Coagulation factor 2 receptor (F2R), also well-known as a protease-activated receptor 1 (PAR1), is the first known thrombin receptor and plays a critical role in transmitting thrombin-mediated activation of intracellular signaling in many types of cells. It has been known that bacterial infections lead to activation of coagulation systems, and recent studies suggest that PAR1 may be critically involved not only in mediating bacteria-induced detrimental coagulation, but also in innate immune and inflammatory responses. Community-acquired pneumonia, which is frequently caused by Streptococcus pneumoniae (S. pneumoniae), is characterized as an intra-alveolar coagulation and an interstitial neutrophilic inflammation. Recently, the role of PAR1 in regulating pneumococcal infections has been proposed. However, the role of PAR1 in pneumococcal infections has not been clearly understood yet. In this review, recent findings on the role of PAR1 in pneumococcal infections and possible underlying molecular mechanisms by which S. pneumoniae regulates PAR1-mediated immune and inflammatory responses will be discussed.
Bacterial Infections ; Blood Coagulation Factors* ; Inflammation ; Negotiating ; Neutrophils ; Pneumococcal Infections* ; Pneumonia ; Receptor, PAR-1 ; Receptors, Thrombin ; Streptococcus pneumoniae

OBJECTIVETo assess the relationship between protease-activated receptor 1 (PAR1) expression in the basilar artery and cerebral vasospasm (CVS) in a rat model of subarachnoid hemorrhage (SAH).

METHODSTwenty-four SD rats were randomized into normal control group, SAH 3-days group, SAH 5-days group and SAH 7-days group. Rat models of SAH were established by two injections of blood into the cisterna magna and the behavioral changes of the rats were observed. The basilar arteries were taken at 3, 5, or 7 days following the modeling for measuring the cross-sectional area of the basilar artery and for immunohistochemical detection of PAR1 expression.

RESULTSThe SAH model rats, especially those in SAH 3-days group, presented with obvious neurological deficits, which was not found in the normal control group. CVS was not observed in the normal control group but occurred in the SAH model rats, which showed reduced cross-sectional area of the basilar artery and worsening spasm over time. The expression level of PAR1 tended to increase gradually in SAH 3-days, SAH 5-days and SAH 7-days groups. Pearson correlation analysis showed an inverse correlation between the expression of PAR1 and the cross-sectional area of the basilar artery (r=-0.779, P<0.01).

CONCLUSIONSThe expression of PAR1 increases significantly in rat basilar artery wall following SAH in positive correlation with the severity of CVS, suggesting the role of thrombin in the pathological process of CVS after SAH.

Animals ; Basilar Artery ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptor, PAR-1 ; metabolism ; Subarachnoid Hemorrhage ; metabolism ; Vasospasm, Intracranial ; metabolism

OBJECTIVETo evaluate the relationship between PAR1 (Protease-Activated Receptor 1) expression and the clinicopathologic features and to investigate the prognostic value of PAR1 expression in hepatocellular carcinoma (HCC) in early stage after curative resection.

METHODSReal-time PCR was used to detect PAR1 expression in 41 pairs of tumors and matched peritumoral samples of HCC in early stage. Prognostic value of PAR1 mRNA expression was evaluated. Meanwhile, another 49 tissue paraffin slices of HCC were tested using immunohistochemistry (Envision) and the prognostic value of PAR1 expression and other clinicopathologic factors were evaluated.

RESULTSPeritumoral PAR1 mRNA expression was significantly increased in HCCs from the patients with tumor recurrence as compared with those without recurrence (P < 0.05). Peritumoral PAR1 protein expression was related to tumor differentiation (P < 0.05). Kaplan-Meier analysis showed that Peritumoral PAR1 protein expression was associated with the overall survival (OS) (P < 0.05) of HCC patients and the time to recurrence (TTR) (P < 0.05). The 1, 3 and 5 -year overall survival time and the cumulative recurrence time in the high PAR1 protein expression group were significantly lower as compared to the low PAR1 expression group in the peritumoral liver tissue.

CONCLUSIONSPeritumoral PAR1 expression is closely associated with the prognosis of early stage HCC patients after curable surgery. PAR1 may be involved in thrombin-mediated invasion process and may be used as a prognostic marker for HCC.

Carcinoma, Hepatocellular ; metabolism ; pathology ; Female ; Humans ; Liver Neoplasms ; metabolism ; pathology ; Male ; Middle Aged ; Postoperative Period ; Prognosis ; Receptor, PAR-1 ; metabolism

AIMTo study the dynamic and long-lasting expression of thrombin receptor after acute intracerebral hemorrhage (ICH) in rats.

