Abstract
The effect of L-carnitine and some of its acyl derivatives on serum TNF production and lethality in a murine experimental endotoxin shock model was investigated. In some instances, serum IL-6 production was also evaluated. In this experimental model, C57BL/6 mice received 30 mg/kg LPS (E. cell 055:B5) injected intraperitoneally, while L-carnitine and its derivatives were administered according to different schedules. Serum levels of TNF and IL-6 were evaluated 1 h following LPS injection. The treated animals were also monitored daily for differences in body temperature, feeding, and survival for 10 days after LPS injection. Although some derivatives were able to significantly affect TNF production, the marked decrease in serum TNF levels of LPS-treated mice was not paralleled by a substantial increase in survival.
Full Text
The Full Text of this article is available as a PDF (794.6 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Aarden L. A., De Groot E. R., Schaap O. L., Lansdorp P. M. Production of hybridoma growth factor by human monocytes. Eur J Immunol. 1987 Oct;17(10):1411–1416. doi: 10.1002/eji.1830171004. [DOI] [PubMed] [Google Scholar]
- Beutler B., Cerami A. The endogenous mediator of endotoxic shock. Clin Res. 1987 Apr;35(3):192–197. [PubMed] [Google Scholar]
- Beutler B., Milsark I. W., Cerami A. C. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science. 1985 Aug 30;229(4716):869–871. doi: 10.1126/science.3895437. [DOI] [PubMed] [Google Scholar]
- Border J. R., Burns G. P., Rumph C., Schenk W. G., Jr Carnitine levels in severe infection and starvation: a possible key to the prolonged catabolic state. Surgery. 1970 Jul;68(1):175–179. [PubMed] [Google Scholar]
- Bremer J. Carnitine--metabolism and functions. Physiol Rev. 1983 Oct;63(4):1420–1480. doi: 10.1152/physrev.1983.63.4.1420. [DOI] [PubMed] [Google Scholar]
- Calandra T., Baumgartner J. D., Grau G. E., Wu M. M., Lambert P. H., Schellekens J., Verhoef J., Glauser M. P. Prognostic values of tumor necrosis factor/cachectin, interleukin-1, interferon-alpha, and interferon-gamma in the serum of patients with septic shock. Swiss-Dutch J5 Immunoglobulin Study Group. J Infect Dis. 1990 May;161(5):982–987. doi: 10.1093/infdis/161.5.982. [DOI] [PubMed] [Google Scholar]
- Cerami A., Ikeda Y., Le Trang N., Hotez P. J., Beutler B. Weight loss associated with an endotoxin-induced mediator from peritoneal macrophages: the role of cachectin (tumor necrosis factor). Immunol Lett. 1985;11(3-4):173–177. doi: 10.1016/0165-2478(85)90165-8. [DOI] [PubMed] [Google Scholar]
- Cohen J., Glauser M. P. Septic shock: treatment. Lancet. 1991 Sep 21;338(8769):736–739. doi: 10.1016/0140-6736(91)91453-2. [DOI] [PubMed] [Google Scholar]
- Damas P., Reuter A., Gysen P., Demonty J., Lamy M., Franchimont P. Tumor necrosis factor and interleukin-1 serum levels during severe sepsis in humans. Crit Care Med. 1989 Oct;17(10):975–978. doi: 10.1097/00003246-198910000-00001. [DOI] [PubMed] [Google Scholar]
- Davis A. T., Crady S. K., Strong S. A., Albrecht R. M., Scholten D. J. Increased acylcarnitine clearance and excretion in septic rats. Biomed Biochim Acta. 1991;50(1):81–86. [PubMed] [Google Scholar]
- Debets J. M., Kampmeijer R., van der Linden M. P., Buurman W. A., van der Linden C. J. Plasma tumor necrosis factor and mortality in critically ill septic patients. Crit Care Med. 1989 Jun;17(6):489–494. doi: 10.1097/00003246-198906000-00001. [DOI] [PubMed] [Google Scholar]
- Dunn D. L. Role of endotoxin and host cytokines in septic shock. Chest. 1991 Sep;100(3 Suppl):164S–168S. doi: 10.1378/chest.100.3_supplement.164s. [DOI] [PubMed] [Google Scholar]
- Elliott G. R., Lauwen A. P., Bonta I. L. The effect of acute feeding of carnitine, acetyl carnitine and propionyl carnitine on basal and A23187-stimulated eicosanoid release from rat carrageenan-elicited peritoneal macrophages. Br J Nutr. 1990 Sep;64(2):497–503. doi: 10.1079/bjn19900049. [DOI] [PubMed] [Google Scholar]
