Endotoxemia in Animals

In a short-term study, Giacometti and coworkers investigated the antiendotoxin activity and therapeutic efficacy of sheep myeloid antimicrobial peptide-29 (SMAP-29), a cathelicidin-derived peptide. SMAP-29 reduced lethality in rat models of intraperitoneal endotoxin injury as well as intraabdominal sepsis from cecal ligation by puncture. SMAP-29 resulted in a significant decrease in endotoxin and TNF- ${alpha}$ plasma concentrations when compared with antibiotic treatment with imipenem and saline treatment, although it exhibited slightly lower antimicrobial activity than imipenem. Some antibiotics can be harmful when administered for treatment for severe gram-negative infections because they can stimulate the release of endotoxin. Thus, there is value to alternative compounds, such as cationic peptides that can kill bacteria and neutralize the effects of endotoxin.

To determine the role of endogenous IL-6 in endotoxin-induced liver injury, Sewnath and coworkers induced extrahepatic cholestasis by bile duct ligation in IL-6^+/+ and IL-6^–/– mice. Hepatic pathology did not show any differences 2 weeks after biliary obstruction, but endotoxin challenge (4 µg/kg intraperitoneally) increased mortality (81%) and liver injury in IL-6^–/– mice compared with IL-6^+/+ mice (44%). Plasma cytokine levels, including IL-1 ${alpha}$ , IL-1ß, and TNF- ${alpha}$ , measured 6 hours after endotoxin challenge significantly increased in cholestatic IL-6^–/– mice. Endotoxin caused neutrophil influx and increases in myeloperoxidase and TNF- ${alpha}$ in lung tissue and lung edema in cholestatic IL-6^–/– mice compared with cholestatic IL-6^+/+ mice. The authors concluded that endogenous IL-6 plays an important role in decreasing hypersensitivity to endotoxin in cholestasis.

ß-Lapachone, a 1,2-naphthoquinone, is a novel chemotherapeutic agent, which is capable of suppressing expression and function of nitric oxide synthase in rat alveolar macrophages. Tzeng and coworkers investigated the molecular mechanisms for the actions of ß-lapachone on the response of rat alveolar macrophages to lipopolysaccharide. Lipopolysaccharide increased the production of nitrite and expression of inducible nitric oxide synthase in macrophages; these actions were inhibited by coincubation with ß-lapachone. Lipopolysaccharide induced the production of tumor necrosis factor- ${alpha}$ ; this action was inhibited by ß-lapachone. Lipopolysaccharide induced phosphorylation of protein tyrosine and binding activity of nuclear factor- ${kappa}$ B in macrophages; these actions were significantly inhibited by ß-lapachone. In in vivo studies, ß-lapachone protected against the development of lung edema, protein expression of inducible nitric oxide synthase, activation of nuclear factor- ${kappa}$ B, plasma nitrite, serum tumor necrosis factor- ${alpha}$ , and mortality induced by lipopolysaccharide. The authors conclude that ß-lapachone suppresses the induction of inducible nitric oxide synthase and production of tumor necrosis factor- ${alpha}$ mediated by inhibiting the phosphorylation of tyrosine kinase and activation of nuclear factor- ${kappa}$ B that is caused by lipopolysaccharide.

In a rat model of acute lung injury induced by lipopolysaccharide, Agorreta and coworkers investigated the effect of hypoxia on expression of nitric oxide synthase-2 (the endothelial, inducible isoform of the enzyme). Exposure to hypoxia alone had no effect on the expression of nitric oxide synthase-2 in rat lungs. Intraperitoneal injection of lipopolysaccharide increased the level of nitric oxide synthase-2 in the lungs, which was further enhanced by concomitant exposure to hypoxia. Resident lung cells showed no changes in the expression of nitric oxide synthase-2 under any conditions. In in vitro experiments, lung epithelial and endothelial cell lines showed no detectable expression of nitric oxide synthase-2 with any treatment. In a macrophage cell line, expression of nitric oxide synthase-2 in response to lipopolysaccharide was not affected by concomitant exposure to hypoxia. The authors conclude that the increase in nitric oxide synthase-2 in acute lung injury caused by lipopolysaccharide results from recruitment of leukocytes that produce the enzyme, and that concomitant hypoxia increases leukocyte recruitment and further enhances the expression of nitric oxide synthase-2.

