific activating peptide (100 microM), as measured by intracellular Ca2+-changes. CONCLUSIONS: We have identified and characterized cDNA encoding the rat PAR4 homologue. PAR4 is expressed predominantly in the upper gastrointestinal tract. It is activated by trypsin, thrombin and its newly identified rat PAR4 specific activating peptide.

Journal Article↗