Cardiovascular and respiratory mechanisms in anaphylactic and anaphylactoid shock reactions

Summary Different mediators such as histamine, leukotrienes, prostaglandins and bradykinin are involved in different reaction mechanisms such as cytotropic anaphylaxis (CA), immune complex anaphylaxis (ICA), reactions due to direct histamine liberation or activation of the complement system or hyperosmolarity induced anaphylactoid reactions.In the monkey CA induces systemic vasodilatation, a transient pulmonary hypertension and increase of cardiac output followed by peripheral blood pooling and depression of cardiac output. ICA induces peripheral vasoconstriction, a severe increase in pulmonary vascular resistance and decreased cardiac output, the latter possibly being partially due to decreased cardiac contractility.In hypersensitivity reactions in man cutaneous vasodilatation as well as vasoconstriction may occur alternatively. Peripheral blood pooling and increased vascular permeability are the cause of severe relative and absolute hypovolemia, respectively. Pulmonary vasoconstriction seems to occur in connection with serious bronchospasm. Decreased venous return, myocardial ischemia and hypoxemia can contribute to a reduction of cardiac performance. The most frequent changes in the ECG are sinus tachycardia, sinus bradycardia, extrasystoles, conduction disturbances as A-V block and bundle branch block; lethal or sublethal shock is often associated with malign arrhythmias or cardiac arrest.Almost normal blood gas values are seen in anaphylactic shock without clinical signs of respiratory obstruction. The very few documented cases of anaphylactic shock with respiratory obstruction indicate that increased airway resistance and reduced lung compliance may be present as well as mild to moderate hypoxemia with normal or subnormal CO₂ values.     

A synthetic 10-kD heat shock protein (hsp10) from Mycobacterium tuberculosis modulates adjuvant arthritis

The heat shock protein, hsp10, is an abundant protein in Mycobacterium tuberculosis (Mtb), its nucleotide sequence encoding a protein of 99 amino acids with a molecular mass of 10±7kD. This sequence is phylogenetically conserved, being represented by the GroES homologue of Escherichia coli. Hsp 10 and GroES are members of the chaperonin 10 family of molecular chaperones, and GroES is necessary for the optimal activity of GroEL, a member of the chaperonin 60 family and the E coli homologue of mycobacterial hsp65. Since hsp65 has been implicated in both experimental and human rheumatoid arthritis, we aimed to assess the immunomodulatory effects of its co-chaperonin, hsp10, in experimental arthritis. Our results show that an aqueous solution of a mycobacterial hsp10 delayed the onset and severity of adjuvant-induced arthritis in rodents when administered after disease induction but before joint involvement occurred. This biological activity was specific for the hsp10 of Mtb, since neither GroES nor the rat homologue was effective. Using synthetic hsp10 fragments, the activity was localized to the N-terminal region of the molecule. Assessment of circulating antibody levels to mycobacterial hsp10 and hsp65 indicated that all arthritic rats had increased litres to both hsp10 and hsp65: hsp10-treated rats showed further elevation of this humoral response not only to hsp10 but also to hsp65 when compared with the untreated arthritic control. This is the first report of the immunomodulatory activity of mycobacterial hsp10 in experimental arthritis, and exhibits a potential role for this co-chaperonin in pathophysiological situations.     

Anti-inflammatory activity of phosphodiesterase (PDE)-IV inhibitors in acute and chronic models of inflammation

Inhibitors of cyclic nucleotide phosphodiesterases are known to suppress lipopolysaccharide (LPS)-induced tumour necrosis factor-alpha (TNF-α) production in vitro in human monocytes. The most potent of these have selectivity for type IV PDEs, suggesting that this class of PDE is the major type involved in the regulation of human TNF-α production. Using compounds of two distinct chemical structural classes, a quinazolinedione (CP-77 059) and a 4 arylpyrrolidinone (rolipram). we show here that PDE-IV-specific inhibitors are also potent in suppressing LPS-induced TNF-α production in vitro in sodium periodate-elicited murine macrophages (IC₅₀s of 1 and 33, respectively). We then report the in vivo anti-inflammatory effect of PDE-IV inhibition in five murine models of inflammation: (i) elevation of serum TNF-α induced by a subtethal LPS injection; (ii) LPS-induced endotoxic shock; (iii) LPS/galactosamine-induced endotoxic shock; (iv) carrageenan-induced paw oedema; and (v) adjuvant arthritis. Following a sublethal (5 μg/mouse) injection of LPS, serum TNF-α levels in mice peaked sharply, reaching concentrations of 3–12 ng/ ml 90 min after injection. In this sublethal LPS assay, CP-77 059 was about 30 times more potent than rolipram, with a minimum effective dose of 0.1 mg/kg versus 3 mg/kg for rolipram. This rank order is in keeping with the relative in vitro IC₅₀S for CP-77059 and rolipram, as well as their relative Ki against the human PDE-IV enzyme (46 nM and 220 nM, respectively). In LPS-induced endotoxic shock, rolipram and CP-77 059 at relatively high doses of 30 and 10 mg/kg, respectively, significantly reduced serum TNF-α levels, and also inhibited mortality 66%. In the LPS/galactosamine shock model, in which mice are rendered exquisitely sensitive to LPS by co-injection with galactosamine, only 0.1 μg of LPS/mouse Is necessary for serum TNF-α elevation and death. Both rolipram and the CP-77059 caused dose-dependent reduction of serum TNF-α and lethality. In the carrageenan-induced paw oedema model, in which there is a pronounced local TNF-α response (without a serum TNF-α elevation), rolipram significantly inhibited paw swelling as well as localized TNF-α levels in the paw. In the adjuvant arthritis model, a chronic model of inflammation also possessing localized TNF-α elevation in the inflamed paw, rolipram and CP-77059 suppressed ankle swelling and radiological evidence of joint damage. These data are consistent with a major role for PDE-IV in regulation of TNF-α production and inflammatory responses in murine systems. It suggests a potential therapeutic use for PDE-IV-specific inhibitors in inflammatory disease such as rheumatoid arthritis, septic shock and other inflammatory diseases where TNF-α has been postulated to be a contributing factor in the pathology of the disease.     

