High-Dose Vitamin C Alleviates Pancreatic Necrosis by Inhibiting Platelet Activation Through the CXCL12/CXCR4 Pathway in Severe Acute Pancreatitis

Background Platelet activation in the early stage of pancreatitis is the key step developing into pancreatic necrosis. Studies suggested that vitamin C (Vit C) can inhibit platelet activity by targeting CXCL12/CXCR4 pathway. High-dose Vit C were showed to reduce pancreatic necrosis in severe acute pancreatitis (SAP) but the mechanism remains unclear. Here we speculate high-dose Vit C reduce pancreatic necrosis by inhibiting platelet activation through downregulating CXCL12/CXCR4 pathway. Methods The pancreatic microcirculation of rats was observed by intravital microscopy. The platelet activity of SAP rats treated with or without high-dose Vit C was analyzed by platelet function test. Besides, the activity of platelets preincubated with high-dose Vit C or vehicle from SAP patients was also evaluated. Then, the TFA (CXCR4 agonist) and rCXCL12 were used to neutralize the effect of high-dose Vit C in SAP rats treated with high-dose Vit C. Meanwhile, the levels of enzymes and inflammatory cytokines in rat plasma, and rats’ pancreatic histopathology and mortality were assessed. Results Platelets from animals and patients with SAP are more sensitive to agonists and are more easily activated. Administration of high-dose Vit C significantly ameliorated excessive activation of platelets in SAP rats, ultimately increasing the microvessel density and inducing microthrombus and blood stasis; these results were consistent with clinical sample analysis. Moreover, high-dose Vit C significantly inhibited the release of amylase, lipase, TNF-α, and IL-6 in SAP rat plasma, reducing pancreatic damage and the mortality of SAP rats. However, using TFA and rCXCL12 significantly reversed the effect of high-dose Vit C on excessive activation of platelets, aggravating microcirculation impairment and pancreatic damage. Conclusion The present study suggests that high-dose Vit C can ameliorate pancreatic necrosis by improving microcirculation disorders of SAP. For the first time, the underlying mechanism is related with inhibiting platelet activation through the CXCL12/CXCR4 pathway.

[1]  X. Wang,et al.  Identification of Early Derangements of Coagulation, Hematological and Biochemical Profiles in Patients with Acute Pancreatitis. , 2022, Clinical biochemistry.

[2]  Vikesh K. Singh,et al.  Immune enhancement in patients with predicted severe acute necrotising pancreatitis: a multicentre double-blind randomised controlled trial , 2022, Intensive Care Medicine.

[3]  F. Underwood,et al.  Global Incidence of Acute Pancreatitis is Increasing Over Time: A Systematic Review and Meta-Analysis. , 2021, Gastroenterology.

[4]  Huanlin Wu,et al.  Naringenin Inhibits Platelet Activation and Arterial Thrombosis Through Inhibition of Phosphoinositide 3-Kinase and Cyclic Nucleotide Signaling , 2021, Frontiers in Pharmacology.

[5]  H. Schunkert,et al.  Efficacy and Safety of Revacept, a Novel Lesion-Directed Competitive Antagonist to Platelet Glycoprotein VI, in Patients Undergoing Elective Percutaneous Coronary Intervention for Stable Ischemic Heart Disease: The Randomized, Double-blind, Placebo-Controlled ISAR-PLASTER Phase 2 Trial. , 2021, JAMA cardiology.

[6]  N. Zhu,et al.  Targets of Vitamin C With Therapeutic Potential for Cardiovascular Disease and Underlying Mechanisms: A Study of Network Pharmacology , 2021, Frontiers in Pharmacology.

[7]  E. Mao,et al.  High-dose vitamin C alleviates pancreatic injury via the NRF2/NQO1/HO-1 pathway in a rat model of severe acute pancreatitis. , 2020, Annals of translational medicine.

[8]  Feng Zhang,et al.  Overexpressed microRNA‐103a‐3p inhibits acute lower‐extremity deep venous thrombosis via inhibition of CXCL12 , 2019, IUBMB life.

[9]  A. Abrantes,et al.  Murine Models of Acute Pancreatitis: A Critical Appraisal of Clinical Relevance , 2019, International journal of molecular sciences.

[10]  Guoqiang Chen,et al.  Sin1 (Stress-Activated Protein Kinase-Interacting Protein) Regulates Ischemia-Induced Microthrombosis Through Integrin &agr;IIb&bgr;3-Mediated Outside-In Signaling and Hypoxia Responses in Platelets , 2018, Arteriosclerosis, thrombosis, and vascular biology.

[11]  P. Marik.  Vitamin C for the treatment of sepsis: The scientific rationale , 2018, Pharmacology & therapeutics.

