Oxidative stress and thromboxane-dependent platelet activation in inflammatory bowel disease: effects of anti-TNF-α treatment.
Patients with inflammatory bowel disease (IBD) are at higher risk of venous thromboembolism and coronary artery disease despite having a lower burden of traditional risk factors. Platelets from IBD patients release more soluble CD40 ligand (CD40L), and this has been implicated in IBD platelet hyper-activation. We here measured the urinary F2-isoprostane 8-iso-prostaglandin (PG)2α (8-iso-PGF2α), urinary 11-dehydro-thromboxane (TX) B2 (11-dehydro-TXB2) and plasma CD40L in IBD patients, and explored the in vitro action of anti-tumour necrosis factor (TNF)-α antibody infliximab on IBD differentiating megakaryocytes. Urinary and blood samples were collected from 124 IBD patients and 37 healthy subjects. Thirteen IBD patients were also evaluated before and after 6-week infliximab treatment. The in vitro effect of infliximab on patient-derived megakaryocytes was evaluated by immunoflorescence microscopy and by flow cytometry. IBD patients had significantly (p<0.0001) higher urinary 8-iso-PGF2α and 11-dehydro-TXB2 as well as plasma CD40L levels than controls, with active IBD patients displaying higher urinary and plasma values when compared to inactive patients in remission. A 6-week treatment with infliximab was associated with a significant reduction of the urinary excretion of 8-iso-PGF2α and 11-dehydro-TXB2 (p=0.008) and plasma CD40L (p=0.001). Infliximab induced significantly rescued pro-platelet formation by megakaryocytes derived from IBD patients but not from healthy controls. Our findings provide evidence for enhanced in vivo TX-dependent platelet activation and lipid peroxidation in IBD patients. Anti-TNF-α therapy with infliximab down-regulates in vivo isoprostane generation and TX biosynthesis in responder IBD patients. Further studies are needed to clarify the implication of infliximab induced-proplatelet formation from IBD megakaryocytes.
Antonio
A
Di Sabatino
Francesca
F
Santilli
Marco
M
Guerci
Paola
P
Simeone
Sandro
S
Ardizzone
Alessandro
A
Massari
Paolo
P
Giuffrida
Romina
R
Tripaldi
Alessandro
A
Malara
Rossella
R
Liani
Evelyn
E
Gurini
Nicola
N
Aronico
Alessandra
A
Balduini
Gino Roberto
GR
Corazza
Prof. Giovanni Davì, Internal Medicine and Center of Excellence on Aging, "G. D'Annunzio" University Foundation, Via Colle dell'Ara, 66013 Chieti, Italy, E-mail: gdavi@unich.it.
Giovanni
G
Davì
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050197:Atherosclerosis / Q000517:prevention & control; D023201:CD40 Ligand / Q000097:blood; D003093:Colitis, Ulcerative / Q000097:blood / Q000188:drug therapy; D003424:Crohn Disease / Q000097:blood / Q000188:drug therapy; D005260:Female; D005765:Gastrointestinal Agents / Q000627:therapeutic use; D006801:Humans; D066298:In Vitro Techniques; D015212:Inflammatory Bowel Diseases / Q000097:blood* / Q000150:complications / Q000188:drug therapy*; D000069285:Infliximab / Q000627:therapeutic use*; D015227:Lipid Peroxidation; D008297:Male; D008533:Megakaryocytes / Q000187:drug effects / Q000473:pathology; D008875:Middle Aged; D018384:Oxidative Stress; D015539:Platelet Activation / Q000187:drug effects; D013931:Thromboxanes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D055815:Young Adult
D005765:Gastrointestinal Agents; D013931:Thromboxanes; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D000069285:Infliximab
CD40 ligand; Crohn’s disease; infliximab; lipid peroxidation; platelet activation; ulcerative colitis