P-Selectin Inhibition Reduces Severity of Acute Experimental Pancreatitis

Hackert, Thilo; Sperber, Rasmus; Hartwig, Werner; Fritz, Stefan; Schneider, Lutz; Gebhard, Martha-Maria; Werner, Jens

doi:10.1159/000212098

Cited by 29 publications

(21 citation statements)

References 28 publications

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“…In a model of sepsis induced by cecal ligation and puncture (CLP), neutrophil infiltration in the lungs was reduced following platelet depletion 11 , suggesting that platelets play a role in neutrophil activation during inflammation. Similar observations were made in other inflammation models, such as pancreatitis and ischemia reperfusion 12, 13 . In a rat model of LPS-induced inflammation, induction of pro-inflammatory cytokines (IL-6 and TNF-α), lung damage, and liver damage were attenuated upon treatment with clopidogrel, a drug that antagonizes the P2Y 12 receptor 14 .…”

Section: Introductionsupporting

confidence: 86%

P2Y ₁₂ Receptor Modulates Sepsis-Induced Inflammation

Liverani

Rico

Tsygankov

et al. 2016

ATVB

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Objective Platelets modulate hemostasis and immune responses via interactions with immune cells, through secretion of immune-modulators and cell-cell interactions. The P2Y12 receptor mediates ADP-induced aggregation and secretion in platelets. Approach using a mouse model of intra-abdominal sepsis and acute lung injury, we investigated the role of the P2Y12 receptor in neutrophil migration and lung inflammation in P2Y12 null mice and in mice pre-treated with the P2Y12 antagonist clopidogrel. Results our data show a decrease in circulating white blood cells and a decrease in platelet activation and platelet-leukocyte interactions in treated mice compared to untreated. Additionally, lung injury and platelet sequestration were diminished in clopidogrel-treated mice compared to their untreated septic littermates. Similar results were observed in P2Y12 null mice: platelet activation and platelet-leukocyte aggregates were decreased in septic P2Y12 null mice compared to wild-type. P2Y12 null mice were refractory to lung injury compared to wild-type. Lastly, to evaluate P2Y12 independent effects of clopidogrel, we pre-treated P2Y12 null mice. Interestingly, the number of circulating neutrophils was reduced in treated septic P2Y12 null mice, suggesting neutrophils as a target for clopidogrel pleiotropic effects. No difference was observed in P2Y1 null mice during sepsis, indicating that the P2Y12 receptor is responsible for the effects. Conclusions P2Y12 null mice are refractory to sepsis-induced lung injury, suggesting a key role for activated platelets and the P2Y12 receptor during sepsis.

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Section: Introductionsupporting

confidence: 86%

P2Y ₁₂ Receptor Modulates Sepsis-Induced Inflammation

Liverani

Rico

Tsygankov

et al. 2016

ATVB

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“…Similar observations were made in mice following myocardial infarction, where leukocyte infiltration in the heart was significantly reduced, when animals were platelet-depleted [23]. Furthermore, liver damage following acute pancreatitis was decreased in platelet-depleted mice as compared with controls [24]. These results suggest that platelets are crucial for neutrophil transmigration during inflammation in key organ systems.…”

Section: Activated Platelets During Inflammationsupporting

confidence: 70%

“…As previously mentioned, platelet characteristics in septic patients appear to be altered in terms of leukocyte-platelet aggregate and P-selectin secretion [33]. In a model of sepsis induced by cecal ligation and puncture (CLP), neutrophil infiltration in the lungs was significantly reduced following platelet depletion [22], suggesting that platelets play a fundamental role in neutrophil activation during inflammation; this was similar to what was observed in other inflammation models, such as pancreatitis and ischemia reperfusion [23, 24]. Furthermore, in a rat model of LPS-induced inflammation induction of pro-inflammatory cytokines (IL-6 and TNF-α) as well as lung and liver damage were attenuated upon treatment with clopidogrel (10mg/kg, 5 days before LPS injection) [13].…”

Section: P2y12 Receptor In Inflammationmentioning

confidence: 74%

The Role of P2Y<sub>12</sub> Receptor and Activated Platelets During Inflammation

