Based on the preceding discussion, I propose that PUFAs need to be administered along with albumin to enhance formation of lipoxins, resolvins and protectins to derive the benefit of albumin therapy in the critically ill [16,17].
Beneficial actions of albumin are limited by: availability of PUFAs in the liver and other tissues; formation of adequate amounts of lipoxins, resolvins and protectins from PUFAs; activity of cyclooxygenase and lipoxygenase enzymes; circulating levels of TNFα and other cytokines that interfere with the formation of arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid and induce hypoalbuminemia; enhanced formation of reactive oxygen species that peroxidize PUFAs and thus reduce their availability; and formation of proinflammatory prostaglandins that antagonize actions of lipoxins, resolvins and protectins [16,17] (see Figure 1). In view of the interactions among albumin, PUFAs, free radicals, prostaglandins, lipoxins, resolvins and protectins, nitric oxide (PUFAs and lipoxins enhance endothelial nitric oxide generation and protect endothelial cells), vascular endothelial growth factor, placental growth factor and cytokines, it is not surprising that albumin infusion alone is unlikely to be of benefit in sepsis. Hence, albumin needs to be given along with PUFAs and lipoxins to antagonize the actions of proinflammatory molecules and restore homeostasis [16,17].
Adipose-fatty acid binding protein (A-FABP), which induces insulin resistance and whose levels are increased in the critically ill [18], is a carrier of fatty acids and is expressed primarily in adipocytes and macrophages. A-FABP regulates systemic insulin sensitivity and lipid and glucose metabolism [19]. Mice deficient in A-FABP are resistant to the development of hyperinsulinemia, hyperglycemia and insulin resistance [18].
A-FABP can be linked to the expression of Toll-like receptors, macrophage activation, synthesis and release of proinflammatory cytokines IL-6 and TNFα, activation of cyclooxygenase-2 expression and eicosanoid synthesis, events that cause insulin resistance and initiation and progression of inflammation and sepsis. PUFAs and lipoxins, resolvins and protectins suppress A-FABP expression, inhibit macrophage and cyclooxygenase-2 activation, and decrease production of proinflammatory cytokines, and thus decrease insulin resistance and resolve inflammation and augment recovery from sepsis [18,19]. Hence, serial measurement of both proinflammatory and anti-inflammatory molecules and correlation of their levels with the progression to or recovery from (or both) sepsis and other inflammatory processes may help to predict prognosis in inflammatory conditions and eventually could lead to the development of new therapeutic strategies.