• T cells
• allergy
• epithelial barrier
• inflammation
• metabolism
• microbiota
• omic technologies
• platelets

• Humans
• Inflammation/immunology
• Systems Biology
• Hypersensitivity/immunology
• Chronic Disease
• Animals

• ARADyAL RD16/0006/0015 and RICORS Red de Enfermedades Inflamatorias (REI) RD21 0002 0008; Ministerio de Ciencia, Innovación y Universidades co-financed with FEDER RTI2018-095166-B24 I00. Ministry of Science and Innovation in Spain (PCI2018- 25 092930); co-funded by the European program ERA HDHL-Nutrition and the Epigenome

• Humans
• Inflammatory Bowel Diseases/pathology
• Inflammation/metabolism
• Intestinal Mucosa/metabolism
• Mucositis/pathology
• Leukocytes/metabolism

Inflammatory bowel disease (IBD), Crohn’s disease and ulcerative colitis are chronic inflammatory disorders of the intestines. The underlying inflammation activates the coagulation cascade leading to an increased risk of developing arterial and venous thromboembolic events such as deep vein thrombosis and pulmonary embolism. Patients with IBD are at a 2–3-fold increased risk of developing thromboembolism. This risk increases in patients with active IBD disease, flare-ups, surgery, steroid treatment, and hospitalization. These complications are associated with significant morbidity and mortality making them important in clinical practice. Clinicians should consider the increased risk of thromboembolic events in patients with IBD and manage them with appropriate prophylaxis based on the risk. In this review, we discuss the literature associated with the pathophysiology of thromboembolism in patients with IBD, summarize the studies describing the various thromboembolic events, and the management of thromboembolism in patients with IBD.

Thromboembolism (TE) is an extraintestinal manifestation (EIM) of inflammatory bowel disease (IBD). According to previous pathological reports, the incidence of IBD complicated with TE is as high as 41%. However, this EIM is often overlooked. This review summarizes the results of the relevant clinical studies to date, analyzes the potential prothrombotic risk of IBD drug therapy, and discusses the current status on the treatment and prevention of TE, with an aim to provide a comprehensive reference for clinical work.

• Inflammatory bowel disease
• Thromboembolic events
• Treatment

• Bcr-Abl tyrosine kinase
• Endothelial activation
• Nilotinib
• P-selectin
• Platelet activation
• Thrombosis

• Crohn's disease
• Inflammatory bowel disease
• Motility
• Secretion
• Ulcerative colitis

• Animals
• Gastrointestinal Hormones/metabolism
• Humans
• Immune System/metabolism
• Inflammatory Bowel Diseases/metabolism
• Inflammatory Bowel Diseases/physiopathology
• Neurons/metabolism
• Neuropeptide Y/metabolism
• Pancreatic Polypeptide/metabolism

One of the main tasks of the immune system is to discriminate and appropriately react to “danger” or “non-danger” signals. This is crucial in the gastrointestinal tract, where the immune system is confronted with a myriad of food antigens and symbiotic microflora that are in constant contact with the mucosa, in addition to any potential pathogens. This large number of antigens and commensal microflora, which are essential for providing vital nutrients, must be tolerated by the intestinal immune system to prevent aberrant inflammation. Hence, the balance between immune activation versus tolerance should be tightly regulated to maintain intestinal homeostasis and to prevent immune activation indiscriminately against all luminal antigens. Loss of this delicate equilibrium can lead to chronic activation of the intestinal immune response resulting in intestinal disorders, such as inflammatory bowel diseases (IBD). In order to maintain homeostasis, the immune system has evolved diverse regulatory strategies including additional non-immunological actors able to control the immune response. Accumulating evidence strongly indicates a bidirectional link between the two systems in which the brain modulates the immune response via the detection of circulating cytokines and via direct afferent input from sensory fibers and from enteric neurons. In the current review, we will highlight the most recent findings regarding the cross-talk between the nervous system and the mucosal immune system and will discuss the potential use of these neuronal circuits and neuromediators as novel therapeutic tools to reestablish immune tolerance and treat intestinal chronic inflammation.

