The endotoxic shock syndrome is characterized by systemic inflammation, multiple organ damage, circulatory collapse and death Systemic release of tumor necrosis factor (TNF)-α and other cytokines purportedly mediates this process However, the primary tissue target remains unidentified The present studies provide evidence that endotoxic shock results from disseminated endothelial apoptosis Injection of lipopolysaccharide (LPS), and its putative effector TNF-α, into C57BL/6 mice induced apoptosis in endothelium of intestine, lung, fat and thymus after 6 h, preceding nonendothelial tissue damage LPS or TNF-α injection was followed within 1 h by tissue generation of the pro-apoptotic lipid ceramide TNF-binding protein, which protects against LPS-induced death, blocked LPS-induced ceramide generation and endothelial apoptosis, suggesting systemic TNF is required for both responses Acid sphingomyelinase knockout mice displayed a normal increase in serum TNF-α in response to LPS, yet were protected against endothelial apoptosis and animal death, defining a role for ceramide in mediating the endotoxic response Furthermore, intravenous injection of basic fibroblast growth factor, which acts as an intravascular survival factor for endothelial cells, blocked LPS-induced ceramide elevation, endothelial apoptosis and animal death, but did not affect LPS-induced elevation of serum TNF-α These investigations demonstrate that LPS induces a disseminated form of endothelial apoptosis, mediated sequentially by TNF and ceramide generation, and suggest that this cascade is mandatory for evolution of the endotoxic syndrome

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Lipopolysaccharide Induces Disseminated Endothelial Apoptosis Requiring Ceramide Generation

Sepsis remains a major cause of morbidity and mortality mainly because of sepsis-induced multiple organ dysfunction. In contrast to preclinical studies, most clinical trials of promising new treatment strategies for sepsis have failed to demonstrate efficacy. Although many reasons could account for this discrepancy, the misinterpretation of preclinical data obtained from experimental studies and especially the use of animal models that do not adequately mimic human sepsis may have been contributing factors. In this review, the potentials and limitations of various animal models of sepsis are discussed to clarify to which extent these findings are relevant to human sepsis. Such models include intravascular infusion of endotoxin or live bacteria, bacterial peritonitis, cecal ligation and perforation, soft tissue infection, pneumonia or meningitis models using different animal species including rats, mice, rabbits, dogs, pigs, sheep, and nonhuman primates. Despite several limitations, animal models remain essential in the development of all new therapies for sepsis and septic shock because they provide fundamental information about the pharmacokinetics, toxicity, and mechanism of drug action that cannot be replaced by other methods. New therapeutic agents should be studied in infection models, even after the initiation of the septic process. Furthermore, debility conditions need to be reproduced to avoid the exclusive use of healthy animals, which often do not represent the human septic patient.

Experimental models of sepsis and their clinical relevance.

BACKGROUND

Protein calorie malnutrition remains endemic in hospitalized patients with both acute and chronic inflammation secondary to either cancer, chronic infectious processes, surgical injury, trauma, or burns. For the patients who cannot support themselves by enteral feeding, total parenteral nutrition remains an essential tool to minimize nitrogen losses and replete the depleted patient. However, in patients with active inflammation, nitrogen retention and lean tissue accretion are often impaired during total parenteral nutrition. Production of humoral factors, including proinflammatory cytokines, regulates many of the anabolic and catabolic processes that accompany inflammation.



METHODS

The investigators' experience with total parenteral nutrition and proinflammatory cytokines is reviewed.



RESULTS

Cytokines such as interleukin-1, tumor necrosis factor-α, and, in particular, interleukin-6 appear to play central roles in both the loss of skeletal muscle protein and the initiation of the acute phase response to inflammation, as well as in modulating the utilization of exogenously administered nutrients.



CONCLUSIONS

Although innovative second- and third-generation nutritional formulations for the acutely ill patient may represent one approach for improving the effectiveness of total parenteral nutrition, understanding the humoral response to inflammation and modifying cytokine actions pharmacologically may prove equally effective in improving the utility of exogenously administered nutrients. Future studies need to determine whether the effectiveness of exogenously administered nutrients in the patient with inflammation can be improved by efforts to modulate the proinflammatory cytokine response through cytokine inhibitors or antagonists. Cancer 1997; 79:1828-39. © 1997 American Cancer Society.

Proinflammatory cytokines, nutritional support, and the cachexia syndrome : Interactions and therapeutic options

Apoptosis is a physiologic process that serves to eliminate cells during development or in response to immunologic regulation. In acute inflammation, however, apoptosis triggered by the overproduction of "death factors" such as TNF-alpha or Fas ligand (FasL) may contribute to tissue injury. Both TNF-alpha and FasL are presumed to convey an apoptotic signal by activating a cascade of cysteine-aspartate proteases, which includes IL-1beta-converting enzyme or caspase-1. In the present study, we evaluated the contribution of TNF-alpha and FasL, as well as the role of caspase-1, in Con A-induced hepatitis. We report here that TNF-alpha and FasL mRNA and protein levels are both increased in the livers of Con A-challenged mice. Using a novel inhibitor of TNF-alpha, we can confirm that Con A-induced hepatitis is primarily TNF-alpha dependent. Blockade of FasL with a soluble Fas immunoadhesin does not prevent liver injury in animals treated with Con A alone. However, administration of a matrix metalloproteinase inhibitor exacerbates liver injury, in part through a FasL-dependent process, since pretreatment with the soluble Fas immunoadhesin reduces liver injury in this model. In addition, mice lacking functional caspase-1 are resistant to Con A-induced hepatitis, even after pretreatment with a matrix metalloproteinase inhibitor. We conclude that TNF-alpha plays a predominant role in Con A-induced liver injury, although concomitant activation of FasL can also lead to apoptotic injury. Furthermore, Con A-induced hepatitis is caspase-1 dependent.

Disparate Roles for TNF-α and Fas Ligand in Concanavalin A-Induced Hepatitis

SPECIFIC AIMThe purpose of the present study was to test the hypothesis that the catabolic state induced by burn injury, sepsis, or endotoxemia is associated with an increase in muscle myostatin mRNA content and a concomitant reduction in muscle IGF-I or IGF-II mRNA The role of endogenous glucocorticoids and tumor necrosis factor α (TNF-α) in mediating the burn-induced changes in myostatin mRNA was also assessed by treating rats with selective antagonists to these catabolic factorsPRINCIPAL FINDINGS1 Effect of burn, endotoxin, or sepsis on myostatin mRNAA full-thickness scald injury covering ∼30% of the total body surface area was produced in male rats Twenty-four hours after thermal injury, Northern blot analysis indicated that steady-state myostatin mRNA levels were increased more than threefold in the gastrocnemius (C=10±02 AU vs B=33±04 AU; P < 005) In contrast, the injection of Escherichia coli endotoxin (100 μg/100 g BW) or the induction of a polymicrobial sepsis did not significantly alt

Regulation of myostatin by glucocorticoids after thermal injury

PEG-BP-30 Monotherapy Attenuates the Cytokine-Mediated Inflammatory Cascade in Baboon Escherichia coli Septic Shock

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PEG-BP-30 Monotherapy Attenuates the Cytokine-Mediated Inflammatory Cascade in Baboon Escherichia coli Septic Shock