METHODS36 rats were randomly divided into 6 groups (n = 6): Normal group and ICH model groups at 6 hours, 24 hours, 3 days, 7 days and 14 days. ICH models were produced with the induction of collagenase type VII-S. Immunohistochemical method was used to detect PAR-1 protein and RT-PCR technique was used to detect PAR-1mRNA in brain tissue around the haematoma in different groups.

RESULTSPAR-1 protein and mRNA were mild positive in normal group. In model groups, intensity of PAR-1 expression started to enhance at 6 hours, and enhanced more at 24 hours. PAR-1 expression reached the peak at 3 days and began to descend. At 7 days the descent was obvious and there was further descent at 14 days. At each time point, the PAR-1 protein positive cell number and PAR-1mRNA absorbance ratio in ICH model groups were significantly higher than those in normal group (P < 0.05 or P < 0.01). In addition, PAR-1 proteins were obviously expressed in vivo in brain capillary endothelial cell.

CONCLUSIONFunctional PAR-1 exists in brain capillary endothelial cells. Activation of PAR-1 after ICH due to the stimulation of thrombin is not only the initiating agent of cerebral edema after ICH, but also participates the development of cerebral edema.

Animals ; Cerebral Hemorrhage ; metabolism ; Disease Models, Animal ; Male ; Rats ; Rats, Wistar ; Receptor, PAR-1 ; metabolism ; Thrombin ; metabolism

Aged ; Aged, 80 and over ; Blood Platelets ; chemistry ; Humans ; Receptor, PAR-1 ; blood ; Receptors, Thrombin ; blood ; Renal Dialysis ; Uremia ; blood ; therapy

Animals ; Cardiovascular Diseases ; etiology ; metabolism ; Humans ; Inflammation ; metabolism ; Periodontitis ; complications ; metabolism ; microbiology ; Platelet Aggregation ; physiology ; Porphyromonas gingivalis ; pathogenicity ; RNA, Messenger ; metabolism ; Receptor, PAR-1 ; metabolism ; Receptor, PAR-2 ; genetics ; metabolism ; Receptors, Proteinase-Activated ; metabolism ; Receptors, Thrombin ; metabolism

OBJECTIVETo investigate the protective effect and mechanism of baicalin on nerve tissue in rat with intracerebral hemorrhage (ICH).

METHODSRats were randomly divided into five groups: the sham-operated group, the ICH model group, and the three baicalin treated groups treated respectively with small, medium and large doses of baicalin. ICH rat model was established by injecting collagenase VII into caudate nucleus. Baicalin was given by peritoneal injection to the baicalin treated groups, and saline was given to the other two groups once a day started from 2 h after modeling. Animals were sacrificed in batches on the 1st, 3rd, 5th and 10th day of treatment to take their brains for detecting protease-activated receptor-1 (PAR-1) expression and cell apoptosis in brain tissue surrounding hematoma by Western blot and TUNEL method, respectively. And the water content of brain was estimated by dry-wet weight method.

RESULTSCompared with the model group, the PAR-1 expression and TUNEL-positive cells were significantly reduced in the baicalin treated groups; and brain edema was also significantly reduced (P<0.01).

CONCLUSIONSThe up-regulated PAR-1 expression after ICH in rats might play an important role in inducing cell apoptosis and brain edema. Baicalin shows significant protective effect on ICH rats, which may be related to its effects in inhibiting PAR-1 expression and decreasing apoptosis cells, so as to reduce brain edema.

Animals ; Apoptosis ; drug effects ; Brain ; metabolism ; pathology ; Cerebral Hemorrhage ; drug therapy ; Depression, Chemical ; Flavonoids ; pharmacology ; therapeutic use ; Male ; Phytotherapy ; Rats ; Rats, Wistar ; Receptor, PAR-1 ; metabolism

This study was designed to compare the effects of protease-activated receptor 1 (PAR-1) and protease-activated receptor 4 (PAR-4) to the expression of platelet surface GPIbalpha and cytoskeleton reorganization, then to investigate the role of PARs in platelet signal transmission. PAR1 (25 micromol/L) and PAR4 (250 micromol/L) were used to stimulate platelet at different time points (0 - 60 minutes), and the platelet surface GPIbalpha, actin and myosin and P-selectin were detected with flow cytometry, the alteration of GPIbalpha, actin and myosin in cytoskeleton was compared by Western blot, the membrane cytoskeleton followed GPIbalpha immunoprecipitation was analyzed. The results showed that an increase of P-selectin and reversible decrease of GPIbalpha expression were obtained after platelet activation by PAR1 o r PAR4, and a different kinetics of redistribution of GPIbalpha was found for the two peptides all over the time course (P < 0.05). PAR1 acted more potently and rapidly than PAR4, but the effect of PAR4 persisted longer in the course of platelet activation. Meanwhile, there was a transient change of actin, myosin and GPIbalpha in cytoskeleton proteins. Similar redistribution was also found in GPIbalpha/myosin and GPIbalpha/actin association. It is concluded that PAR1 and PAR4 possess an important role in platelet signal transmission. Either of the receptors can mediate platelet activation and GPIbalpha redistribution, which is correlated with cytoskeleton reorganization. PAR1 acts more rapidly, and effect of PAR4 persists longer.
Cytoskeleton ; chemistry ; Flow Cytometry ; Humans ; Myosins ; analysis ; P-Selectin ; analysis ; Platelet Activation ; Platelet Glycoprotein GPIb-IX Complex ; Receptor, PAR-1 ; physiology ; Receptors, Thrombin ; physiology

