RGD Reference Report - Activated protein C reduces stress-induced gastric mucosal injury in rats by inhibiting the endothelial cell injury. - Rat Genome Database

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Activated protein C reduces stress-induced gastric mucosal injury in rats by inhibiting the endothelial cell injury.

Authors: Isobe, H  Okajima, K  Harada, N  Liu, W  Okabe, H 
Citation: Isobe H, etal., J Thromb Haemost. 2004 Feb;2(2):313-20.
RGD ID: 1578389
Pubmed: PMID:14995995   (View Abstract at PubMed)

Background and objective: Activated protein C (APC) is a natural anticoagulant with anti-inflammatory activity. APC inhibits neutrophil activation through inhibition of tumor necrosis factor (TNF)-alpha production. Such anti-inflammatory activity of APC has recently been shown to be critical in the treatment of patients with severe sepsis. We previously demonstrated that activated neutrophils play a crucial role in the development of stress-induced gastric mucosal injury. Thus, inhibition of neutrophil activation by APC should reduce endothelial cell damage, maintain gastric blood flow, and lessen gastric mucosal injury. In the present study, we examined this possibility by using a rat model of water-immersion restraint stress (WIRS)-induced gastric mucosal injury. Methods and results: Gastric mucosal injury was observed 4 h after WIRS, without increases in gastric mucosal levels of either myeloperoxidase activity or TNF-alpha, but with significant increases in plasma levels of TNF-alpha 1 h after WIRS. Intravenous administration of APC (100 micro g kg-1) significantly reduced WIRS-induced gastric mucosal injury by inhibiting decrease in gastric mucosal blood flow. Administration of APC also inhibited both the decrease in gastric tissue levels of 6-keto-prostaglandin F1alpha and the increase in gastric mucosal micorvascular permeability in animals subjected to WIRS. Furthermore, APC inhibited WIRS-induced increases in plasma levels of TNF-alpha. Neither active site-blocked factor Xa, which is a selective inhibitor of thrombin generation, nor active site-blocked APC had any effect on these events. Intraperitoneal administration of anti-rat TNF-alpha antibody produced effects similar to those of APC. Conclusions: The observations in the present study strongly suggest that APC reduces stress-induced gastric mucosal injury by inhibiting the decrease in gastric mucosal blood flow through attenuation of the activated neutrophil-induced endothelial cell injury via inhibition of TNF-alpha production. In addition, we show that serine protease activity of APC, rather than its anticoagulant activity, is critical for the protective mechanism(s) by which TNF-alpha production could be inhibited.




Biological Process

  
Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
ProcRatnegative regulation of coagulation  TAS  RGD 

RGD Manual Annotations


  
Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
PROCHumanprotein C anticoagulant pathway   ISS  RGD 
ProcRatprotein C anticoagulant pathway   TAS  RGD 
ProcMouseprotein C anticoagulant pathway   ISS  RGD 

Genes (Rattus norvegicus)
Proc  (protein C, inactivator of coagulation factors Va and VIIIa)

Genes (Mus musculus)
Proc  (protein C)

Genes (Homo sapiens)
PROC  (protein C, inactivator of coagulation factors Va and VIIIa)