Shock endotoxic

Thromboxane A-2 has been implicated in a number of disorders of the circulatory system including coronary artery spasms, unstable angina pectoris, traumatic and endotoxic shock, and heart attacks. It is formed normally very near its receptors and is rapidly deactivated by metabolizing enzymes so circulating levels are quite low. Furthermore, it is opposed in its actions by the prostacyclins. When these controls are defective, pathology results and drugs can be the resort in attempts to restore the normal healthy balance. For one example, furegrelate (6) is a throm-... 

CD C14 C14.001 Caspase-1 Potential drug target for down-regulation of the inflammatory mediator, interleukin 1beta, which could ameliorate inflammation and endotoxic shock... 

The effects of corticosteroids, cyclooxygenase blockers, leukotriene blockers, PAF antagonists, anti-TNF antibodies, oxygen radical scavengers, opiate antagonists, antihistamines, and calcium channel blockers in endotoxic shock were reviewed in 1990 (H17). In this section studies on this subject that have been published during the last few years are summarized. 

Gl. Gadina, M., Bertini, R., Mengozzi, M., Zandalasini, M., and Ghezzi, P., Protective effect of chlorpromazine on endotoxin toxicity and TNF production in glucocorticoid-sensitive and glucocorticoid-resistant models of endotoxic shock. J. Exp. Med. 173, 1305-1310 (1991). 

MacMicking, J.D. et al., Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase, Cell, 81, 641, 1995. 

To set up and validate the in vitro systems we initiated a study with rat Uver slices. Stimulation by Upopolysaccharide (LPS) in liver slices was used to evoke a pro-inflammatory response in the Uver. Lipopolysaccharide (LPS), a component of Gram-negative bacterial ceU walls (also called endotoxin), has been associated with tissue injury and sepsis. In the Uver LPS activates the resident macrophages, the Kupffer ceUs, which results in cytokine release [96]. Furthermore, LPS is cleared by the Uver, mainly by Kupffer ceUs [97]. One of the major features of endotoxic shock is the induction of nitric oxide S5mthase in the Uver [98]. Inducible nitric oxide synthase (iNOS), the expression of which is induced by LPS and cytokines, produces nitric oxide (NO) in large quantities [99]. 

Chavali, S. R., W. W. Zhong, T. Utsunomiya, and R. A. Forse. Decreased production of interleukin-1-beta, pros-taglandin-E2 and thromboxane-B2, and elevated levels of interleukin-6 and -10 are associated with increased survival during endotoxic shock in mice consuming diets enriched with sesame seed oil supplemented with Quil-A saponin. Int Arch Allergy Immunol 1997 114(2) 153-160. 

Chamulitrat, W., Jordan, S. J., and Mason, R. P. (1994). Nitric oxide production during endotoxic shock in carbon tetrachloride-treated rats. Mol. Pharmacol. 46, 391-397. 

Wang, Q. Z., Jacobs, J., DeLeo, J., Kruszyna, H., Kruszyna, R., Smith, R., and Wilcox, D. (1991). Nitric oxide hemoglobin in mice and rats in endotoxic shock. Life Sci. 49, PL55-PL60. 

The increased expression of adhesion molecules by the endothelium may activate polymorphonuclear neutrophils (PMN) in rabbits [72], During endotoxic shock, activated PMNs release their granule content and secrete both proinflammatory and cytotoxic molecules. Pickaver et al. [73] were the first to show PMN cytotoxicity against tumor cells. We showed that PMNs are toxic for PROb colon tumor cells [74] in BDEX rats. In vivo, PMNs have been implicated in the Schwartzman reaction [75], and may be involved in LPS-induced tumor necrosis. PMNs, when activated by LPS, synthesize and release NO. The role of NO in tumor growth will be discussed later. The decrease in tumor growth after intradermal injections of LPS is attributed to the induction of TNF-a secretion by PMNs both in intradermal tumors (Meth A sarcoma in BALB/c mice, MH-134 hepatoma in C3H/He mice, Lewis Lung carcinomas in C57BL/6 mice) and pulmonary Meth A metastases [76,77],... 