• inflammatory bowel disease
• intestinal immune system
• neuropeptide
• oral tolerance
• parasympathetic system
• peptidergic pathway
• sympathetic system

• RANTES promoter
• polymorphism
• ulcerative colitis

Interleukin-17A (IL-17A), the most widely studied member of the IL-17 cytokine family, is a cytokine which emerged to be critical for host defense as well as in the pathogenesis of autoimmune disorders. Moreover, IL-17A is involved in the pathogenesis of cardiovascular diseases, such as atherosclerosis and acute coronary syndrome and in the cardiovascular risk associated with systemic immunological disorders. Consistent with this, we have recently shown that IL-17A increases human and murine platelet response to ADP. In this study we expanded our previous observation and we describe for the first time an in vivo prothrombotic effect of the cytokine. Our results show that IL-17A is synergic with a low FeCl₃ concentration in inducing carotid thrombus in rats and suggest that the effect is likely related to a downregulation of CD39 vascular expression and hydrolyzing activity. Our findings indicate that IL-17A might be an important molecule at the interface between hemostasis and inflammation.

“This paper is dedicated to the memory of Professor Alfredo Colonna”

• ENS
• inflammation
• neurogenic inflammation
• neuropeptides

• Animals
• Cytokines/metabolism
• Enteric Nervous System/immunology
• Enteric Nervous System/metabolism
• Humans
• Intestinal Mucosa/immunology
• Intestinal Mucosa/metabolism
• Neurogenic Inflammation/immunology
• Neurogenic Inflammation/metabolism
• Neuropeptide Y/metabolism
• Vasoactive Intestinal Peptide/metabolism

• R01 DK080684 NIDDK NIH HHS
• R01-DK80684 NIDDK NIH HHS

• Antiplatelet agent
• IBD
• Oxazolone
• TNBS
• clopidogrel

To evaluate the anti-inflammatory effect of antiplatelet agent, clopidogrel, in experimentally induced inflammatory bowel disease (IBD).

TNBS induced Crohn's disease model and oxazolone induced ulcerative colitis model were used to evaluate the role of clopidogrel in IBD. Spargue Dawley female and Wistar male rats were used respectively. The colitis was induced by a single intra-colonic application of TNBS (0.25 ml, 120 mg/ml in 50% ethanol) and oxazolone (450 μl 5% oxazolone in 50% ethanol). Rats were divided into four groups (n=6) in each model namely normal control, sham control, test and standard group. Drug treatment was carried out for 21 days. After 21 days, animals were sacrificed and evaluated for weight change, colon mucosal damage index (CMDI), disease activity Index (DAI) and myeloperoxidase (MPO) activity.

Results showed that clopidogrel provided significant protection against mucosal damage in both the models of IBD. It significantly reduced (P<0.05) the decrease in body weight and CMDI, DAI and MPO scores.

The results indicate that clopidogrel may be effective in treatment of Crohn's disease and ulcerative colitis. Platelet inhibition may be one of the mechanism for effectiveness of clopidogrel in the treatment of IBD.

