No abstract

Activation of the kallikrein-kinin system, as indicated by increased plasma kallikrein and depleted plasma kininogen, prekallikrein, and kallikrein inhibitor, was observed in five patients with Rocky Mountain spotted fever. Four of the patients had petechial rashes characteristic of vasculitis. Three patients had alterations in coagulation consistent with disseminated intravascular coagulation, although no hemorrhagic syndrome was found. Our data, along with the known physiologic actions of kinins, suggest a possible role for the kallikrein-kinin system in the pathophysiology of vasculitis, disseminated intravascular coagulation, circulatory shock, and other complications of infection with Rickettsia rickettsii.

SUMMARY Staphylococcal enterotoxin B, a protein exotoxin from Staphylococcus aureus, produced progressive hypotension and shock when injected (1 mg/kg, iv) into rhesus monkeys. Plasma levels of factors which have been implicated in the pathogenesis of other types of shock were measured. Endotoxin-like activity was measured by the Limulus lysate technique, fibrin degradation products (FDP) were quantified by electroimmunoassay, and activation of the complement system was assayed by measuring total hemolytic complement. Activation of the intrinsic coagulation cascade was assessed by measuring activated partial thromboplastin time (APTT). Activation of the kinin system was evaluated by measuring prekallikrein activity and kininogen. Myocardial depressant factor (MDF) was measured by paper chromatography. Endotoxin-like activity did not appear in plasma, and the complement system was not activated. The appearance of FDP and a significant trend for prolongation of APTT indicated activation of fibrinolysis and the intrinsic coagulation cascade, and suggested that disseminated intravascular coagulation was occurring. Activation of the kinin system was shown by a progressive and significant depletion of kininogen from 338 ± 37 to 226 ± 22 ng kallidin generated/ml, and a significant depletion of plasma prekallikrein activity from 169 ± 8 to 110 ± 15 tosyl arginine methyl ester (TAMe) esterase U/ml. Analysis of covariance indicated that activation of the kinin system was related to changes in blood pressure. MDF did not increase until immediately before death (increase from 1.08 ± 0.15 to 1.92 ± 0.11 paper chromatographic U//tl, n = 6). We conclude that kinins, MDF, and disseminated intravascular coagulation, but not complement or endotoxin, may contribute to the pathogenesis of enterotoxic shock in rhesus monkeys.ENTEROTOXINS isolated from cultures of Staphylococcus aureus are protein exotoxins (28,000-29,000 daltons, molecular weight) which are capable of producing acute food poisoning in humans 1 and other primates.2 Intravenous (iv) injection of enterotoxins in very small doses in rabbits and monkeys produces lethargy, fever, shock, and death.3 There is evidence that during staphylococcal wound infections and purulent skin lesions, enough enterotoxin is released into the circulation of an infected patient to stimulate synthesis of antibody specific to the toxins produced. 4 Since circulating enterotoxins might contribute to the hypotension and shock often observed in these patients, we decided to study possible mechanisms by which enterotoxin causes circulatory shock.When Josefczyk 4 measured anti-enterotoxin antibodies in normal patients and patients with staph- ylococcal infections, antibody to staphylococcal enterotoxin type B (SEB) was the most common type in each group. SEB has been isolated in purity greater than 99%, 5 and its amino acid sequence has been determined. 6 To help to elucidate the mechanisms by which enterotoxins produce shock, we injected SEB (1 mg/kg, iv) into rhesus monkeys and measured plasma l...

A B S T R A C T The normal metabolic turnover of plasma kininogens was studied by measuring the disappearance of intravenously administered radiolabeled human and monkey plasma kininogens from the circulation of healthy adult rhesus monkeys. Curves obtained by plotting log radioactivity against time could be expressed as double exponential equations, with the first term representing diffusion, and the second, catabolism. No significant difference between the turnovers of human and monkey kininogens was observed. The difference between the t112 of high molecular weight kininogen (25.95±1.60 h) (mean +SEM) and that of low molecular weight kininogen (18.94±1.93 h) was only marginally significant (P < 0.05). In contrast, a highly significant (P < 0.001) difference in their mean catabolic rates (1.12±0.08 d-l for high molecular weight kininogen vs. 2.07±0.09 d-l for low molecular weight kininogen) was observed. These differences between the two kininogens were attributed to differences in their distribution between the intra-and extravascular pools. Studies of kininogen turnover will be useful in elucidating the in vivo func-

Radiolabelled purified plasma kininogens were injected into healthy rhesus monkeys for the purpose of studying their normal metabolic turnover. Human kininogen was purified using affinity chromatography and further fractionated into high molecular weight (HMW) and low molecular weight (LMW) proteins as described by Pierce and Guimaraes (Fogarty International Center Proceedings No. 27, pp. 113-119, 1976). The kininogens were labelled with 125I using either the choramine-T or microdiffusion techniques. Labelled mixed kininogen, LMW kininogen, and HMW kininogen preparations were injected into 6, 4, and 6 rhesus monkeys respectively. Blood samples were drawn at various time intervals, and assayed in a gamma counter. The disappearance of injected labelled kininogen from the intravascular compartment could be expressed as a double exponential equation. The difference between the half-life of HMW kininogen (26.0 ± 1.6 h) (± SE) and that of LMW kininogen (20.2 ± 2.1 h) was only marginal (P >0.05). In contrast there was a highly significant (P < 0.001) difference in their fractional catabolic rates (1.12 ± 0.09 day-1 for HMW kininogen and 2.05 ± 0.12 day-1 for LMW kininogen). These observations indicate that although there is a minimal difference in the metabolic rates of intravascular HMW and LMW kininogens, a considerable difference exists in their rates of flux between the intravascular and extravascular spaces.