Contribution of the platelet activating factor signaling pathway to cerebral microcirculatory dysfunction during experimental sepsis by ExoU producingPseudomonas aeruginosa

Abstract

Intravital microscopy was used to assess the involvement of ExoU, a Pseudomonas aeruginosa cytotoxin with phospholipase A2 activity, in dysfunction of cerebral microcirculation during experimental pneumosepsis. Cortical vessels from mice intratracheally infected with low density of the ExoU-producing PA103 P. aeruginosa strain exhibited increased leukocyte rolling and adhesion to venule endothelium, decreased capillar density and impaired arteriolar response to vasoactive acetylcholine. These phenomena were mediated by the platelet activating factor receptor (PAFR) pathway because they were reversed in mice treated with a PAFR antagonist prior to infection. Brains from PA103-infected animals exhibited a perivascular inflammatory infiltration that was not detected in animals infected with an exoU deficient mutant or in mice treated with the PAFR antagonist and infected with the wild type bacteria. No effect on brain capillary density was detected in mice infected with the PAO1 P. aeruginosa strain, which do not produce ExoU. Finally, after PA103 infection, mice with a targeted deletion of the PAFR gene exhibited higher brain capillary density and lower leukocyte adhesion to venule endothelium, as well as lower increase of systemic inflammatory cytokines, when compared to wild-type mice. Altogether, our results establish a role for PAFR in mediating ExoU-induced cerebral microvascular failure in a murine model of sepsis.

Loss of PAFR prevents neuroinflammation and brain dysfunction after traumatic brain injury

“…A variety of potent lipid mediated receptor inhibitors, including BN52021 and WEB2086, have been characterized2029 and shown to have therapeutic potential in a number of neurological disorders, including models of ischemia-reperfusion injury30, neuroinflammatory disease31, neurotoxic injury32. PAFR inhibitors display neuroprotective properties after TBI33343536 and these compounds might exert their effects via an inhibitory mechanism involving the interaction between PAF and PAFR3738. Our studies have demonstrated that PAFR inhibitors caused a reduction in PAF release resulting in a down regualtion of TBI induced inflammatory cytokines394041 in animal models of brain injury.…”

Unraveling the host's immune response to infection: Seeing is believing

“…Notably, it has become apparent that inflammation triggered by systemic infections can negatively impact the brain and two recent studies used IVM to examine these changes after bacterial sepsis . Plotkowski et al .…”

“…Notably, it has become apparent that inflammation triggered by systemic infections can negatively impact the brain and two recent studies used IVM to examine these changes after bacterial sepsis . Plotkowski et al . used a Pseudomonas aeruginosa pneumonia model of sepsis and observed significant leukocyte rolling and adhesion to the cerebral vessels accompanied by impaired capillary perfusion in the brain.…”

“…used a Pseudomonas aeruginosa pneumonia model of sepsis and observed significant leukocyte rolling and adhesion to the cerebral vessels accompanied by impaired capillary perfusion in the brain. Moreover, they showed that these effects were primarily mediated by the release of the cytotoxin ExoU by Pseudomonas aeruginosa , which initiated an inflammatory response in the cerebral vasculature by activating the platelet‐activating factor receptor pathway . Another study, by Andonegui et al., imaged the brains of mice following Streptococcus pneumoniae pneumonia.…”

“…Notably, it has become apparent that inflammation triggered by systemic infections can negatively impact the brain and two recent studies used IVM to examine these changes after bacterial sepsis. 47,48 Plotkowski et al 48 used a Pseudomonas aeruginosa pneumonia model of sepsis and observed significant leukocyte rolling and adhesion to the cerebral vessels accompanied by impaired capillary perfusion in the brain. Moreover, they showed that these effects were primarily mediated by the release of the cytotoxin ExoU by Pseudomonas aeruginosa, which initiated an inflammatory response in the cerebral vasculature by activating the platelet-activating factor receptor pathway.…”