Skip to main content
NCBI home page
Springer Nature - PMC COVID-19 Collection logoLink to Springer Nature - PMC COVID-19 Collection
. 2000;32(4):179–184. [Article in German] doi: 10.1007/BF02949260

Liposomen-mediierter Gentransfer — die zukünftige Therapieform bei Sepsis und intraabdomineller Infektion?

Liposome mediated gene transfer — the future therapy for sepsis and intraabdominal infection?

M A Rogy 1,✉, B G Beinhauer 1, M Fang 1
PMCID: PMC7102152  PMID: 32287332

Summary

Background: It is now generally accepted that over-production of pro-inflammatory cytokines (TNF-α, IL-1β) produced by inflammatory cells contributes to the pathological consequences of septic shock. Neutralizing this exaggerated immune response by monoclonal antibodies (anti-TNF-α), receptor antagonists (IL-1rα) and anti-inflammatory cytokines (IL-10) did not result in a better outcome in septic patients. Firstly, this is due to the short biological half-lives of these natural antagonists or inhibitors of pro-inflammatory cytokines. Secondly, exaggerated pro-inflammatory cytokine production may contribute to pathology in one body compartment while, simultaneously, the same mediators may have beneficial effects in another compartment. Thus, systemic administration of cytokine inhibitors at levels sufficient to neutralize exaggerated cytokine production in one organ may also block the presumably beneficial aspects of cytokine production in another.

Methods: Our own results of animal experiments of the liposome mediated gene transfer are presented.

Results: Liposome mediated gene transfer seems to be a promising low-risk alternative to systemic anti-inflammatory therapies as it ensures the local delivery of high doses of cytokine inhibitors and antagonists over a prolonged period of time.

Conclusions: The pathophysiological mechanism of sepsis and septic shock are well established. The concept of local intervention or compartimental blockade of overwhelming mediator production by gene transfer will be a new challenge in the future.

Keywords: Septic shock, gene transfer, liposomes, pro-inflammatory response, anti-inflammatory response

