title: Critical role for oxidative stress, platelets, and coagulation in capillary blood flow impairment in sepsis.
abstract: Sepsis is a complex multifaceted response to a local infectious insult. One important facet is the circulatory system dysfunction, which includes capillary bed plugging. This review addresses the mechanisms of capillary plugging and highlights our recent discoveries on the roles of NO, ROS, and activated coagulation in platelet adhesion and blood flow stoppage in septic mouse capillaries. We show that sepsis increases platelet adhesion, fibrin deposition and flow stoppage in capillaries, and that NADPH oxidase-derived ROS, rather than NO, play a detrimental role in this adhesion/stoppage. P-selectin and activated coagulation are required for adhesion/stoppage. Further, platelet adhesion in capillaries (i) strongly predicts capillary flow stoppage, and (ii) may explain why severe sepsis is associated with a drop in platelet count in systemic blood. Significantly, we also show that a single bolus of the antioxidant ascorbate (injected intravenously at clinically relevant dose of 10 mg/kg) inhibits adhesion/stoppage. Our data suggest that eNOS-derived NO at the platelet-endothelial interface is anti-adhesive and required for the inhibitory effect of ascorbate. Because of the critical role of ROS in capillary plugging, ascorbate bolus administration may be beneficial to septic patients whose survival depends on restoring microvascular perfusion.
authors.affiliation: Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada. ktyml@lhsc.on.ca
authors.forename: Karel
authors.initials: K
authors.lastname: Tyml
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D001777:Blood Coagulation / Q000502:physiology*; D001783:Blood Flow Velocity; D001792:Blood Platelets / Q000502:physiology*; D002196:Capillaries / Q000187:drug effects / Q000503:physiopathology*; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009569:Nitric Oxide / Q000097:blood; D018384:Oxidative Stress; D010973:Platelet Adhesiveness; D017382:Reactive Oxygen Species / Q000097:blood; D018805:Sepsis / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology*
chemical_list: D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D005337:Fibrin; D001205:Ascorbic Acid