A new animal model of binge eating: key synergistic role of past caloric restriction and stress

Dieting and stress are important in the etiology and maintenance of eating disorders, and dieting strongly predicts stress-induced overeating in humans. We hypothesized that caloric restriction and stress interact in a unique manner to promote binge eating. To test this hypothesis, a group of young female rats were cycled through a restriction period (4 days of 66% of control food intake) followed by 6 days of free feeding prior to being stressed by acute foot shock. After three of these cycles, the food intake of rats exposed only to restriction (R), or only to stress (S), did not differ from controls. However, R+S rats that were restricted and refed, despite normal body weight and food intake after free feeding, engaged in a powerful bout of hyperphagia when stressed (Experiment 1). The R + S effect was replicated in an older group of rats (Experiment 2). The hyperphagia was characteristically binge-like, it constituted a 40% selective increase in highly palatable (HP) food (P < .001) over a discrete period of time (within 24 h post-stress), and reflected feeding for reward (higher HP:chow ratio) over metabolic need as occurred after restriction (higher chow:HP ratio). Subsequent experiments revealed that binge eating did not occur if only chow was available (Experiment 3) or if restriction-refeeding (R-R) did not proximally precede stress (Experiment 4). Experiment 5 revealed that a history of R-R cycles followed by only one stress episode was sufficient to increase intake to 53% above controls as early as 2 h after stress (P < .001). This animal model of binge eating should facilitate investigations into the neurochemical changes induced by dieting and environmental stress to produce disordered eating and provide a preclinical tool to test preventive strategies and treatments more relevant to bulimia nervosa, multiple cases of binge eating disorder (BED) and binge-purge type anorexia nervosa.     

RESPONSE CONTINGENCY AND HUMAN GASTRIC ACIDITY

The purpose of this study was to investigate the relationship between avoidance behavior of human subjects and gastric acid changes. An intragastric radio transmitter was employed to record stomach acid secretion rates. The subjects were divided into two groups. The members of the Response-Contingent (RC) group were led to believe that they would be able to avoid a strong electric shock during the Test phase of their session. In the No-Response (NR) group, subjects were correctly told that they would be without means of avoiding shock. The results demonstrated that (a) subjects could not be differentiated according to gastric acid secretion rate strictly on the basis of whether or not they made an avoidance response to an aversive stimulus; (b) a non-significant majority of subjects in both groups exhibited decreased gastric acid secretion rates during the Test phase; and (c) both groups showed a significantly faster rate of gastric acid secretion during the Post-Test phase than during the Test condition.     

NO及NO合成酶与感染性休克

感染性休克病理生理学过程十分复杂。NO在其中的作用既具有有害的一面，同时也存在有利的一面。受内毒素、细胞因子等诱导，iNOS表达上调并产生大量NO，引起循环衰竭、组织细胞损伤以及通过调节炎症介质基因表达扩大全身炎症反应。另一方面，eNOS所产生的NO对机体具有保护作用。然而，感染性休克时，eNOS蛋白质合成及其功能受到损害，反而成为血管内皮功能失常、诱发多器官功能障碍的重要原因。     

Production of tumour necrosis factors by human T cells stimulated by a superantigen,toxic shock syndrome toxin-1

The capacity of human T cell subsets, CD4⁺ or CD8⁺ T cells, to produce tumour necrosis factors (TNF-α and TNF-β) upon stimulation with toxic shock syndrome toxin-l (TSST-I) and the requirement for MHC ctass II molecules on accessory cells (AC) in the response were investigated. The capacity of CD4⁺ T cells was much higher than that of CD8⁺ T cells in TSST-1-induced production of TNF-α and TNF-β. The expression of MHC class II molecules on AC was required in the response.     

Increased production of tumor necrosis factor during endotoxin shock in mice presensitized with serum of mice with tumors or with tumor cell factors

Laboratory of Cellular Immunopathology and Biotechnology, Research Institute of Human Morphology, Academy of Medical Sciences of the USSR, Moscow (Presented by Academician of the Academy of Medical Sciences of the USSR N. K. Permyakov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 112, No. 7, pp. 78–80, July, 1991.