Abstract
Phospholipase A2 (PLA2) regulates eicosanoids and platelet activating factor production and plays an important role in regulating critical mediators in inflammatory diseases. PLA2 activity is significantly enhanced during sepsis and multiple organ failure and therefore offers an intriguing target in developing anti-inflammatory drugs. We have identified several kinds of biflavonoids with inhibition of PLA2 activity, which are isolated from plant sources, as potential putative anti-inflammatory and anti-septic agents. Two of them (bilobetin and ginkgetin) potently inhibit several kinds of type II 14 kDa PLA2 but exhibits a weaker inhibition of type I 14 kDa PLA2 using 2-linol-[1-14C]PE as substrate. These inhibitors have been tested for their ability to inhibit the production of TNF-α and the formation of two enzymes, inducible NO synthase (iNOS) and inducible cyclooxygenase (COX-2) using LPS-stimulated Raw264.7 macrophages as assay systems. In the Raw264.7 cells, bacterial LPS induced the protein of COX-2 and iNOS as well as TNF-α release. The inhibitors consistently inhibited the production of TNF-α in a dose-dependent manner. The inhibitory effect of TNF-α was observed at concentrations similar to those related by PLA2. Moreover, treatment of cells with bilobetin and ginkgetin inhibited nitrite production, one of the stable end products of NO production measured in culture supernatants. The inhibition of NO products is caused by decreased iNOS protein levels as assessed by immunoblotting using a specific anti-iNOS antibody. The inhibitors treatment also reduce the expression of COX-2 protein level to about 80% in LPS-stimulated cells, which coincided with reduction of the iNOS protein. These results suggest that inhibition of PLA2 and subsequent metabolism of arachidonic acid by COX-2 contribute to LPS-induced NOS pathway including TNF-α in Raw264.7 cells and these two inhibitors may develop as useful agents for anti-inflammation.
Highlights
Ill patients requiring intensive care are at risk of iatrogenic ocular damage
Intensive Care Unit (ICU) management of critically ill patients often includes the requirement for tracheostomy and feeding access, most often a pecutaneous endoscopic gastrostomy (PEG)
Percutaneous tracheostomy is performed routinely in many medical intensive care unit (ICU) settings, in high risk surgical and trauma patients who often have unstable cervical spine injury and tissue edema, direct visualization of the cervical structures and trachea is imperative during tracheostomy
Summary
Ill patients requiring intensive care are at risk of iatrogenic ocular damage. We designed an experimental situation where external cardiac pressure conditions were controlled and adjusted to physiological extremes to mimic clinically relevant situations, while cardiac performance was assessed using left ventricular pressure–volume relationships (LVPVR) which are relatively preload and afterload independent This prospective, controlled study was undertaken to evaluate the response to therapy aimed at achieving supranormal cardiac and oxygen transport values (cardiac index >4.5 l/min/m2, oxygen delivery >600 l/min/m2, and oxygen consumption >170 l/min/m2) in patients older than 60 or with previous severe cardiorespiratory illnesses, who have undergone elective extensive ablative surgery planned for carcinoma or abdominal aortic aneurism. Whilst some human studies conducted in the critically ill and in high risk surgical patients have suggested that dopexamine may cause an increase in tonometrically measured gastric intra-mucosal pH (pHi) and an improvement in clinical outcome, this has not been confirmed in other randomised trials. In the present study the association of platelet function to inflammatory markers indicating disease severity was investigated
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