Inhibition of platelet-activating factor, intercellular adhesion molecule 1 and platelet endothelial cell adhesion molecule 1 reduces experimental pancreatitis-associated gut endothelial barrier dysfunction

Abstract

Treatment with lexipafant and monoclonal antibodies against ICAM-1 or PECAM-1 reduced the severity of pancreatitis-associated gut endothelial dysfunction, and decreased systemic concentrations of IL-1 and local leucocyte recruitment.

Influence of the Platelet-Activating Factor Receptor Antagonist BB-882 on Intra-Abdominal Adhesion Formation in Rats

“…It can act as an intercellular signal responsible for cell communication and an inflammatory mediator involved in the pathogenesis of inflammation. The major contributions of PAF during the inflammatory reaction include acting as an inflammatory stimulator on the leukocyte system, causing leukocyte rolling on the endothelium, adhesion and passage through inter-endothelial cells to the interstitium [18]. Leukocyte-endothelial cell interaction leads to excessive movement of leukocytes to the tissues, as well as endothelial barrier compromise, responsible for the initiation of the inflammatory reaction, serious tissue injury and organ dysfunction.…”

Multimodal management — of value in fulminant acute pancreatitis?

“…Haraldsen/Sun/Börjesson/Olanders/Lasson/ Andersson Sterile saline or saline containing the PAF inhibitor (PAFI) lexipafant (5.0 mg/kg), anti-PECAM-1-MAb (0.5 mg/kg) or both in a volume of 0.2 ml was injected intraperitoneally [26], and NAC (0.2 g/kg) was administered intravenously 1 or 3 h after sham operation or induction of acute pancreatitis, i.e. at a time point when endothelial barrier permeability was impaired and organ dysfunction developed [24,26].…”

“…Previous experimental studies have indicated beneficial effects of both pretreatment and early treatment strategies using an inhibitor of PAF (a pro-inflammatory mediator and intercellular signaling substance), monoclonal antibodies against the platelet endothelial cell adhesion molecule 1 (PECAM-1, a key participant in the adhesion cascade leading to extravasation of leukocytes) and N-acetyl-L-cystein (NAC, an oxygen free radical scavenger) [24,26,[30][31][32][33]. In order to better mimic the clinical situation, the present study aimed at evaluating endothelial permeability and protease inhibitors following late treatment with these agents, either alone or in combination, i.e.…”

Mast Cells Contribute to Early Pancreatitis-Induced Systemic Endothelial Barrier Dysfunction

“…Capillary endothelial permeability was assessed by leakage of 125 I-HSA from blood into the tissues and expressed as isotopic flux, defined as the proportion of 125 I radioactivity per gram of tissue sample as compared with 125 I radioactivity per gram of blood as described previously [10]. To assay for the possible redistribution of tissue blood, tissue blood content was calculated by the proportion of 131 I radioactivity per gram of tissue and 131 I radioactivity per gram of blood.…”

“…Pancreatic sepsis is another common cause of major morbidity and mortality in severe AP [9]. The infectious complications are often caused by bacteria of primarily enteric origin and experimental studies have demonstrated that failure of the gastrointestinal tract and its barrier function occurs in AP and results in increased permeability and enteric bacterial translocation into extra-intestinal sites and the systemic circulation (gut origin sepsis) [9,10]. These observations have been supported by clinical observations of an increase in gut barrier permeability during the early course of severe AP [11,12].…”