Normal and abnormal neutrophil physiology. (A) Normal PMN emigration from the vasculature to the site of infection or inflammation in the tissues. In response to an infection (grouped ovals) in the tissues, inflammatory signals (stage 1, arrows) diffuse through the tissues to the vasculature and activate the vascular endothelium, causing release of chemokines (stage 2, 4-pointed stars), which attract PMNs to the endothelial surface (stages 3-4).^20,102-104  Attraction is followed by selectin-mediated PMN rolling (stage 3) and β₂-integrin/ICAM-1–mediated firm adhesion of PMNs to ECs (stage 4).^20,102-104  These PMNs, which have undergone a change from a nonadhesive to an adhesive phenotype, are now primed (stage 4).²⁰  Priming of PMNs enhances the microbicidal function of PMNs to a subsequent stimulus and changes the activity of PMNs such that stimuli that normally do not cause the activation of quiescent neutrophils are able to activate primed PMNs.^20,88  It is important to note that priming is part of the orderly process of PMN transmigration to the tissues. Although there are benefits to enhanced PMN function, including efficient destruction of pathogens, it is clear priming may be detrimental to the host and may lead to PMN-mediated organ injury, especially ARDS.²⁰  The PMNs then pass by diapedesis through the endothelial layer (stage 5), orient by chemotaxis to the site of infection (stage 5), and phagocytize (stage 6) and destroy the bacterial invaders (stage 6).^20,102-104  (B) PMN-mediated tissue injury. If the orderly process of PMN transmigration is altered by a stimulus coming from the intravascular space (4-pointed stars, crosses, triangles) rather than the tissues, these intravascular stimuli activate vascular ECs (arrows) and cause attraction (stage 2), selectin-mediated rolling (stage 3), firm adhesion through the ICAM-1/β₂-integrin interaction (stage 4), and priming of PMNs (stage 4).²⁰  However, because there are no signals to cause diapedesis and PMN chemotaxis into the tissues, the PMNs become sequestered in the microvasculature.²⁰  These primed, hyperreactive leukocytes may be activated by stimuli (stage 5, large triangle with diamonds) that normally have no effect, including antibodies directed against specific leukocyte antigens or the lipids that accumulate during routine storage of cellular blood components.²⁰  Activation of these adherent PMNs causes endothelial damage (stage 5, ECs with lines) with lines, capillary leak (large arrow, stage 6), and organ injury.²⁰