- Feuerstein G., Hallenbeck J. M., Vanatta B., Rabinovici R., Perera P. Y., Vogel S. N. Effect of gram-negative endotoxin on levels of serum corticosterone, TNF alpha, circulating blood cells, and the survival of rats. Circ Shock. 1990 Mar;30(3):265–278. [PubMed] [Google Scholar]
- Fieren M. W., van den Bemd G. J., Ben-Efraim S., Bonta I. L. Prostaglandin E2 inhibits the release of tumor necrosis factor-alpha, rather than interleukin 1 beta, from human macrophages. Immunol Lett. 1992 Jan;31(1):85–90. doi: 10.1016/0165-2478(92)90015-g. [DOI] [PubMed] [Google Scholar]
- Flick D. A., Gifford G. E. Comparison of in vitro cell cytotoxic assays for tumor necrosis factor. J Immunol Methods. 1984 Mar 30;68(1-2):167–175. doi: 10.1016/0022-1759(84)90147-9. [DOI] [PubMed] [Google Scholar]
- Fong Y., Tracey K. J., Moldawer L. L., Hesse D. G., Manogue K. B., Kenney J. S., Lee A. T., Kuo G. C., Allison A. C., Lowry S. F. Antibodies to cachectin/tumor necrosis factor reduce interleukin 1 beta and interleukin 6 appearance during lethal bacteremia. J Exp Med. 1989 Nov 1;170(5):1627–1633. doi: 10.1084/jem.170.5.1627. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Franks A. K., Kujawa K. I., Yaffe L. J. Experimental elimination of tumor necrosis factor in low-dose endotoxin models has variable effects on survival. Infect Immun. 1991 Aug;59(8):2609–2614. doi: 10.1128/iai.59.8.2609-2614.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Girardin E., Grau G. E., Dayer J. M., Roux-Lombard P., Lambert P. H. Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med. 1988 Aug 18;319(7):397–400. doi: 10.1056/NEJM198808183190703. [DOI] [PubMed] [Google Scholar]
- Glauser M. P., Zanetti G., Baumgartner J. D., Cohen J. Septic shock: pathogenesis. Lancet. 1991 Sep 21;338(8769):732–736. doi: 10.1016/0140-6736(91)91452-z. [DOI] [PubMed] [Google Scholar]
- Handley D. A., Van Valen R. G., Melden M. K., Houlihan W. J., Saunders R. N. Biological effects of the orally active platelet activating factor receptor antagonist SDZ 64-412. J Pharmacol Exp Ther. 1988 Nov;247(2):617–623. [PubMed] [Google Scholar]
- Katakami Y., Nakao Y., Koizumi T., Katakami N., Ogawa R., Fujita T. Regulation of tumour necrosis factor production by mouse peritoneal macrophages: the role of cellular cyclic AMP. Immunology. 1988 Aug;64(4):719–724. [PMC free article] [PubMed] [Google Scholar]
- Kelly N. M., Cross A. S. Interleukin-6 is a better marker of lethality than tumor necrosis factor in endotoxin treated mice. FEMS Microbiol Immunol. 1992 Aug;4(6):317–322. doi: 10.1111/j.1574-6968.1992.tb05011.x. [DOI] [PubMed] [Google Scholar]
- Klosterhalfen B., Hörstmann-Jungemann K., Vogel P., Flohé S., Offner F., Kirkpatrick C. J., Heinrich P. C. Time course of various inflammatory mediators during recurrent endotoxemia. Biochem Pharmacol. 1992 May 28;43(10):2103–2109. doi: 10.1016/0006-2952(92)90167-h. [DOI] [PubMed] [Google Scholar]
- Marcinkiewicz J. In vitro cytokine release by activated murine peritoneal macrophages: role of prostaglandins in the differential regulation of tumor necrosis factor alpha, interleukin 1, and interleukin 6. Cytokine. 1991 Jul;3(4):327–332. doi: 10.1016/1043-4666(91)90501-4. [DOI] [PubMed] [Google Scholar]
- Marks J. D., Marks C. B., Luce J. M., Montgomery A. B., Turner J., Metz C. A., Murray J. F. Plasma tumor necrosis factor in patients with septic shock. Mortality rate, incidence of adult respiratory distress syndrome, and effects of methylprednisolone administration. Am Rev Respir Dis. 1990 Jan;141(1):94–97. doi: 10.1164/ajrccm/141.1.94. [DOI] [PubMed] [Google Scholar]
- Michie H. R., Manogue K. R., Spriggs D. R., Revhaug A., O'Dwyer S., Dinarello C. A., Cerami A., Wolff S. M., Wilmore D. W. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med. 1988 Jun 9;318(23):1481–1486. doi: 10.1056/NEJM198806093182301. [DOI] [PubMed] [Google Scholar]
