Clopidogrel reduces post-transplant obliterative bronchiolitis

Preidl, Raimund; Eckl, S.; Ramsperger-Gleixner, M.; Koch, N.; Spriewald, Bernd M.; Weyand, Michael; Ensminger, Stephan

doi:10.1111/tri.12163

Cited by 17 publications

(6 citation statements)

References 65 publications

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“…Both receptors promote platelet aggregation and P2Y12 receptors are the primary targets of modern antithrombotic therapies [33,34]. However, P2Y1 and P2Y12 receptors may also have pro-inflammatory effects that are unrelated to platelet activation [35][36][37][38]. We show that P2Y1 receptors contribute to T cell activation, suggesting that antiplatelet drugs could influence T cell activation, which may ameliorate inflammatory processes but may also attenuate T cell-mediated immune defenses.…”

Section: Discussionmentioning

confidence: 74%

Autocrine stimulation of P2Y1 receptors is part of the purinergic signaling mechanism that regulates T cell activation

Woehrle

Ledderose

Rink

et al. 2019

Purinergic Signalling

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Previous studies have shown that T cell receptor (TCR) and CD28 coreceptor stimulation involves rapid ATP release, autocrine purinergic feedback via P2X receptors, and mitochondrial ATP synthesis that promote T cell activation. Here, we show that ADP formation and autocrine stimulation of P2Y1 receptors are also involved in these purinergic signaling mechanisms. Primary human CD4 T cells and the human Jurkat CD4 T cell line express P2Y1 receptors. The expression of this receptor increases following T cell stimulation. Inhibition of P2Y1 receptors impairs the activation of mitochondria, as assessed by mitochondrial Ca 2+ uptake, and reduces cytosolic Ca 2+ signaling in response to TCR/CD28 stimulation. We found that the addition of exogenous ADP or overexpression of P2Y1 receptors significantly increased IL-2 mRNA transcription in response to TCR/ CD28 stimulation. Conversely, antagonists or silencing of P2Y1 receptors reduced IL-2 mRNA transcription and attenuated T cell functions. We conclude that P2Y1 and P2X receptors have non-redundant, synergistic functions in the regulation of T cell activation. P2Y1 receptors may represent potential therapeutic targets to modulate T cell function in inflammation and host defense.

show abstract

Section: Discussionmentioning

confidence: 74%

Autocrine stimulation of P2Y1 receptors is part of the purinergic signaling mechanism that regulates T cell activation

Woehrle

Ledderose

Rink

et al. 2019

Purinergic Signalling

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show abstract

“…Clopidogrel attenuated the renal cortical fibrin deposition of rats which underwent five-sixths nephrectomy and effectively prevented the early progression of renal injury 14. Clopidogrel decreased TGF-β mRNA expression levels in mice which had received orthotopic tracheal transplantation 15.…”

Section: Introductionmentioning

confidence: 99%

Clopidogrel Reduces Fibronectin Accumulation and Improves Diabetes-Induced Renal Fibrosis

Zheng

Lian

et al. 2019

Int. J. Biol. Sci.

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Hyperglycemia-induced renal fibrosis causes end-stage renal disease. Clopidogrel, a platelet inhibitor, is often administered to decrease cardiovascular events in diabetic patients. We investigated whether clopidogrel can reduce diabetes-induced renal fibrosis in a streptozotocin-induced type 1 diabetes murine model and fibronectin involvement in this protective response. Diabetic and age-matched controls were sacrificed three months after the onset of diabetes, and additional controls and diabetic animals were further treated with clopidogrel or vehicle for three months. Diabetes induced renal morphological changes and fibrosis after three months. Clopidogrel, administered during the last three months, significantly decreased blood glucose, collagen and fibronectin expression compared to vehicle-treated diabetic mice. Diabetes increased TGF-β expression, inducing fibrosis via Smad-independent pathways, MAP kinases, and Akt activation at three months but returned to baseline at six months, whereas the expression of fibronectin and collagen remained elevated. Our results suggest that activation of TGF-β, CTGF, and MAP kinases are early profibrotic signaling events, resulting in significant fibronectin accumulation at the early time point and returning to baseline at a later time point. Akt activation at the three-month time point may serve as an adaptive response in T1D. Mechanisms of clopidogrel therapeutic effect on the diabetic kidney remain to be investigated as this clinically approved compound could provide novel approaches to prevent diabetes-induced renal disease, therefore improving patients' survival.

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“…It is not clear what causes the elevated levels of RANTES, IL‐4, and IFN‐γ. Medication with antiplatelet drugs 33–38 and statins 39–42 after ischemic stroke may affect concentrations of RANTES, IL‐4, IFN‐γ, and several other cytokines. However, from our results and from what has been described in previous studies, it seems unlikely that the elevated levels are explained solely by these treatments.…”

Section: Discussionmentioning

confidence: 99%

Proinflammatory protein signatures in cryptogenic and large artery atherosclerosis stroke

et al. 2020

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Objectives The cause of ischemic stroke remains unknown, cryptogenic, in 25% of young and middle‐aged patients. We hypothesized that if atherosclerosis is prominent in cryptogenic stroke, it would have a similar proinflammatory protein signature as large artery atherosclerosis (LAA) stroke. Materials & Methods Blood was collected in the acute phase and after 3 months from cryptogenic (n = 162) and LAA (n = 73) stroke patients aged 18–69 years and once from age‐matched controls (n = 235). Cryptogenic stroke was divided into Framingham Risk Score (FRS) quartiles to compare low and high risk of atherosclerosis. Plasma concentrations of 25 proteins were analyzed using a Luminex multiplex assay. The discriminating properties were assessed with discriminant analysis and C‐statistics. Results We identified proteins that separated cryptogenic and LAA stroke from controls (area under the curves, AUCs ≥ 0.85). For both subtypes, RANTES, IL‐4, and IFN‐γ contributed the most at both time points. These associations were independent of risk factors of atherosclerosis. We also identified proteins that separated cryptogenic strokes in the lowest quartile of FRS from those in the highest, and from LAA stroke (AUCs ≥ 0.76), and here eotaxin and MCP‐1 contributed the most. Conclusions The protein signature separating cases from controls was different from the signature separating cryptogenic stroke with low risk of atherosclerosis from those with high risk and from LAA stroke. This suggests that increased RANTES, IL‐4, and IFN‐γ in stroke may not be primarily related to atherosclerosis, whereas increased eotaxin and MCP‐1 in cryptogenic stroke may be markers of occult atherosclerosis as the underlying cause.

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Clopidogrel reduces post-transplant obliterative bronchiolitis

Cited by 17 publications

References 65 publications

Autocrine stimulation of P2Y1 receptors is part of the purinergic signaling mechanism that regulates T cell activation

Autocrine stimulation of P2Y1 receptors is part of the purinergic signaling mechanism that regulates T cell activation

Clopidogrel Reduces Fibronectin Accumulation and Improves Diabetes-Induced Renal Fibrosis

Proinflammatory protein signatures in cryptogenic and large artery atherosclerosis stroke

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