Mediators of vascular leak in dengue infections

Abstract

Although plasma leakage is the hallmark of severe dengue infections the factors that cause increased vascular permeability have not been identified. As platelet activating factor (PAF), lipid mediators and cytokines are associated with increase in vascular permeability, we set out to investigate the role of these mediators in acute dengue infection. Levels of inflammatory lipid mediators and cytokines were initially evaluated in 25 patients with confirmed acute dengue infection and 12 healthy individuals. After determining which inflammatory mediators were associated with severe dengue, serial assays of the above lipid mediators, and cytokines were done in an additional 36 patients in serum samples collected 12 hours apart throughout the course of their hospital stay. We found that PAF levels were significantly higher in patients (p=0.001) when compared to healthy individuals and that PAF levels rose just before the onset of the critical phase. PAF values of >100ng/ml were associated with reduced expression of gap junction proteins leading to increased vascular permeability. A similar effect was seen with serum from patients with dengue infection which was reversed by a PAF receptor antagonist. S1P levels which are associated with increasing the integrity of the endothelial barrier were significantly reduced in patients with DHF. Serum IL-10, TNFα and IL-1β levels were elevated in patients with DHF and followed the same patterns as PAF. In conclusion, our results show that PAF is likely to be a potent mediator of vascular leak in dengue and use of PAF blockers could be therapeutically useful.