- Mózes T., Ben-Efraim S., Tak C. J., Heiligers J. P., Saxena P. R., Bonta I. L. Serum levels of tumor necrosis factor determine the fatal or non-fatal course of endotoxic shock. Immunol Lett. 1991 Feb;27(2):157–162. doi: 10.1016/0165-2478(91)90144-y. [DOI] [PubMed] [Google Scholar]
- Nanni G., Pittiruti M., Giovannini I., Boldrini G., Ronconi P., Castagneto M. Plasma carnitine levels and urinary carnitine excretion during sepsis. JPEN J Parenter Enteral Nutr. 1985 Jul-Aug;9(4):483–490. doi: 10.1177/0148607185009004483. [DOI] [PubMed] [Google Scholar]
- Natanson C., Eichenholz P. W., Danner R. L., Eichacker P. Q., Hoffman W. D., Kuo G. C., Banks S. M., MacVittie T. J., Parrillo J. E. Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock. J Exp Med. 1989 Mar 1;169(3):823–832. doi: 10.1084/jem.169.3.823. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Niehörster M., Schönharting M., Wendel A. A novel xanthine derivative counteracting in vivo tumor necrosis factor alpha toxicity in mice. Circ Shock. 1992 Aug;37(4):270–273. [PubMed] [Google Scholar]
- Parrillo J. E., Parker M. M., Natanson C., Suffredini A. F., Danner R. L., Cunnion R. E., Ognibene F. P. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med. 1990 Aug 1;113(3):227–242. doi: 10.7326/0003-4819-113-3-227. [DOI] [PubMed] [Google Scholar]
- Pogrebniak H. W., Merino M. J., Hahn S. M., Mitchell J. B., Pass H. I. Spin trap salvage from endotoxemia: the role of cytokine down-regulation. Surgery. 1992 Aug;112(2):130–139. [PubMed] [Google Scholar]
- Schinetti M. L., Mazzini A. Effect of l-carnitine on human neutrophil activity. Int J Tissue React. 1986;8(3):199–203. [PubMed] [Google Scholar]
- Shaunak S., Wendon J., Monteil M., Gordon A. M. Septic scarlet fever due to Streptococcus pyogenes cellulitis. Q J Med. 1988 Nov;69(259):921–925. [PubMed] [Google Scholar]
- Starnes H. F., Jr, Warren R. S., Jeevanandam M., Gabrilove J. L., Larchian W., Oettgen H. F., Brennan M. F. Tumor necrosis factor and the acute metabolic response to tissue injury in man. J Clin Invest. 1988 Oct;82(4):1321–1325. doi: 10.1172/JCI113733. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Strieter R. M., Remick D. G., Ward P. A., Spengler R. N., Lynch J. P., 3rd, Larrick J., Kunkel S. L. Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxifylline. Biochem Biophys Res Commun. 1988 Sep 30;155(3):1230–1236. doi: 10.1016/s0006-291x(88)81271-3. [DOI] [PubMed] [Google Scholar]
- Takeyama N., Takagi D., Matsuo N., Kitazawa Y., Tanaka T. Altered hepatic fatty acid metabolism in endotoxicosis: effect of L-carnitine on survival. Am J Physiol. 1989 Jan;256(1 Pt 1):E31–E38. doi: 10.1152/ajpendo.1989.256.1.E31. [DOI] [PubMed] [Google Scholar]
- Tracey K. J., Fong Y., Hesse D. G., Manogue K. R., Lee A. T., Kuo G. C., Lowry S. F., Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987 Dec 17;330(6149):662–664. doi: 10.1038/330662a0. [DOI] [PubMed] [Google Scholar]
- Van der Meer J. W., Helle M., Aarden L. Comparison of the effects of recombinant interleukin 6 and recombinant interleukin 1 on nonspecific resistance to infection. Eur J Immunol. 1989 Feb;19(2):413–416. doi: 10.1002/eji.1830190229. [DOI] [PubMed] [Google Scholar]
- Vassalli P. The pathophysiology of tumor necrosis factors. Annu Rev Immunol. 1992;10:411–452. doi: 10.1146/annurev.iy.10.040192.002211. [DOI] [PubMed] [Google Scholar]
- Waage A., Brandtzaeg P., Halstensen A., Kierulf P., Espevik T. The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin 6, interleukin 1, and fatal outcome. J Exp Med. 1989 Jan 1;169(1):333–338. doi: 10.1084/jem.169.1.333. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yoshitake J., Nomoto Y., Kono S., Takasugi S., Tada S., Yoshimura N., Oda T. Metabolic deterioration in shock state and its modulation. Prog Clin Biol Res. 1983;111:21–38. [PubMed] [Google Scholar]
- Zhang Y., Lin J. X., Vilcek J. Synthesis of interleukin 6 (interferon-beta 2/B cell stimulatory factor 2) in human fibroblasts is triggered by an increase in intracellular cyclic AMP. J Biol Chem. 1988 May 5;263(13):6177–6182. [PubMed] [Google Scholar]