Deficiency of PAR4 Attenuates Cerebral Ischemia/Reperfusion Injury in Mice

Mao, Yingying; Zhang, Ming; Tuma, Ronald F.; Kunapuli, Satya P.

doi:10.1038/jcbfm.2009.283

Cited by 50 publications

(26 citation statements)

References 38 publications

(45 reference statements)

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“…PAR-2 has been found to regulate mast cells infiltration and Tcell activation and the Th1/inflammatory response in experimental periodontitis of mice [31], and activation of PAR-2 results in mast cell degranulation [32]. PAR-4 has been reported to participate platelet activation and microvascular inflammation in cerebral ischemia/ reperfusion (I/R) injury [33], and to leads to proinflammatory changes in the knee joint [34]. These findings implicate the importance of PARs in promoting inflammation.…”

Section: Discussionmentioning

confidence: 92%

TNF Increases Expression of IL-4 and PARs in Mast Cells

Zhang

Yang²,

He³

2010

Cell Physiol Biochem

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Tumor necrosis factor (TNF) is a proinflammatory cytokine which has been shown to be actively involved in the pathogenesis of allergic inflammation. However, little is known of the effects of TNF on cytokine secretion and protease activated receptor (PAR) expression in mast cells. In the present study, we examined potential influence of TNF on IL-4 and IL-12 release from P815 cells and PAR expression in P815 cells by using flow cytometry analysis, quantitative real time PCR, ELISA and cellular activation of signaling ELISA (CASE) techniques. The results showed that TNF induced up to 2.7-fold increase in IL-4, but not IL-12 release from P815 cells, and PAR-2 antagonist peptide FSLLRY-NH₂ and PAR-4 antagonist peptide trans-cinnamoyl (tc)-YPGKF-NH₂ did not affect TNF induced IL-4 release. Approximately up to 2.4 and 2.3 fold increases in expression of PAR-2 and PAR-4 were observed when cells were incubated with TNF. Pretreatment of cells with TNF for 60 min enhanced trypsin and tryptase induced PAR-2 expression by 2.4 and 2.3 fold; PAR-3 expression by 1.6 and 1.7 fold and PAR-4 expression by 1.6 and 1.7 fold, respectively. LY294002, an inhibitor PI3K abolished TNF induced IL-4 release and phosphorylation of Akt in P815 cells, indicating Akt cell signalling pathway is involved in the event. In conclusion, TNF can stimulate IL-4 release from mast cells through an Akt cell signalling pathway dependent, but PAR independent mechanism. TNF may serve as a regulator for IL-4 production and PAR expression, and through which participates in the mast cell related inflammation.

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Section: Discussionmentioning

confidence: 92%

TNF Increases Expression of IL-4 and PARs in Mast Cells

Zhang

Yang²,

He³

2010

Cell Physiol Biochem

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“…While these findings demonstrate a major role for platelet PAR4 in promoting leukocyte recruitment in our endothelial injury model, PARs' contributions to thromboinflammatory responses such as ischaemia-reperfusion injury remain controversial. Some studies have suggested that PAR activation is critical for ischaemia-reperfusion-induced organ injury 52 ; however, others failed to identify a role of PARs in linking coagulation with inflammation 53 . Such discordant conclusions may reflect the variable influence of platelet activation on thromboinflammatory reactions in different experimental models.…”

Section: Discussionmentioning

confidence: 99%

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

et al. 2015

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Thrombin is a central regulator of leukocyte recruitment and inflammation at sites of vascular injury, a function thought to involve primarily endothelial PAR cleavage. Here we demonstrate the existence of a distinct leukocyte-trafficking mechanism regulated by components of the haemostatic system, including platelet PAR4, GPIba and fibrin. Utilizing a mouse endothelial injury model we show that thrombin cleavage of platelet PAR4 promotes leukocyte recruitment to sites of vascular injury. This process is negatively regulated by GPIba, as seen in mice with abrogated thrombin-platelet GPIba binding (hGPIba D277N ). In addition, we demonstrate that fibrin limits leukocyte trafficking by forming a physical barrier to intravascular leukocyte migration. These studies demonstrate a distinct 'checkpoint' mechanism of leukocyte trafficking involving balanced thrombin interactions with PAR4, GPIba and fibrin. Dysregulation of this checkpoint mechanism is likely to contribute to the development of thromboinflammatory disorders.

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“…3 Consistent with this, platelet depletion or inhibition of platelet activation improves microvascular perfusion and reduces tissue inflammation and injury. [4][5][6][7] Experimental and clinical evidence has demonstrated that thrombi are highly efficient at recruiting leukocytes from flowing blood 8 with the extent of the thromboinflammatory response correlating with the degree of organ injury and clinical outcome. 9 Despite its clinical importance, there is limited understanding of the mechanisms by which microvascular thrombi guide leukocytes to sites of vascular injury.…”

Section: Introductionmentioning

confidence: 99%