Toxic shock syndrome.

In the past 10 years, we have learned much about TSS and S. aureus and its toxins. A number of important biologic principles have been reemphasized in this first decade of TSS research: S. aureus is a very complex organism, one not likely to yield quick answers; in vitro observations must always be confirmed in the patient; animal models may not always be reliable replicates of human disease; and epidemiologic associations cannot be equated with causation. Toxic shock is an intricate phenomenon with many interesting scientific facets. Unraveling its mysteries will undoubtedly teach us more about the complex interaction of patients and microorganisms.     

Blood coagulation and shock.

This report describes how a finding at the autopsy table led to the observation of a clinical syndrome. A synthesis of autopsy experience, clinical investigations, and experimental and biochemical studies were able to shed light on one factor in the pathogenesis of this syndrome, namely blood coagulation with pulmonary microemboli and release and delayed elimination of peptides from fibrin degradation extravascularly in the lungs. These peptides may both induce increased permeability in the microcirculation and stimulate fibroblast proliferation. Knowledge about the pathogenesis has led to improved prophylaxis and therapy and a reduction of the number of deaths.     

Heat shock response and heat shock protein antigens of Vibrio cholerae.

Sixteen heat shock proteins (Hsps) have been identified in the hypertoxinogenic strain 569B of Vibrio cholerae which are synthesized in response to small and large elevations of temperature. The induction of the Hsps is necessary for the cells to survive the deleterious effects of heat. There is no difference in the pattern of induction of the Hsps in V. cholerae strains varying in levels of toxinogenicity. One of the major low-molecular-mass Hsps, a 16-kDa protein, is preferentially degraded following shift down of temperature. This protein is induced at a much lower level at high temperatures in cells maintained in the laboratory for a prolonged period. The only Hsp located in the outer membrane of V. cholerae cells is a 23-kDa protein. Western immunoblot analysis with human immune sera collected from convalescent cholera patients revealed that this protein is markedly immunogenic. The human immune serum also reacted with the 69- and 16-kDa major Hsps and the 88-, 66-, and 46-kDa Hsps but not with the 61-kDa major Hsp identified as the groEL gene product. All major Hsps reacted with rabbit anti-V. cholerae sera. Ethanol stress leads to the induction of four of the major Hsps and three additional proteins.     

Heat shock response of spirochetes.

We examined the heat shock response of the pathogenic spirochetes Treponema pallidum, Borrelia burgdorferi, and Leptospira interrogans and certain saprophytic spirochetes. Cellular proteins synthesized after shifts to higher temperatures were [35S]methionine labeled and analyzed by gel electrophoresis and fluorography. Only T. pallidum failed to exhibit an obvious heat shock response. GroEL and DnaK homologs were identified in the various species, although these proteins were not thermoinducible in T. pallidum or Treponema denticola. DNA hybridization studies indicate that spirochetal groEL and dnaK genes are highly conserved.     

Heart rate during haemorrhagic shock.

In a prospective study, heart rate and mean arterial pressure were related to estimated blood loss in 34 consecutive patients aged 23-92 years during resuscitation from haemorrhagic shock. Eighteen patients with a blood loss of less than 31 (1.9 [0.9-3.0] l) (median and range), corresponding to 34 (16-46) % of estimated blood volume, had a heart rate of 83 (60-160) beats min-1 and a mean arterial pressure of 62 (35-73) mmHg. In 16 patients with a blood loss of more than 3 l (4.0 [3.3-5.0] l) corresponding to 89 (35-100) % of the estimated blood volume, heart rate was 120 (110-160) beats min-1 (P < 0.05) and mean arterial pressure 52 (0-70) mmHg (P < 0.05). Six patients died due to severe bleeding (3.1 [2.5-5.0] l) with a heart rate of 129 (110-160) beats min-1 and a mean arterial pressure of 40 (0-70) mmHg. It is concluded that reversible hypovolaemic shock is associated with a relatively low heart rate (approximately 80 beats min-1) and that tachycardia (approximately 120 beats min-1) is associated with profound bleeding. Hypovolaemic shock with tachycardia may represent a transition to an irreversible stage.     

Liver function in septic shock.

Serum liver function tests were estimated in 57 patients admitted to an Intensive Therapy Unit (ITU) with a diagnosis of septic shock. Following an initial biochemical disturbance, persisting hyperbilirubinaemia was associated with a poor prognosis. Post-mortem liver histology in 22 patients showed varying degrees of non-specific reactive change, venous congestion, ischaemic necrosis, fatty change and intrahepatic cholestasis in 16 cases. In the remaining six cases there was moderately severe cholestasis with inspissated bile in the cholangioles. The possible aetiology of the observed cholestasis is discussed.     

Heat shock proteins and autoimmunity.

Heat shock proteins are major antigens of the T cell response to many pathogens. Because of their marked conservation of sequence in pro- and eukaryotes, they have also been postulated as target antigens in autoimmune disease. Despite substantial in vitro evidence to suggest T cell recognition of self hsp, it has proved more difficult to implicate such recognition in autoimmune disease. Nevertheless, their dominance in T cell responses generally and the ability to manipulate certain autoimmune diseases by altering responses to hsp suggests that T cell recognition of hsp is important in these diseases; however at present the mechanisms involved remain obscure.     

Heat shock proteins in immunopathology.

