Endotoxin-induced sepsis

In animal studies on endotoxin-induced sepsis, raising HDL or administering human HDL and/or other lipoproteins reduced mortality (Harris et al., 1990 Levine et al., 1993). Using a hypolipemic animal model an increase in cytokine production and mortality with endotoxin challenge has been demonstrated (Feingold et al., 1995). After lipoprotein administration, the authors showed the mortality return to the same level as the control group. 

CLP-R CLP induced sepsis-Rats CLP-P CLP-induced sepsis-Piglets IVE-R IV Endotoxin-induced sepsis-Rats ILD interstitial lung disease NE neutrophil elastase... 

The beneficial effects of berberine as anti-inflannnatory agent have also been shown in vivo during endotoxin-induced sepsis. Berberine treatment reduces mortality [43] and prevents heart and limg injury after endotoxin administration in mice [43 5]. The mechanism by which berberine exerts this function seems to be related to the inhibitirMi of TNF-a production and phospholipase A2 activity [45]. 

Copper status effects on resistance to endotoxin-induced injuries because burn and trauma patients show moderate copper deficiency and high risk to sepsis, and copper deficient rats are sensitive to endotoxins causing sepsis (DiSilvestro et al. 1995)... 

Angus, D.C., Wax, R.S. Epidemiology of sepsis an update. Crit Care Med 29 (2001) S109-16. Armstrong, P.B., Rickies, F.R. Endotoxin-induced degranulation of the Limulus amoebocyte. Exp... 

Whether or not Hb accentuates lethal effects of endotoxin is also not resolved. When inoculation with living E. coli or endotoxin has been used to induce sepsis in mice, some Hb preparations have been found to demonstrate deleterious effects. " In contrast, other studies using better characterized, modified Hb solutions have failed to confirm these findings, both in mice and in other animal models. ... 

Levosimendan is a novel inotropic calcium-sensitizing drug. In advanced congestive heart failure, it improves cardiac contractility by sensitizing troponin C to calcium. It has been used recently in a porcine model of endotoxin-induced septic shock, in which pretreatment with levosimendan improved cardiac output and systemic and gut oxygen delivery." There are currently two ongoing clinical trials of levosimendan in septic shock. The role of levosimendan in the supportive management of circulatory failure in sepsis remains to be determined. 

It has been proposed that NO mediates the myocardial depression associated with sepsis (F6, L14). NO synthesis induced by endotoxin blunts beta-adrenergic responsiveness (B2). In vivo, the use of NO synthase inhibitors led to conflicting results (M26), with a general decreased cardiac output and oxygen delivery being observed. NO synthase inhibition improved left ventricular contractility in endo-toxemic pigs but also increased ventricular afterloads, which ultimately is detrimental to cardiac function (H20). Possible sources of NO in the heart may be the vascular cells, the endothelial cells, and the cardiac myocytes (P6). 

Bacterial products such as lipopolysaccharides (endotoxins) and cytokines (IL-2) are able to activate the contact system in vitro and in vivo (D9, H4, H7, M41). Immediately after severe trauma or after surgical intervention and particularly during sepsis, a reduction of plasma contact system proteins has been found (C10, K1, N9). Gel filtration studies of plasma demonstrated that plasma PK after activation becomes complexed with a2-M and Cl-Inh (W4). These complexes are rapidly eliminated from the circulation in vivo. In experimental studies in which pulmonary insufficiency was induced in dogs, a significant reduction of plasma kallikrein inhibitors was observed together with reduced HMK. Analysis of the relation be-... 

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]. 

Inflammation is a common component associated with sepsis, meningitis, as well as respiratory tract, urinary tract, viral, and bacterial infections (Table 1). Bik is elevated during bacterial or viral infection. The presence of urinary Bik correlates well with standard urinalysis tests for urinary tract infections [20]. Endotoxins released from infectious pathogens induce inflammation and immune cell activation. Macrophages release interleukins and cytokines (IL-1, IL-6, IL-12, IL-15, IL-18, TNF-a) on exposure to lipo-polysaccharide (LPS) and lipoteichoic acid (LTA) endotoxins. These cytokines act as a chemotactic factors causing immune cell migration to the site of the infection followed by activation and release of proteases. Cytokines also induce increased vascular permeability in the endothelial. Bik suppresses further cytokine release by protease and intern additional migration and activation of immune cells. Additionally, a stabilization of the immune cell membrane prevents further release of proteases [4]. 

A considerable body of evidence implicates TNF as a major mediator of mischief in bacterial sepsis and endotoxic shock. It is produced in large quantities after the administration of endotoxins and enterotoxins such as TSST-1 (D6, F14, F19). After binding to high-affinity receptors expressed on all nucleated cells, TNF induces physiological responses such as capillary permeability and endothelial coagulability. These give rise to the hypotension, pulmonary edema, and disseminated hemorrhagic necrosis typical of septic shock. 

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