Liverani¹,

Kilpatrick²,

Tsygankov³

et al. 2014

CDT

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Platelets play an important role not only during thrombosis, but also in modulating immune responses through their interaction with immune cells and by releasing inflammatory mediators upon activation. The P2Y12 receptor is a Gi-coupled receptor that not only regulates ADP-induced aggregation but that can also dramatically potentiate secretion, when platelets are activated by other stimuli. Considering the importance of P2Y12 receptor in platelet function, a class of anti-platelet drugs, thienopyridines, have been designed and successfully used to prevent thrombosis. This review will focus on the role of activated platelets in inflammation and the effects that P2Y12 antagonism exerts on the inflammatory process. A change in platelet functions was noted in patients treated with thienopyridines during inflammatory conditions, suggesting that platelets may modulate the inflammatory response. Further experiments in a variety of animal models of diseases, such as sepsis, rheumatoid arthritis, myocardial infarction, pancreatitis and pulmonary inflammation have also demonstrated that activated platelets influence the inflammatory state. Platelets can secrete inflammatory modulators in a P2Y12–dependent manner, and, as a result, directly alter the inflammatory response. P2Y12 receptor may also be expressed in other cells of the immune system, indicating that thienopyridines could directly influence the immune system rather than only through platelets. Overall the results obtained to date strongly support the notion that activated platelets significantly contribute to the inflammatory process and that antagonizing P2Y12 receptor can influence the immune response.

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“…Additionally, upon stimulation by TNF-α and IL-1β, endothelial cells synthesize P-selectin. In experimental AP, prophylactic inhibition of P-selectin resulted in reduced platelet activation, platelet-endothelium and leukocyte-endothelium interactions and reduced pancreatic tissue inflammation and necrosis [127]. Both P- and E-selectins are overexpressed in lung tissue during experimental AP.…”

Section: Laboratory Markers Of Endothelial Activation and Injury Imentioning

confidence: 99%

The Interplay between Inflammation, Coagulation and Endothelial Injury in the Early Phase of Acute Pancreatitis: Clinical Implications

Dumnicka

Maduzia

Ceranowicz

et al. 2017

IJMS

160

113

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Acute pancreatitis (AP) is an inflammatory disease with varied severity, ranging from mild local inflammation to severe systemic involvement resulting in substantial mortality. Early pathologic events in AP, both local and systemic, are associated with vascular derangements, including endothelial activation and injury, dysregulation of vasomotor tone, increased vascular permeability, increased leukocyte migration to tissues, and activation of coagulation. The purpose of the review was to summarize current evidence regarding the interplay between inflammation, coagulation and endothelial dysfunction in the early phase of AP. Practical aspects were emphasized: (1) we summarized available data on diagnostic usefulness of the markers of endothelial dysfunction and activated coagulation in early prediction of severe AP; (2) we reviewed in detail the results of experimental studies and clinical trials targeting coagulation-inflammation interactions in severe AP. Among laboratory tests, d-dimer and angiopoietin-2 measurements seem the most useful in early prediction of severe AP. Although most clinical trials evaluating anticoagulants in treatment of severe AP did not show benefits, they also did not show significantly increased bleeding risk. Promising results of human trials were published for low molecular weight heparin treatment. Several anticoagulants that proved beneficial in animal experiments are thus worth testing in patients.

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P-Selectin Inhibition Reduces Severity of Acute Experimental Pancreatitis

Cited by 29 publications

References 28 publications

P2Y ₁₂ Receptor Modulates Sepsis-Induced Inflammation

P2Y ₁₂ Receptor Modulates Sepsis-Induced Inflammation

The Role of P2Y<sub>12</sub> Receptor and Activated Platelets During Inflammation

The Interplay between Inflammation, Coagulation and Endothelial Injury in the Early Phase of Acute Pancreatitis: Clinical Implications

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P-Selectin Inhibition Reduces Severity of Acute Experimental Pancreatitis

Cited by 29 publications

References 28 publications

P2Y 12 Receptor Modulates Sepsis-Induced Inflammation

P2Y 12 Receptor Modulates Sepsis-Induced Inflammation

The Role of P2Y<sub>12</sub> Receptor and Activated Platelets During Inflammation

The Interplay between Inflammation, Coagulation and Endothelial Injury in the Early Phase of Acute Pancreatitis: Clinical Implications

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P2Y ₁₂ Receptor Modulates Sepsis-Induced Inflammation

P2Y ₁₂ Receptor Modulates Sepsis-Induced Inflammation