Rat model of sepsis

A study using a rat model of sepsis induced by cecal ligation and perforation (CLP) showed that PMXB hemoperfusion performed 24 hours after the CLP procedure reduced plasminogen activator inhibitor -1 expression in the lung, and apoptosis in renal tubular cells (Ito et al., 2009). 

Flolly MK, Dear JW, Flu X, Schechter AN, Gladwin MT, Flewitt SM, Yuen PS, Star RA Biomarker and drug-target discovery using proteomics in a new rat model of sepsis-induced acute renal failure. Kidney International 70 496-506, 2006... 

Unlike Tx synthetase inhibitors and receptor antagonists, NSAIDs given alone or with other adjunctive therapy (discussed below) improve survival or survival time in the rat model of sepsis . The beneficial action of the cyclo-oxygenase inhibitors in these sepsis modelis must therefore be attributed to inhibition of other prostanoid metabolites, e.g. PGE2, id... 

Heuer, J.G., et al. (2004) Evaluation of protein C and other biomarkers as predictors of mortality in a rat cecal ligation and pimcture model of sepsis. Crit Care Med. 32, 1570-8. 

Voisin, L., Breuille, D., Combaret, L., Pouyet, C., Taillandier, D., Aurousseau, E., Obled, C., and Attaix, D., 1996, Muscle wasting in a rat model of long-lasting sepsis results from the activation of lysosomal, Ca2+-activated, and ubiquitin-proteasome proteolytic pathways, J Clin Invest, 97, pp 1610-1617. 

In a rat model of neonatal sepsis, recombinant HL or talactoferrin was shown to improve survival (Venkatesh et al., 2007). In ex vivo studies, HL increased synergy of commonly used antibiotics against coagulase-negative staphylococcus and Candida (Venkatesh and Rong, 2008) and reduced biofilm of infected catheters (Venkatesh et al., 2009). 

For example, the hypothesis that DCLHb would improve blood pressure, organ perfusion, and mortality was tested in a rodent model of sepsis. Administration of this tHb to moribund, septic rats immediately reversed the decreased MAP, increased systemic vascular resistance (SVR) and by 24 h, significantly elevated perfusion to vital areas (intestines, heart, and brain) as compared to albumin-treated animals. In addition, areas that did not display an increase in perfusion also did not demonstrate any deficits, suggesting that they were being adequately perfused. 

Liposomal ATP protected human endothelial cells from energy failure in a cell culture model of sepsis (21). ATP-L increased the number of ischemic episodes tolerated before electrical silence and brain death in the rat (22,23). In a hypovolemic shock-reperfusion model in rats, the administration of ATP-L increased hepatic blood flow during shock and reperfusion of the liver (24). The addition of the ATP-L during cold storage preservation of rat liver improved its energy state and metabolism (25,26). Co-incubation of ATP-L with sperm cells improved their motility (27). Finally, biodistribution studies demonstrated significant accumulation of ATP-L in ischemia-damaged canine myocardium (28). 

Drusano, G. L. et ah. Pharmacodynamics of a fluoroquinolone antimicrobial agent in a neutropenic rat model of Pseudomonas sepsis, Antimicrob. Agents Chemother., 37(3) 483 90, 1993. 

In one prospective study, AKI occurred in 51% of septic shock patients [80]. The combination of AKI and sepsis is associated with a greater than 80% mortahty [79]. Over the past 3 decades, sepsis and septic shock have been studied in various species including rats, dogs, pigs, primates. Only recently has a mouse model of septic AKI been developed. Administration of different doses of endotoxin (5-30 mg/kg intraperitoneal) to mice is associated with sepsis and septic shock, respectively [81]. 

Prostaglandins have also been suggested as important regulators of skeletal muscle protein breakdown. Enhanced protein catabolism and synthesis of PGE2 is seen in skeletal muscle of rats injected with endotoxin " . Indomethacin reduced leukocyte-pyrogen-induced proteolysis of skeletal muscle in vitro " however, in a canine model of E. coli sepsis, ibuprofen had minimal effects on protein catabolism . 