In recent years, studies have suggested that autoimmunity and/or immunopathology may sometimes result from the immune response to heat shock proteins of autologous cells and microorganisms. Focusing on the T-cell mediated responses, we review the latest literature on this issue with regard to three hypothetical concepts of immunopathology in which heat shock proteins might play a role.     

Anaphylatoxin-induced shock and two patterns of anaphylactic shock: hemodynamics and mediators.

In the dog, different cardiorespiratory reactions were identified in two types of anaphylactic shock and in C5a-AT (anaphylatoxin)-induced shock. All three types had in common a portal blood pooling with consequent decrease in the venous return, cardiac output, and arterial pressure. In anaphylaxis (a) of the first type, at a low titer of hemagglutinating antibodies, the latent period was 68 s and heart and lung function was unchanged. In the second type, at high titer, the latency was 19 s and pulmonary hypertension and decreased heart contractility occurred. After AT injection pulmonary hypertension appeared with tachypnea and unchanged heart function. Tachyphylaxis, but not cross-over tachyphylaxis against the anaphylactic agent and AT was observed in dogs and isolated guinea pig lungs. AT induced a transient release and a, a prolonged release of histamine, prostaglandins (PGs), and thromboxane A2 and endoperoxides from guinea pig lungs. SRS-A was released only in a. Indomethacin inhibited AT-induced release of PGs in guinea-pig lungs and AT-induced hypotension in the dog though it did not prevent the drop in cardiac output. These model studies suggest that different patterns of clinical a. can occur, depending on the type of antibodies and/or mediators involved.     

Morphologic development of human shock lung.

In the initial phase of shock, edema spreads throughout the alveolar interstitium even before injury occurs in the alveolar epithelium and endothelium. The endothelium and the epithelium are damaged only subsequently, causing reduction in the average barrier thickness of the epithelium and the endothelium. A point of irreversibility is reached by the end of the first week. While early cell regeneration may be observed within the alveolar endothelium and epithelium, proliferation of fibroblasts and fibrosis of the alveolar wall occur in addition to edema which spreads within the interstitium. This widening of the gas exchange barrier may be considered as the anatomic substrate of respiratory insufficiency induced by shock. This enlargement continues up to the moment when thickening of the alveoli impedes satisfactory functioning of the lung, and, as consequence, threatens the life of the patient.     

Chlamydial heat shock proteins and trachoma.

Two chlamydial proteins (HSP-60 and HSP-70) have marked homology with bacterial and mammalian heat shock proteins. Previous studies have indicated that when inoculated into the eyes of immune animals, a Triton X-100 extract of chlamydia containing HSP-60 induces an ocular delayed-type hypersensitivity reaction. The potential for HSP-70 to induce a similar reaction was tested in six cynomolgus monkeys that had been sensitized to both antigens by previous ocular chlamydial infection. Whereas the chlamydial extract containing HSP-60 induced a marked clinical response within 24 h of inoculation, no response followed inoculation of HSP-70 in the contralateral eye. The lack of a response to HSP-70 suggests that further assessment of its potential as a trachoma vaccine is warranted.     

Significance of leukocytes in endotoxic shock.

Peripheral blood leukopenia and the sequestration of large numbers of polymorphonuclear leukocytes in pulmonary capillaries have been observed in experimental shock. It has been suggested that the lysosomal enzymes released from these damaged and sequestered leukocytes may contribute to systemic hypotension and pulmonary capillary damage. This study was undertaken to evaluate the role of leukocytes in endotoxic shock.Six rhesus monkeys rendered leukopenic by total body irradiation (mean white blood count, 358/cu mm) were compared with six normal nonleukopenic monkeys (mean white blood count, 10,550/cu mm) for two hours after injection of E. coli endotoxin. The effects of irradiation alone were evaluated in three additional animals which did not receive endotoxin.Following the injection of endotoxin, the mean cardiac output and systemic pressure decreased more than 50% in both the leukopenic and normal groups. Metabolic acidosis developed in both groups. The mean arterial PO₂ was unchanged, but the alveolar-arterial O₂ gradients increased. Differences between the two injected groups were not significant in these parameters.Light and electron microscopy demonstrated sequestered polymorphonuclear leukocytes and platelets in pulmonary capillaries in the nonirradiated group, but leukocytes were virtually absent in sections from lungs of the leukopenic animals. In spite of this difference, significant endothelial swelling and perivascular edema were demonstrable in both groups. No significant histologic abnormalities were noted in the three irradiated leukopenic control animals who did not receive endotoxin.Leukopenia provided no protection from the hemodynamic effects or the histological damage in pulmonary capillaries observed after administration of endotoxin.     

Morphology of cardiac muscle in septic shock. Observations with a porcine septic shock model

The morphology of cardiac muscle was investigated in a porcine model of septic shock, created by intermitted application of Escherichia coli-endotoxin. The earliest lesions, found after 18 h of septic shock, were endothelial cell swelling, marked leucostasis and slight ischaemic alterations of the muscle fibres. At the end point of the experiments, after 48 h, some fibrin thrombi were found associated with more pronounced ischaemic alterations of cardiac muscle cells and some necrotic fibres. Comparing these findings with the severe endothelial and muscle fibre lesions found in skeletal muscle, the endothelial cells of the heart microvasculature, are clearly more resistant to the attack of the endotoxins and mediators liberated in septic shock.