Literatur

  • (1).Alexander HR, Doherty GM, Venzon DJ, Merino MJ, Fraker DL, Norton JA. Recombinant interleukin-1 receptor antagonist (IL-1rα): effective therapy against gram-negative sepsis in rats. Surgery. 1992;112:188–193. [PubMed] [Google Scholar]
  • (2).Anderson WF. Human gene therapy. Science. 1992;256:808–813. doi: 10.1126/science.1589762. [DOI] [PubMed] [Google Scholar]
  • (3).Ashkenazi A, Marsters SA, Capon DJ, Chamow SM, Figari IS, Pennica D, Goeddel DV, Palladino MA, Smith DH. Protection against endotoxic shock by a tumor necrosis factor receptor immunoadhesin. Proc Natl Acad Sci USA. 1991;88:10535–10539. doi: 10.1073/pnas.88.23.10535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (4).Baumhofer JM, Beinhauer BG, Wang JE, Brandmeier H, Geissler K, Losert UM, Philip R, Aversa G, Rogy MA. Gene transfer with IL-4 and IL-13 improves survival in lethal endotoxemia in the mouse and ameliorates peritoneal macrophage immune competence. Eur J Immunol. 1998;28:610–615. doi: 10.1002/(SICI)1521-4141(199802)28:02<610::AID-IMMU610>3.0.CO;2-5. [DOI] [PubMed] [Google Scholar]
  • (5).Beutler B, Krochin N, Milsark IW, Luedke C, Cerami A. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science. 1986;232:977–980. doi: 10.1126/science.3754653. [DOI] [PubMed] [Google Scholar]
  • (6).Beutler BA, Milsark IW, Cerami A. Cachectin/tumor necrosis factor: production, distribution and metabolic fatein vivo. J Immunol. 1985;135:3972–3977. [PubMed] [Google Scholar]
  • (7).Beutler B, Cerami A. Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature. 1986;320:584–588. doi: 10.1038/320584a0. [DOI] [PubMed] [Google Scholar]
  • (8).Block MI, Berg M, McNamara MJ, Norton JA, Fraker DI, Alexander HR. Passive immunization of mice against D factor blocks lethality and cytokine release during endotoxemia. J Exp Med. 1993;178:1085–1099. doi: 10.1084/jem.178.3.1085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (9).Bone RC. The pathogenesis of sepsis. Ann Intern Med. 1991;115:457–469. doi: 10.7326/0003-4819-115-6-457. [DOI] [PubMed] [Google Scholar]
  • (10).Bone RC. Monoclonal antibodies to tumor necrosis factor in sepsis: help or harm? Crit Care Med. 1993;21:311–312. doi: 10.1097/00003246-199303000-00001. [DOI] [PubMed] [Google Scholar]
  • (11).Cerami A. Tumor necrosis factor as a mediator of shock, cachexia and inflammation. Blood Purif. 1993;11:108–117. doi: 10.1159/000170104. [DOI] [PubMed] [Google Scholar]
  • (12).Cournoyer D, Caskey CT. Gene therapy of the immune system. Annu Rev Immunol. 1993;11:297–329. doi: 10.1146/annurev.iy.11.040193.001501. [DOI] [PubMed] [Google Scholar]
  • (13).Czuprynski CJ, Haak Frenscho M, Maroushek N, Brown JF. Effects of recombinant human interleukin-6 alone and in combination with recombinant interleukin-1 alpha and tumor necrosis factor alpha on antibacterial resistance in mice. Antimicrob Agents Chemother. 1992;36:68–70. doi: 10.1128/aac.36.1.68. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (14).Debs R, Pian M, Gaensler K, Clements J, Friend DS, Dobbs L. Prolonged transgene expression in rodent lung cells. Am J Respir Cell Mol Biol. 1992;7:406–413. doi: 10.1165/ajrcmb/7.4.406. [DOI] [PubMed] [Google Scholar]
  • (15).Donahue RE, Kessler SW, Bodine D, McDonagh K, Dunbar C, Goodman S, Agricola B, Byrne E, Raffeld M, Moen R. Helper virus induced T cell lymphoma in non-human primates after retroviral mediated gene transfer. J Exp Med. 1992;176:1125–1135. doi: 10.1084/jem.176.4.1125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (16).Echtenacher B, Falk W, Mannel DN, Krammer PH. Requirement of endogenous tumor necrosis factor/cachectin for recovery from experimental peritonitis. J Immunol. 1990;145:3762–3766. [PubMed] [Google Scholar]
  • (17).Ellison V, Abrams H, Roe T, Lifson J, Brown P. Human immunodeficiency virus integration in a cell-free system. J Virol. 1990;64:2711–2715. doi: 10.1128/jvi.64.6.2711-2715.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (18).Felgner PL, Gadek TR, Holm M, Roman R, Chan HW, Wenz M, Northrop JP, Ringold GM, Danielson M. Lipofectin: A highly efficient, lipid-mediated DNA-transfection procedure. Proc Natl Acad Sci USA. 1987;84:7413–7417. doi: 10.1073/pnas.84.21.7413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (19).Felgner PL, Ringold GM. Cationic liposome-mediated transfection. Nature. 1989;337:387–388. doi: 10.1038/337387a0. [DOI] [PubMed] [Google Scholar]