• Antiplatelet agent
• IBD
• Oxazolone
• TNBS
• clopidogrel

Although angiogenesis is viewed as a fundamental component of inflammatory bowel disease (IBD) pathogenesis, we presently lack a thorough knowledge of the cell type(s) involved in its induction and maintenance in the inflamed intestinal mucosa. This study aimed to determine whether platelet (PLT) adhesion to inflamed intestinal endothelial cells of human origin may favour angiogenesis. Unstimulated or thrombin-activated human PLT were overlaid on resting or tumour necrosis factor (TNF)-α-treated human intestinal microvascular endothelial cells (HIMEC), in the presence or absence of blocking antibodies to either vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, integrin α_vβ₃, tissue factor (TF) or fractalkine (FKN). PLT adhesion to HIMEC was evaluated by fluorescence microscopy, and release of angiogenic factors (VEGF and soluble CD40L) was measured by ELISA. A matrigel tubule formation assay was used to estimate PLT capacity to induce angiogenesis after co-culturing with HIMEC. TNF-α up-regulated ICAM-1, α_vβ₃ and FKN expression on HIMEC. When thrombin-activated PLT were co-cultured with unstimulated HIMEC, PLT adhesion increased significantly, and this response was further enhanced by HIMEC activation with TNF-α. PLT adhesion to HIMEC was VCAM-1 and TF independent but ICAM-1, FKN and integrin α_vβ₃ dependent. VEGF and sCD40L were undetectable in HIMEC cultures either before or after TNF-α stimulation. By contrast, VEGF and sCD40L release significantly increased when resting or activated PLT were co-cultured with TNF-α-pre-treated HIMEC. These effects were much more pronounced when PLT were derived from IBD patients. Importantly, thrombin-activated PLT promoted tubule formation in HIMEC, a functional estimate of their angiogenic potential. In conclusion, PLT adhesion to TNF-α-pre-treated HIMEC is mediated by ICAM-1, FKN and α_vβ₃, and is associated with VEGF and sCD40L release. These findings suggest that inflamed HIMEC may recruit PLT which, upon release of pro-angiogenic factors, actively contribute to inflammation-induced angiogenesis.

• trefoil factor family 3

• platelets
• inflammation
• p2y₁
• p2y₁₂
• p-selectin
• gpiib/iiia
• cd40
• s1p
• ppar

• Animals
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/therapeutic use
• Autoimmune Diseases/drug therapy
• Blood Platelets/drug effects
• Blood Platelets/immunology
• Humans
• Hypersensitivity/drug therapy
• Inflammation/drug therapy
• Leukocytes/drug effects
• Leukocytes/immunology
• Platelet Aggregation Inhibitors/pharmacology
• Platelet Aggregation Inhibitors/therapeutic use
• Receptors, Cell Surface/drug effects

• Cell Adhesion
• Cytokines/biosynthesis
• Cytokines/metabolism
• Humans
• Immune System/physiopathology
• Immunotherapy
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/therapy
• Leukocytes

AIM: To observe if the total amount of platelet P-selectin (tP-selectin) in patients with inflammatory bowel disease (IBD) was related to disease entity or activity, 5-aminosalicylic acid (5-ASA) medication or gender.

METHODS: tP-selectin was measured by immunoassay in seventeen IBD patients and twelve healthy controls.

RESULTS: Compared to controls, there was no difference of tP-selectin in patients related to disease entity or activity and 5-ASA medication. When the groups were split according to gender the male patient group showed higher levels of tP-selectin compared to male controls (153 ng/mL vs 94 ng/mL, P< 0.05).

CONCLUSION: Increased tP-selectin levels may alter the inflammatory response and susceptibility to thromboembolic disease. As previously shown with soluble P-selectin, tP-selectin shows gender dependent differences important to consider in future studies.

• Platelet
• P-selectin
• Inflammatory bowel disease
• 5-aminosalicylic acid
• Gender

• Adult
• Aged
• Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
• Blood Platelets/chemistry
• Colitis, Ulcerative/blood
• Colitis, Ulcerative/drug therapy
• Colitis, Ulcerative/physiopathology
• Crohn Disease/blood
• Crohn Disease/drug therapy
• Crohn Disease/physiopathology
• Disease Progression
• Disease Susceptibility
• Female
• Humans
• Male
• Mesalamine/therapeutic use
• Middle Aged
• P-Selectin/blood
• Risk Factors
• Sex Characteristics
• Thromboembolism/epidemiology

• Adenosine Diphosphate/pharmacology
• Adult
• Blood Coagulation/physiology
• Collagen/pharmacology
• Enzyme-Linked Immunosorbent Assay
• Epinephrine/pharmacology
• Female
• Humans
• Inflammatory Bowel Diseases/blood
• Male
• Platelet Aggregation/drug effects
• Platelet Aggregation/physiology
• Severity of Illness Index