OBJECTIVETo investigate the roles of protease-activated receptors (PARs) in thrombin-induced brain injury and neurogenesis in rats.

METHODSNinety male SD rats were randomly assigned to receive intra-hippocampus injection of NS, thrombin or specific agonists of 3 protease-activated receptors (PAR-1, PAR-3 and PAR-4), respectively. At 1,3 and 7 d after injection, the area of the hippocampus was determined with HE staining, the density and morphology of astrocyte were detected with GFAP staining, degenerated neurons were detected with Fluoro-Jade C staining, and the neurogenesis was examined with DCX staining.

RESULTSCompared to NS injection, the area of the hippocampus significantly increased at 1-3 d and decreased at 7 d after the injection of thrombin and PAR-1 agonist (P<0.05). In addition, injection of thrombin and PAR-1 agonist significantly increased the density of astrocyte and Fluoro-Jade C positive cells at 1-7 d after injection (P<0.05), and significantly increased the density of DCX positive cells at 3-7 d after injection(P<0.05). The injection of PAR-3 agonist and PAR-4 agonist had no affect on the area of the hippocampus, the density of astrocyte, Fluoro-Jade C positive cells and DCX positive cells.

CONCLUSIONThe activation of protease-activated receptor-1 may be related to the thrombin-induced brain injury and neurogenesis in rat hippocampus.

Animals ; Brain Injuries ; chemically induced ; metabolism ; pathology ; Hippocampus ; pathology ; Male ; Neurogenesis ; drug effects ; Rats ; Rats, Sprague-Dawley ; Receptor, PAR-1 ; agonists ; physiology ; Receptors, Thrombin ; agonists ; Thrombin ; toxicity

BACKGROUNDPrevious studies have indicated that thrombin (TM) may play a major role in brain edema after intracerebral hemorrhages (ICHs). However, the mechanism of TM-induced brain edema is poorly understood. In this study, we explored the effect of TM on the permeability of the blood brain barrier (BBB) and investigated its possible mechanism, aiming at providing a potential target for brain edema therapy after ICHs.

METHODSTM or TM + cathepsin G (CATG) was stereotaxically injected into the right caudate nucleus of Sprague-Dawley rats in vivo. BBB permeability was measured by Evans-Blue extravasation. Brain water content was determined by the dry-wet weight method. Brain microvascular endothelial cells were then cultured in vitro. After TM or TM + CATG was added to the endothelial cell medium, changes in the morphology of cells were dynamically observed by phase-contrast light microscopy, and the expression of matrix metalloproteinase-2 (MMP-2) protein was measured by immunohistochemical method.

RESULTSBBB permeability increased at 6 hours after a TM injection into the ipsilateral caudate nucleus (P < 0.05), peaked between 24 hours (P < 0.01) and 48 hours (P < 0.05) after the injection, and then declined. Brain water content changed in parallel with the changes in BBB permeability. However, at all time points, BBB permeability and brain water content after a TM + CATG injection were not significantly different from the respective parameters in the control group (P > 0.05). TM induced endothelial cell contraction in vitro in a time-dependent manner and enhanced the expression of MMP-2 protein. After incubation with TM + CATG, cell morphology and MMP-2 expression did not change significantly as compared to the control group (P > 0.05).

CONCLUSIONSIncreased BBB permeability may be one of the mechanisms behind TM-induced cerebral edema. TM induces endothelial cell contraction and promotes MMP-2 expression by activating protease activated receptor-1 (PAR-1), possibly leading to the opening of the BBB.

Animals ; Blood-Brain Barrier ; drug effects ; Body Water ; metabolism ; Brain Edema ; etiology ; Cathepsin G ; Cathepsins ; pharmacology ; Cerebral Hemorrhage ; complications ; Matrix Metalloproteinase 2 ; analysis ; Permeability ; Rats ; Rats, Sprague-Dawley ; Receptor, PAR-1 ; physiology ; Serine Endopeptidases ; Thrombin ; toxicity