Bowers, R., Ellis, E., Brigham, K. and Oates, J. (1983). Effects of prostaglandin cyclic endoperoxides on the lung circulation of sheep. J. Clin. Invest., 63, 131-137 Short, B.L., Miller, M.K., Stround, C.Y. and Fletcher, J.R. (1983). Comparison of the thromboxane inhibitors to cyclooxygenase inhibitors on survival in a newborn rat model for group B-streptococcal sepsis. In Samuelsson, B., Paoletti, R. and Ramwell, P. (eds.) Advances in Prostaglandin, Thromboxane and Leukotriene Research, Vol. 12, pp. 113-116. (New York Raven Press)... 

Bluth MH, KandU E, Mueller CM, ShahV, LinYY, Zhang H, et al. Sophorolipids block lethal effects of septic shock in rats in a cecal hgation and puncture model of experimental sepsis. Crit Care Med 2006 34 188-95. 

Tinospora cordifolia has been evaluated in several animal models for immunosuppression. In a model of irreversible cholestasis, Escherichia coli sepsis was created [22]. Rats from the Tinospora cordifolia-lrtdXtd groups resisted Escherichia coli infection and mortality was only 16.7%. Blood cultures of the surviving animals were sterile. In comparison, the control rats showed a mortality of 77.8 % and the blood culture of surviving animals from these groups showed the presence of Escherichia coli. 

NOx levels are increased in plasma and urine of septic animals. Many nonse-lective NO synthase inhibitors (e.g., L-NMMA) are used in several models with experimental induced sepsis (S40). In most studies it was shown that the cardiovascular abnormalities associated with sepsis were reversed, increasing blood pressure and systemic vascular resistance (F7, K9, M26, N5), together with a improvement in renal function (B42, H24). Also, selective inhibition of iNOS prolonged survival in septic rats (A7). 

To study the importance of KC-HC cell interaction in sepsis, we developed a rat KC and HC coculture model. An entire range of KC to HC ratios were tested (0.5 1 to 10 1). LPS was used as the relevant septic stimulus. As anticipated, the addition of even small amounts of LPS resulted in induction of acute phase reactant synthesis (Kispert et al., 1990). Of greater interest was a profound decrease in total protein synthesis seen when higher concentrations of LPS (0.1 /rg/ml or greater) was added to KC-HC cocultures with KC HC ratios greater than 2 1 (Figure 1). The decrease was first detected at 6-8 hr and became maximal at 24 hr. 

Abstract The diet of industrialised countries is usually rich in amino acids, which are partly used as a source of calories. However, metabolic alterations are observed in diseased patients and a preferential retention of Sulphurated Amino Acids (SAA) occurs during the inflammatory response. It has been demonstrated in an acute sepsis phase model in rats that the metabolism of L-Cysteine (Cys) is modified. Glutathione (GSH) concentration is greater in the liver, kidneys and other organs and Cys incorporation into proteins is higher in the spleen and lungs. In the plasma Acute Phase Proteins are released while Albumin is decreased. The pro-inflammatory cytokines such as Interleukin-1, lnterleukin-6 and TNF-a are the main initiators altering protein and amino acid metabolism. 

Animal disease models for acquired AT deficiency, such as Escherichia cofi-induced sepsis, were used to assess the biological consistency of the rhAT compared to hpAT. Although in these models the exact contributions of the anti-coagulant and anti-inflammatory properties of AT are still somewhat controversial [81], they do allow for some comparison of the properties of rhAT with hpAT. Human plasma-derived AT has been shown to prevent the lethal effects of experimentally induced sepsis in several animal models [82-89], and to block cytokine production in vitro. To date, several dose- response studies have been performed with rhAT in rats (GTC Biother-... 

The effect of glucan on survival time and eicosanoid synthesis in the rat faecal peritonitis (LDioq) model has also been assessed . A high dose of glucan decreased survival time from 11.5 0.4 h to 7.3 0.5 h during sepsis... 

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