TNF-a IL-1, IL-2, GM-CSF, LPS Tumor necrosis, endotoxic shock-like syndrome, cachexia, fever, acute-phase protein response IL-1, IL-6, GM-CSF, MHC I, MHC II Macrophages... 

In animal models of acute renal failure induced in rats by bilateral nephrectomy and bilateral ureteral ligation, TAC increased, probably due to the accumulation of urate and uremic toxins with scavenging capacity, such as hyppurate (B19, S9). TAC of blood plasma was reduced in a rat endotoxic shock model (rats given i.p. 5 mg/kg lipopolysaccharide) (Cl6). 

The Tlr4 has emerged as a specific conduit for the LPS response, and many relatively uncommon variants have been observed, but a single Tlr4 allelic receptor variant predominates. Such receptors may also play a role in airway disease in addition to their role in Gram-negative endotoxic shock. 

Dioxin, 2,3,7,8-tetrachlorodibenzo-dioxin Receptor implicated in endotoxic shock... 

Can, C., Demirci, B., Uysal, A., Akcay, Y.D., and Kocay, S. 2003. Contradictory effects of chlorpromazine on endothelial cells in a rat model of endotoxic shock in association with its actions on serum TNF- levels and antioxidant enzyme activities. Pharmacologic Res 48(3) 223-230. 

Studies with the irreversible mu antagonist beta-FNA provided a linkage between the in vitro ligand binding evidence for a mu-delta opioid receptor complex and the in vivo evidence described above [18]. As noted above, in vivo administration of beta-FNA blocks delta agonist modulation in the antinociception models and delta antagonist effects in the seizure, endotoxic shock, and striatal cAMP models. As reported by Rothman et al. [18], either pretreating membranes with beta-FNA or ICV administration of... 

D Amato R, Holaday JW. Multiple opiate receptors in endotoxic shock evidence for delta involvement and mu-delta interactions in vivo. Proc Natl Acad Sci USA 1984 81 2898-2901. 

Karima, R., Matsumoto, S., Higashi, H., Matsushima, K. The molecular pathogenesis of endotoxic shock and organ failure. Mol Med Today 5(3) (1999) 123-132. 

Jiang, J., Zhu, P., Wang, Z., Liu, D., He, Y., Xie, G., Xu, H. Protective effects of bactericidal/permeability-increasing protein on the vital organ function after endotoxic shock in rats. Zhonghua Wai Ke Za Zhi 37 (1999b) 120-122. 

Caspase-1 Yes Normal development Defects in death receptor-mediated apoptosis, resistant to lipopolysaccaharide (LPS)-induced endotoxic shock Normal [57-59]... 

Caspase-11 Yes Normal development Resistant to LPS-induced endotoxic shock, defects in oligodendrocyte-mediated cell death Normal [69-71]... 

Li P, Allen H, Banerjee S, Franklin S, Herzog L, Johnston C, et al. Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. Cell 1995 80 401-411. 

Reichardt HM, Umland T, Bauer A, Kretz O, Schutz G. Mice widi an increased glucocorticoid receptor gene dosage show enhanced resistance to stress and endotoxic shock. Mol. Cell. Biol. 2000 20 9009-9017. 

Hai boui DV, Smidi EM, Blalock JE (1987) Splenic lymphocyte producdon of an endorphin duiing endotoxic shock. Bram Behav Immuii 1 123—133. 

Delgado M, Gomaiiz RP, Martinez C, Abad C, Leceta J (2000) Anti-inflammatory properties of the type 1 and type 2 vasoactive intestinal peptide receptors Role in lethal endotoxic shock. Eur J Immunol 30 3236-3246. 

In fact, a medley of substances (autacoids), kinins, prostaglandins, leukotrienes, histamine, endorphins, serotonin, vasopressin, has been implicated. In endotoxic shock, the toxin also induces synthesis of nitric oxide, the endogenous vasodilator, in several types of cells other than the endothelial cells which are normally its main source. 

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