Staging of the pathophysiologic responses of the primate microvasculature to Escherichia coli and endotoxin: Examination of the elements of the compensated response and their links to the corresponding uncompensated lethal variants

Objective: Review of primate studies of Escherichia coli sepsis and endotox emia with a reexamination of the rationale for diagnosis and treatment of t hese multistage disorders. Setting: Animal research and intensive care units in a university medical s chool. Subjects: Cyanocephalus baboons (E. coli) and normal human subjects (endoto xin). Interventions: Baboon studies: anti-tissue factor, protein C, endothelial p rotein C receptor, and anti-tumor necrosis factor antibodies, and active si te inhibited factor recombinant Vlla and factor Xa. Results and Conclusions:This review concerns the primate microvascular endo thelial response to inflammatory and hemostatic stress. Studies of the impa ct of inflammatory and hemostatic stress on this microvasculature have fall en into four categories. First, studies of pure hemostatic stress using fac tor Xa phaspholipid vesicles showed that blockade of protein C as well as p rotein C plus tissue plasminogen activator produced a severe but transient consumptive and a lethal thrombotic coagulopathy, respectively. These studi es showed that the protein C and fibrinolytic systems can work in tandem to regulate even a severe response if the endothelium is not rendered dysfunc tional by metabolic or inflammatory factors. Second, studies of compensated (nonlethal) inflammatory stress using E. coli or endotoxin in baboon and h uman subjects showed that even under minimal stress in which there is no ev idence of overt disseminated intravascular coagulation, injury of the endot helium and activation of neutrophils and hemostatic factors are closely ass ociated. This showed that molecular markers of hemostatic activity could be used to detect microvascular endothelial stress (nonovert disseminated int ravascular coagulation) in patients who are compensated but at risk. These studies also showed that the compensated response to inflammatory stress co uld exhibit two stages, each with its unique inflammatory and hemostatic re sponse signature. The first is driven by vasoactive peptides, cytokines, an d thrombin, followed 12 to 14 hrs later by a second stage driven by C-react ive protein/complement complexes, tissue factor, end plasminogen activator inhibitor 1 secondary to oxidative stress after reperfusion. Third, studies of uncompensated (lethal) inflammatory stress using E. coil showed that ir reversible thrombosis of the microvasculature was not a link in the lethal chain of events even though inhibition of components of the protein C netwo rk (protein C and endothelial protein C receptor) converted compensated res ponses to sublethal E. cell into uncompensated lethal responses. Fourth, th ese studies also showed that there were variants of the lethal response ran ging from capillary leak and shock to recurrent sustained inflammatory diso rders. We believe that each of these variants arises from their sublethal c ounterparts, depending on underlying or modulating host factors operating a t the time of challenge. Such underlying conditions range from preexisting microvascular ischemia, reperfusion, and oxidative stress to alteration or reprogramming of monocyte/macrophage responses (tolerance to hyperresponsiv eness). Characterization of these underlying conditions in patients who are at risk should aid in identifying and optimizing management of these varia nts.