[12]  H. Gooszen,et al.  Impact of characteristics of organ failure and infected necrosis on mortality in necrotising pancreatitis , 2018, Gut.

[13]  P. Proost,et al.  The unique structural and functional features of CXCL12 , 2018, Cellular & Molecular Immunology.

[14]  S. Vlachos,et al.  E and P Selectins as Potential Markers in the Assessment of the Severity of Acute Pancreatitis , 2018, Pancreas.

[15]  J. Tenhunen,et al.  HMGB1 and Histones Play a Significant Role in Inducing Systemic Inflammation and Multiple Organ Dysfunctions in Severe Acute Pancreatitis , 2017, International journal of inflammation.

[16]  X. Ming,et al.  A Naphthalenic Derivative ND-1 Inhibits Thrombus Formation by Interfering the Binding of Fibrinogen to Integrin αIIbβ3 , 2016, BioMed research international.

[17]  M. Levine,et al.  Vitamin C: the known and the unknown and Goldilocks. , 2016, Oral diseases.

[18]  M. Chatterjee,et al.  Role of chemokine receptors CXCR4 and CXCR7 for platelet function. , 2015, Biochemical Society transactions.

[19]  S. Scala.  Molecular Pathways: Targeting the CXCR4–CXCL12 Axis—Untapped Potential in the Tumor Microenvironment , 2015, Clinical Cancer Research.

[20]  A. Chauhan,et al.  Endothelial PPAR-&ggr; Protects Against Vascular Thrombosis by Downregulating P-Selectin Expression , 2015, Arteriosclerosis, thrombosis, and vascular biology.

[21]  A. Poole,et al.  SDF-1α is a novel autocrine activator of platelets operating through its receptor CXCR4 , 2015, Cellular signalling.

[22]  G. Mai,et al.  N-Acetylcysteine Improves Pancreatic Microcirculation and Alleviates the Severity of Acute Necrotizing Pancreatitis , 2013, Gut and liver.

[23]  M. Burdick,et al.  Plasma CXCL12 Levels as a Predictor of Future Stroke , 2012, Stroke.

[24]  A. Dabrowski,et al.  Platelet Activation in Acute Pancreatitis , 2012, Pancreas.

[25]  B. Lindkvist,et al.  P‐selectin mediates neutrophil rolling and recruitment in acute pancreatitis , 2012, The British journal of surgery.

[26]  Pallavi Sachdev,et al.  Discovery of a CXCR4 agonist pepducin that mobilizes bone marrow hematopoietic cells , 2010, Proceedings of the National Academy of Sciences.

[27]  M. Büchler,et al.  Targeting P-selectin in acute pancreatitis , 2010, Expert opinion on therapeutic targets.

[28]  C. Ellis,et al.  Impaired microvascular perfusion in sepsis requires activated coagulation and P-selectin-mediated platelet adhesion in capillaries , 2010, Intensive Care Medicine.

[29]  J. Werner,et al.  P-Selectin Inhibition Reduces Severity of Acute Experimental Pancreatitis , 2009, Pancreatology.

[30]  Chen Huang,et al.  Emodin and baicalein inhibit pancreatic stromal derived factor-1 expression in rats with acute pancreatitis. , 2009, Hepatobiliary & pancreatic diseases international : HBPD INT.

[31]  Roberto Weigert,et al.  Intravital Two‐Photon Microscopy for Studying the Uptake and Trafficking of Fluorescently Conjugated Molecules in Live Rodents , 2008, Traffic.

[32]  T. Tsuda,et al.  Ascorbic acid deficiency stimulates hepatic expression of inflammatory chemokine, cytokine-induced neutrophil chemoattractant-1, in scurvy-prone ODS rats. , 2006, Journal of nutritional science and vitaminology.

[33]  C. Stefanadis,et al.  Vitamin C affects thrombosis/ fibrinolysis system and reactive hyperemia in patients with type 2 diabetes and coronary artery disease. , 2003, Diabetes care.

[34]  Z. Wajda,et al.  Microcirculatory disturbances of the pancreas in cerulein-induced acute pancreatitis in rats with reference to L-arginine, heparin, and procaine treatment. , 1997, Pharmacological research.

[35]  J. Devière,et al.  Interleukin 10 prevents necrosis in murine experimental acute pancreatitis. , 1995, Gastroenterology.

[36]  K. Messmer,et al.  Pancreatic ischaemia in experimental acute pancreatitis: Mechanism, significance and therapy , 1990, The British journal of surgery.

[37]  C. Alessandri,et al.  Influence of ascorbic acid on platelet aggregation in vitro and in vivo. , 1982, Atherosclerosis.