• Adult
• Aged
• Albendazole/therapeutic use
• Anthelmintics/therapeutic use
• Blood Platelets/metabolism
• Echinococcosis/blood
• Echinococcosis/drug therapy
• Female
• Gene Expression Regulation/physiology
• Humans
• Male
• Middle Aged
• P-Selectin/genetics
• P-Selectin/metabolism
• Platelet Activation/physiology

AIM: To investigate the effect of dermatan sulfate (DS) derivatives on platelet surface P-selectin expression and blood activated protein C (APC) activity in patients with inflammatory bowel disease (IBD), and to clarity the anti-inflammatory mechanism of DS derivatives.

METHODS: Dermatan sulfate (DS) was sulfated with chlorosulfonic acid to prepare polysulfated dermatan sulfate (PSDS). The major disaccharides of DS and PSDS were determined by ¹H nuclear magnetic resonance spectroscopy (¹H-NMR) and ¹³C-NMR. Both DS and PSDS were depolymerized with hydrogen peroxide. The fragments were separated by gel filtration chromatography. The effects of DS derivatives on P-selectin expression were assayed by ELISA method, and blood APC activity was assayed by the synthetic chromogenic substrate method.

RESULTS: The major disaccharides of DS and PSDS were IdoA-1→3-GalNAc-4-SO₃ and IdoA-2SO₃-1→3-GalNAc4, 6-diSO₃, respectively. Compared with the adenosine diphosphate stimulated group and IBD control group, DS and its derivatives all had significant inhibitory effects on P-selectin expression (P < 0.01), but there was no difference between DS-derived oligosaccharides (DSOSs) and PSDS-derived oligosaccharides (PSDSOSs). The experiments on APC activity showed that DS and its derivatives all enhanced APC activity. The most active DSOS was the one with a relative molecular weight (M_r) of 4825, which enhanced the APC activity from 106.5% ± 11.5% to 181.8% ± 22.3% (P < 0.01). With the decrease of M_r, the activity of DSOSs decreased gradually. The effect of PSDS on APC activity enhancement was more significant than that of DS, and the APC activity was raised to 205.2% ± 22.1% (P < 0.01). All the PSDSOSs were more active than DSOSs on the basis of comparable M_r. With the decrease of M_r, the activity of PSDSOSs increased gradually, and the most active PSDSOS was PSDSOS₃ with M_r of 2749, which enhanced the APC activity to 331.2% ± 27.8% (P < 0.01), then the activity of PSDSOSs decreased gradually.

CONCLUSION: DS and its derivatives can significantly inhibit P-selectin expression on platelet surface, but the effect has no correlation with DS molecular mass and sulfation. The effect of DS or its derivatives on APC activity at molecular level involves complex mechanisms that depend on the molecular mass, the degree of sulfation, and the heterogeneous composition of DS. On the same molecular size, the higher the degree of DS sulfation, the more significant the effect on enhancing APC activity.

• Anticoagulants/chemistry
• Anticoagulants/pharmacology
• Blood Platelets/drug effects
• Blood Platelets/immunology
• Blood Platelets/metabolism
• Carbon Isotopes
• Dermatan Sulfate/chemistry
• Dermatan Sulfate/pharmacology
• Humans
• In Vitro Techniques
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/metabolism
• Magnetic Resonance Spectroscopy
• P-Selectin/metabolism
• Protein C/metabolism
• Protons
• Sulfates/chemistry
• Sulfates/pharmacology

AIM: To explore the abnormal function of platelets and the role of angelica sinensis injection (ASI) in patients with ulcerative colitis (UC).

