Platelet-activating factor (PAF) is a potent and versatile mediator of inflammation that is produced by numerous cell types and tissues, and particularly by leukocytes. PAF acts on a single receptor (PAFR) that may be expressed on the plasma membrane or the outer leaflet of the nucleus of various cell types, but especially leukocytes, platelets, and endothelial cells. The endogenous release of PAF may account for several of the manifestations of acute inflammation. The administration of PAF to rodents or humans reproduces many features of the systemic inflammatory response syndrome, including hypotension, increased vascular permeability, hemoconcentration, cytokine release, and shock.
Dengue fever and dengue shock or hemorrhagic syndromes (DSS) are mosquito-borne diseases caused by 1 of 4 serotypes of Dengue virus (DEN 1–4). There are an estimated 50–100 million cases of dengue fever and 20,000 deaths annually mostly in tropical and subtropical regions of the world. The large number of infected individuals, the lack of clinical or laboratory markers that indicate which patients will develop severe disease, and the lack of specific treatment place an enormous burden on health systems of low-income countries. Treatment of dengue fever and of the severe forms of dengue infection is supportive only.
DSS is defined as fever with hemorrhage manifestations, thrombocytopenia, and hemoconcentration or other signs of plasma leakage. Severe dengue infection is characterized by increased vascular permeability, altered number of leucocytes, increased hematocrit, thrombocytopenia, and varying degree of hemorrhage. The extensive plasma leakage in various serous cavities of the body may result in profound and intractable shock. Hemorrhage, when it occurs, may contribute to hypotension. These features remarkably resemble the pathophysiological changes observed after the systemic activation of PAFR in experimental animals.
This data provide strong evidence of the involvement of PAFR in the pathogenesis of experimental dengue infection in mice. It also suggest that therapeutic use of PAFR antagonists may be feasible in humans, as this class of compounds prevents the manifestations and lethality of dengue infection even when given days after the onset of disease. The PAFR antagonist UK-74,505 used in this study has a good safety profile and has been shown to effectively block the PAFR in humans when given orally. It is possible that therapeutic use of PAFR antagonists in humans may ameliorate manifestations of dengue and prevent evolution to severe disease.
Essential role of platelet-activating factor receptor in the pathogenesis of Dengue virus infection. PNAS USA July 30, 2009. doi: 10.1073/pnas.0906467106
Severe dengue infection in humans causes a disease characterized by thrombocytopenia, increased levels of cytokines, increased vascular permeability, hemorrhage, and shock. Treatment is supportive. Activation of platelet-activating factor (PAF) receptor (PAFR) on endothelial cells and leukocytes induces increase in vascular permeability, hypotension, and production of cytokines. We hypothesized that activation of PAFR could account for the major systemic manifestations of dengue infection. Inoculation of adult mice with an adapted strain of Dengue virus caused a systemic disease, with several features of the infection in humans. In PAFR−/− mice, there was decreased thrombocytopenia, hemoconcentration, decreased systemic levels of cytokines, and delay of lethality, when compared with WT infected mice. Treatment with UK-74,505, an orally active PAFR antagonist, prevented the above-mentioned manifestations, as well as hypotension and increased vascular permeability, and decreased lethality, even when started 5 days after virus inoculation. Similar results were obtained with a distinct PAFR antagonist, PCA-4246. Despite decreased disease manifestation, viral loads were similar (PAFR−/−) or lower (PAFR antagonist) than in WT mice. Thus, activation of PAFR plays a major role in the pathogenesis of experimental dengue infection, and its blockade prevents more severe disease manifestation after infection with no increase in systemic viral titers, suggesting that there is no interference in the ability of the murine host to deal with the infection. PAFR antagonists are disease-modifying agents in experimental dengue infection.
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For more than three years (since April 2006) I’ve been experimenting with podcasts covering all aspects of microbiology. I decided to have a break over the last month, and during that time I have been thinking about the future. On balance, I feel that the audio format of the podcasts does not add much value to the content beyond what could be achieved with text and images in the style of standard posts on this site. In some circumstances though, a video can add significant value, so I have decided not to post any more audio podcasts for the foreseeable future and to invest the time in producing occasional videos which you will be able to view on this site. All of the old podcast files will remain available here.