  • (20).Felgner PL, Rhodes G. Gene therapeutics. Nature. 1991;349:351–352. doi: 10.1038/349351a0. [DOI] [PubMed] [Google Scholar]
  • (21).Felgner JH, Kumar R, Sridhar CN, Wheeler CJ, Tsai YJ, Border R, Ramsey P, Martin M, Felgner PL. Enhanced gene delivery and mechanism studies with a novel series of cationic lipid formulations. J Biol Chem. 1994;269:2550–2561. [PubMed] [Google Scholar]
  • (22).Fisher CJ, Opal SM, Dhainaut JF, Stephens S, Zimmerman JL, Nightingale P, Harris SJ, Schein RM, Panacek EA, Vincent JL, et al. Influence on an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. The CB0006 Sepsis Syndrome Study Group. Crit Care Med. 1993;21:318–327. doi: 10.1097/00003246-199303000-00006. [DOI] [PubMed] [Google Scholar]
  • (23).Fischer E, Marano MA, Van Zee KJ, Rock CS, Hawes AS, Thompson WA, DeForge L, Kenney JS, Remick DG, Bloedow DC, et al. Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock but fails to alter host responses to sublethal endotoxemia. J Clin Invest. 1992;89:1551–1557. doi: 10.1172/JCI115748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (24).Fisher CJ, Slotman GJ, Opal SM, Pribble JP, Bone RC, Emmanuel G, Ng D, Bloedow DC, Catalano MC, et al. IL-1rα Sepsis Syndrome Study Group Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome. A randomized open-label, placebo-controlled multicenter trial. Crit Care Med. 1994;22:12–21. doi: 10.1097/00003246-199404000-00008. [DOI] [PubMed] [Google Scholar]
  • (25).Fischer E, Marano MA, Barber AE, Hudson A, Lee K, Rock CS, Hawes AS, Anderson TD, Benjamin WR, Lowry SF, Moldawer LL. Comparison between effects of interleukin-1 alpha administration and sublethal endotoxemia in primates. Am J Physiol. 1991;26:R442–452. doi: 10.1152/ajpregu.1991.261.2.R442. [DOI] [PubMed] [Google Scholar]
  • (26).Fischer E, Van Zee KJ, Marano MA, Rock CS, Kenney JS, Poutsiaka DD, Dinarello CA, Lowry SF, Moldawer LL. Interleukin-1 receptor antagonist circulates in experimental inflammation and in human disease. Blood. 1992;79:2196–2200. [PubMed] [Google Scholar]
  • (27).Fisher CJ, Dhainaut J-FA, Opal SM, Pribble JP, Balk RA, Slotman GJ, Iberti TJ, Rackow EC, Shapiro MJ, Greenman RL, Reines HD, Shelly MP, Thompson BW, LaBrecque JF, Catalano MA, Knaus WA, Sadoff JC. Recombinant human interleukin-1 receptor antagonist in the treatment of patients with sepsis syndrome: Results from a randomized, double-blind, placebo-controlled trial. JAMA. 1994;271:1836–1843. doi: 10.1001/jama.271.23.1836. [DOI] [PubMed] [Google Scholar]
  • (28).Fong Y, Moldawer LL, Shires GT, Lowry SF. The biologic characteristics of cytokines and their implication in surgical injury. Surg Gynecol Obstet. 1990;170:363–378. [PubMed] [Google Scholar]
  • (29).Fong Y, Tracey KJ, Moldawer LL, Hesse DG, Manogue KB, Kenney JS, Lee AT, Kuo GC, Allison AC, Lowry SF, et al. Antibodies to cachectin/tumor necrosis factor reduce interleukin-1 beta and interleukin-6 appearance during lethal bacteremia. J Exp Med. 1989;170:1627–1633. doi: 10.1084/jem.170.5.1627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (30).Gerard C, Bruyns C, Marchant A, Abramowicz D, Vandenabeele P, Delvaux A, Fiers W, Goldman M, Velu T. Interleukin-10 reduces the release of tumor necrosis factor and prevents lethality in experimental endotoxemia. J Exp Med. 1993;177:547–550. doi: 10.1084/jem.177.2.547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (31).Ginsberg HS, Moldawer LL, Sehgal PB, Redington M, Kilian PL, Chanock RM, Prince GA. A mouse model for investigating the molecular pathogenesis of adenovirus pneumonia. Proc Natl Acad Sci USA. 1991;88:1651–1655. doi: 10.1073/pnas.88.5.1651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (32).Granowitz EV, Vannier E, Poutsiaka DD, Dinarello CA. Effect of interleukin-1 (IL-1) blockade on cytokine synthesis: II IL-1 receptor antagonist inhibits lipopolysaccharide-induced cytokine synthesis by human monocytes. Blood. 1992;79:2364–2369. [PubMed] [Google Scholar]
