Mechanism of platelet adhesion to neutrophils in sepsis (94.3)

Abstract Sepsis is a systemic inflammatory response to infection which has a high mortality rate in the intensive care unit (ICU) resulting in 215000 deaths a year in United States. Neutrophils and platelets play an important role in the induction of inflammation and defense against infection in this pathology. Recent studies by our group have revealed that in severe sepsis TLR4 stimulated platelets interact with already adherent neutrophils. This interaction leads to the formation of Neutrophil Extracellular Traps (NETs) in the circulation, which helps to enhance bacterial trapping and clearance from the body; however, this may also enhance host injury in the liver sinusoids and pulmonary capillaries. To further elucidate the mechanisms by which activated platelets can adhere to immobilized neutrophils in the setting of sepsis, we used an in vitro flow chamber system using LPS and septic plasma as platelet stimulants. Antibodies to several adhesion molecules on platelets and neutrophils were tested. TLR4 activated platelets did not express P-Selectin on their surface and their interaction with immobilized neutrophils was not P-selectin-dependent. Findings show that LFA-1 and CD11c/CD18 on neutrophils, and JAM-A and ICAM-2 on platelets are involved in LPS-induced platelet adhesion to immobilized neutrophils. In addition, results from septic plasma stimulated platelets show that LFA-1 and CD11c/CD18, but not JAM-A, are involved in platelet adhesion to immobilized neutrophils. Blocking the adhesion molecules that take place in platelet adhesion to immobilized neutrophil could prevent NET formation and tissue damage specifically in lungs and liver capillaries providing a target for new therapeutics in this pathology.