METHODS: In 39 patients with active UC, 25 patients with remissive UC and 30 healthy people, α-granule membrane protein (GMP-140) and thromboxane B₂ (TXB₂) were detected by means of ELISA, 6-keto-PGF_1a was detected by radioimmunoassay, platelet count (PC) and 1 min platelet aggregation rate (1 min PAR) were detected by blood automatic tester and platelet aggregation tester respectively, and von Willebrand factor related antigen (vWF:Ag) was detected by the means of monoclonal-ELISA. The 64 patients with UC were divided into two therapy groups. After routine treatment and angelica sinensis injection (ASI) + routine treatment respectively for 3 weeks, all these parameters were also detected.

RESULTS: The PC, 1 min PAR and levels of GMP-140, TXB₂, and vWF:Ag in active UC were significanrly higher than those in remissive UC and normal controls (P < 0.05-0.01).Meanwhile, 1 min PAR and levels of GMP-140, TXB₂, and vWF:Ag in remissive UC were still significantly higher than those in normal controls (P < 0.05). Furthermore, 6-keto-PGF_1a level in active and remissive UC was remarkably lower than that in normal control (P < 0.05-0.01). These parameters except 6-keto-PGF_1a were significantly improved after the treatment in ASI therapy group (P < 0.05-0.01), whereas they all were little changed in routine therapy group (P > 0.05).

CONCLUSION: Platelets can be significantly activated in UC, which might be related with vascular endothelium injury and imbalance between TXB₂ and 6-keto-PGF_1a in blood. ASI can significantly inhibit platelet activation, relieve vascular endothelial cell injury, and improve microcirculation in UC.

• Adult
• Aged
• Angelica sinensis
• Blood Platelets/drug effects
• Blood Platelets/physiology
• Colitis, Ulcerative/drug therapy
• Colitis, Ulcerative/physiopathology
• Female
• Humans
• Male
• Middle Aged
• Phytotherapy
• Plant Preparations/administration & dosage
• Platelet Aggregation/drug effects
• Platelet Aggregation/physiology

• Adjuvants, Immunologic/administration & dosage
• Adjuvants, Immunologic/therapeutic use
• Adult
• Cytokines/blood
• Cytokines/immunology
• Female
• Humans
• Infusions, Intravenous
• Male
• Middle Aged
• Nicotine/administration & dosage
• Nicotine/therapeutic use
• Reactive Oxygen Species/blood
• Reactive Oxygen Species/immunology
• Renal Insufficiency/blood
• Renal Insufficiency/immunology
• Smoking/blood
• Smoking/immunology
• Smoking Prevention

• Blood Platelets/cytology
• Blood Platelets/immunology
• Blood Platelets/metabolism
• CD40 Antigens/metabolism
• CD40 Ligand/metabolism
• Cell Adhesion/immunology
• Cells, Cultured
• Chemokine CCL5/metabolism
• Coculture Techniques
• Endothelium, Vascular/cytology
• Endothelium, Vascular/immunology
• Humans
• Inflammatory Bowel Diseases/etiology
• Inflammatory Bowel Diseases/immunology
• Intercellular Adhesion Molecule-1/metabolism
• Interleukin-8/metabolism
• MAP Kinase Signaling System/immunology
• Microcirculation/immunology
• Mitogen-Activated Protein Kinases/metabolism
• Platelet Aggregation
• T-Lymphocytes/cytology
• Up-Regulation/immunology
• Vascular Cell Adhesion Molecule-1/metabolism
• p38 Mitogen-Activated Protein Kinases

• DK30399 NIDDK NIH HHS
• DK50984 NIDDK NIH HHS
• DK58867 NIDDK NIH HHS

• Animals
• Catecholamines/metabolism
• Humans
• Immune System/physiology
• Immune System Diseases/immunology
• Immune System Diseases/metabolism
• Immune System Diseases/physiopathology
• Leukocytes/immunology
• Leukocytes/metabolism
• Neuroimmunomodulation/physiology
• Neuropeptide Y/metabolism
• Neurotransmitter Agents/antagonists & inhibitors
• Neurotransmitter Agents/immunology
• Signal Transduction/immunology
• Sympathetic Nervous System/metabolism