  • (33).Haak Frendscho M, Kurtz RS, Czuprynski CJ. rIL-1 alpha enhances adoptive transfer of resistance to Listeria monocytogenes infection. Microb Pathog. 1991;10:385–392. doi: 10.1016/0882-4010(91)90083-M. [DOI] [PubMed] [Google Scholar]
  • (34).Hinshaw LB, Tekamp Olson P, Chang AC, Lee PA, Taylor FB, Murray CK, Peer GT, Emerson TE, Passey RB, Kuo GC. Survival of primates in LD100 septic shock following therapy with antibody to tumor necrosis factor (TNF alpha) Circ Shock. 1990;30:279–292. [PubMed] [Google Scholar]
  • (35).Howard M, Muchamuel T, Andrade S, Menon S. Interleukin-10 protects mice from lethal endotoxemia. J Exp Med. 1993;177:1205–1208. doi: 10.1084/jem.177.4.1205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (36).Kaneda Y, Kunimitsu I, Uchida T. Increased Expression of DNA cointruduced with Nuclear Protein in Adult Rat Liver. Science. 1989;243:375–378. doi: 10.1126/science.2911748. [DOI] [PubMed] [Google Scholar]
  • (37).Kenefick KB, Adams JL, Steinberg H, Czuprynski CJ. In vivo administration of a monoclonal antibody against the type I IL-1 receptor inhibits the ability of mice to eliminate Mycobacterium paratuberculosis. J Leukocyte Biol. 1994;55:719–722. doi: 10.1002/jlb.55.6.719. [DOI] [PubMed] [Google Scholar]
  • (38).Kotin RM, Siniscalco M, Samulski RJ, Zhu XD, Hunter L, Laughlin CA, McLaughlin S, Muzyczka N, Rocchi M, Berns KI. Site-specific integration by adeno-associated virus. Proc Natl Acad Sci USA. 1990;87:2211–2215. doi: 10.1073/pnas.87.6.2211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (39).Kriegler M, Perez C, DeFay K, Albert I, Lu SD. A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell. 1988;53:45–53. doi: 10.1016/0092-8674(88)90486-2. [DOI] [PubMed] [Google Scholar]
  • (40).Lesslauer W, Tabuchi H, Gentz R, Brockhaus M, Schlaeger EJ, Grau G, Piguet PF, Pointaire P, Vassalli P, Loetscher H. Recombinant soluble tumor necrosis factor receptor proteins protect mice from lipopolysaccharide-induced lethality. Eur J Immunol. 1991;21:2883–2886. doi: 10.1002/eji.1830211134. [DOI] [PubMed] [Google Scholar]
  • (41).Mancilla J, Garcia P, Dinarello CA. The interleukin-1 receptor antagonist can either reduce or enhance the lethality of Klebsiella pheumoniae sepsis in newborn rats. Infect Immun. 1993;61:926–932. doi: 10.1128/iai.61.3.926-932.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (42).Mathison JC, Wolfson E, Ulevitch RJ. Participation of tumor necrosis factor in the mediation of gram-negative bacterial lipopolysaccharide-induced injury in rabbits. J Clin Invest. 1988;81:1925–1937. doi: 10.1172/JCI113540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (43).Morsy MA, Mitani K, Clemens P, Caskey T. Progress toward human gene therapy. JAMA. 1993;270:2338–2345. doi: 10.1001/jama.270.19.2338. [DOI] [PubMed] [Google Scholar]
  • (44).Mulligan RC. The basic science of gene therapy. Science. 1991;260:926–932. doi: 10.1126/science.8493530. [DOI] [PubMed] [Google Scholar]
  • (45).Ohlsson K, Bjork P, Bergenfeldt M, Hageman R, Thompson RC. Interleukin-1 receptor antagonist reduces mortality from endotoxin shock. Nature. 1990;348:550–552. doi: 10.1038/348550a0. [DOI] [PubMed] [Google Scholar]
  • (46).Perez C, Albert I, DeFay K, Zachariades N, Godding L, Kriegler M. A nonsecretable cell surface mutant of tumor necrosis factor (TNF) kills by cell-to cell contact. Cell. 1990;63:251–258. doi: 10.1016/0092-8674(90)90158-B. [DOI] [PubMed] [Google Scholar]
  • (47).Philip R, Liggitt D, Philip M, Dazin P, Debs R: In vivo gene delivery efficient transfection of T lymphocytes in adult mice. J Biol Chem 1993; 16087–16090. [PubMed]
  • (48).Roe T, Reynolds TC, Yu G, Brown PO. Integration of murine leukemia virus DNA depends on mitosis. EMBO J. 1993;12:2099–2108. doi: 10.1002/j.1460-2075.1993.tb05858.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (49).Rogy MA, Lutge B, Espat NJ, Copeland EM, Moldawer LL. Human TNF receptor and Interleukin-10 gene transfer in the mouse reduces mortality to lethal endotoxemia. Surgical Forum. 1994;XLV:21–23. [Google Scholar]