Because mitochondria are the principal organelles that consume oxygen and generate reactive oxygen species, Suliman and coworkers determined whether cell activation by lipopolysaccharide would cause damage to mitochondria through activation of mitochondrial DNA. A single injection of lipopolysaccharide caused a decrease in copy number of mitochondrial DNA in the liver of rats. Lipopolysaccharide caused an oxidant-dependent 3.8-kb mitochondrial DNA deletion in the region encoding NADH dehydrogenase subunits 1 and 2 and cytochrome c oxidase subunit I (which correlated with depletion of mitochondrial glutathione). Expression of mitochondrial messenger RNA and transcription of mitochondrial RNA were suppressed; expression of messenger RNA was increased for selected nuclear-encoded mitochondrial proteins. Resolution of the damage to mitochondrial DNA was mediated by importing mitochondrial transcription factor A protein (a central regulator of the copy number of mitochondrial DNA), accompanied by binding of mitochondrial protein extract to the mitochondrial transcription factor A DNA–binding site. The authors conclude that hepatic injury induced by lipopolysaccharide is associated with a specific oxidative mitochondrial DNA deletion, which inhibits mitochondrial transcription and is restored by activation of mechanisms that lead to biogenesis.

Citations 1-5 of 5 total displayed.

Cholestatic Interleukin-6–Deficient Mice Succumb to Endotoxin-induced Liver Injury and Pulmonary Inflammation

Miguel E. Sewnath, Tom van der Poll, Cornelis J. F. van Noorden, Fiebo J. W. ten Kate, and Dirk J. Gouma
Am. J. Respir. Crit. Care Med. 169: 413 -420. First published online as doi:10.1164/rccm.200303-311OC [Abstract] [Full text]

Cathelicidin Peptide Sheep Myeloid Antimicrobial Peptide-29 Prevents Endotoxin-induced Mortality in Rat Models of Septic Shock

Andrea Giacometti, Oscar Cirioni, Roberto Ghiselli, Federico Mocchegiani, Giuseppina D'Amato, Raffaella Circo, Fiorenza Orlando, Barbara Skerlavaj, Carmela Silvestri, Vittorio Saba, Margherita Zanetti, and Giorgio Scalise
Am. J. Respir. Crit. Care Med. 169: 187 -194. First published online as doi:10.1164/rccm.200307-971OC [Abstract] [Full text]

Effects of Acute Hypoxia and Lipopolysaccharide on Nitric Oxide Synthase-2 Expression in Acute Lung Injury

Jackeline Agorreta, Mercedes Garayoa, Luis M. Montuenga, and Javier J. Zulueta
Am. J. Respir. Crit. Care Med. 168: 287 -296. First published online as doi:10.1164/rccm.200209-1027OC [Abstract] [Full text]

ß-Lapachone Reduces Endotoxin-induced Macrophage Activation and Lung Edema and Mortality

Huei-Ping Tzeng, Feng-Ming Ho, Kuo-Fang Chao, Min-Liang Kuo, Shoei-Yn Lin-Shiau, and Shing-Hwa Liu
Am. J. Respir. Crit. Care Med. 168: 85 -91. First published online as doi:10.1164/rccm.200209-1051OC [Abstract] [Full text]

Postlipopolysaccharide Oxidative Damage of Mitochondrial DNA

Hagir B. Suliman, Martha S. Carraway, and Claude A. Piantadosi
Am. J. Respir. Crit. Care Med. 167: 570 -579. First published online as doi:10.1164/rccm.200206-518OC [Abstract] [Full text]

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