  • (50).Rogy MA, Auffenberg T, Espat NJ, Philip R, Remick D, Wollenberg GK, Copeland EM, Moldawer LL. Human tumor necrosis factor receptor p55 and IL-10 gene transfer in the mouse reduces mortality to lethal endotoxemia and also attenuates local inflammatory responses. J Exp Med. 1995;181:2289–2293. doi: 10.1084/jem.181.6.2289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (51).Roll JT, Young KM, Kurtz RS, Czuprynski CJ. Human rTNF alpha augments anti-bacterial resistance in mice: potentiation of ist effects by recombinant human rIL-1 alpha. Immunology. 1990;69:316–322. [PMC free article] [PubMed] [Google Scholar]
  • (52).Rothe J, Lesslauer W, Lotscher H, Lang Y, Koebel P, Kontgen F, Althage A, Zinkernagel R, Steinmetz M, Bluethmann H. Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature. 1993;364:798–802. doi: 10.1038/364798a0. [DOI] [PubMed] [Google Scholar]
  • (53).Rothstein JL, Schreiber H. Synergy between tumor necrosis factor and bacterial products causes hemorrhagic necrosis and lethal shock in normal mice. Proc Natl Acad Sci USA. 1988;85:607–611. doi: 10.1073/pnas.85.2.607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (54).Rosenfeld MA, Siegfried W, Yoshimura K, Yoneyama K, Fukayama M, Stier LE, Paakko PK, Gilardi P, Stratford-Perricaudet LD, Perricaudet M, Jallat S, Pavirani A, Lecocq JP, Crystal RG. Adenovirus-Mediated Transfer of a Recombinant 1-Antitrypsin Gene to the Lung Epithelium in vivo. Science. 1991;252:431–434. doi: 10.1126/science.2017680. [DOI] [PubMed] [Google Scholar]
  • (55).Salmons B, Gunzburg WH. Targeting of retroviral vectors for gene therapy. Hum Gene Ther. 1993;4:129–141. doi: 10.1089/hum.1993.4.2-129. [DOI] [PubMed] [Google Scholar]
  • (56).Schmidt E, Christoph G, Zeller R, Leder P. Cytomegalovirus enhancer: a pan-active control element in transgenic mice. Mol Cell Biol. 1990;10:4406–4411. doi: 10.1128/mcb.10.8.4406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (57).Stribling R, Brunette E, Liggitt D, Gaensler K, Debs R. Aerosol gene delivery in vivo. Proc Natl Acad Sci USA. 1992;89:11277–11281. doi: 10.1073/pnas.89.23.11277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (58).Suter PM, Suter S, Girardin E, Roux Lombard P, Grau GE, Dayer JM. High bronchoalveolar levels of tumor necrosis factor and its inhibitors interleukin-1, interferon and elastase, in patients with adult respiratory distress syndrome after trauma, shock, or sepsis. Am Rev Respir Dis. 1992;145:1016–1022. doi: 10.1164/ajrccm/145.5.1016. [DOI] [PubMed] [Google Scholar]
  • (59).Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987;330:662–664. doi: 10.1038/330662a0. [DOI] [PubMed] [Google Scholar]
  • (60).Tracey KJ, Wei H, Manogue KR, Fong Y, Hesse DG, Nguyen HAT, Kuo GC, Beutler B, Cotran RS, Cerami A, et al. Cachectin/tumor necrosis factor induces cachexia, anemia and inflammation. J Exp Med. 1988;167:1211–1227. doi: 10.1084/jem.167.3.1211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (61).Tracey KJ, Lowry SF, Fahey TJ, Albert JD, Fong Y, Hesse DG, Beutler B, Manogue KR, Calvano S, Wei H, et al. Cachectin/tumor necrosis factor induces lethal shock and stress hormone response in the dog. Surg Gynecol Obstet. 1987;164:415–422. [PubMed] [Google Scholar]
  • (62).Van Zee KJ, Kohno T, Fischer E, Rock CS, Moldawer LL, Lowry SF. Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo. Proc Natl Acad Sci USA. 1992;89:4845–4849. doi: 10.1073/pnas.89.11.4845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (63).Van der Meer JW, Vogels M, Curfs JH, Eling WM. Interleukin-1 as a possible agent for treatment of infection. Eur J Clin Microbiol Infect Dis. 1993;12(Suppl 1):S73–S77. doi: 10.1007/BF02389883. [DOI] [PubMed] [Google Scholar]
  • (64).Van der Meer JW, 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;19:413–416. doi: 10.1002/eji.1830190229. [DOI] [PubMed] [Google Scholar]
  • (65).Waage A, Espervik T. Interleukin-1 potentiates the lethal effect of tumor necrosis factor alpha/cachectin in mice. J Exp Med. 1988;167:1987–1992. doi: 10.1084/jem.167.6.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (66).Wakabayashi G, Gelfand JA, Burke JF, Thompson RC, Dinarello CA. A specific receptor antagonist for interleukin-1 prevents Escherichia coli-induced shock in rabbits. FASEB J. 1991;5:338–343. doi: 10.1096/fasebj.5.3.1825816. [DOI] [PubMed] [Google Scholar]

Articles from Acta Chirurgica Austriaca are provided here courtesy of Nature Publishing Group

RESOURCES