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Complement-mediated acute effects of liposome-encapsulated hemoglobin

ARTIFICIAL CELLS BLOOD SUBSTITUTES AND IMMOBILIZATION BIOTECHNOLOGY 1999年第1期27卷 23-41页

作者： Szebeni, J Alving, CR Walter Reed Army Inst Res Dept Membrane Biochem Washington DC 20307 USA

Recent studies an liposome-encapsulated hemoglobin (LEH) have indicated that this potential blood substitute can activate the complement (C) system of rats, pigs and man. The reaction can involve both the classical and the alternative pathways, and is mediated, in part, by the binding of natural anti-lipid antibodies to the lipid membrane of liposomes. The significance of these discoveries lies in the fact that C activation appears to be the primary cause of the acute physiological, hematological and laboratory changes that have been observed previously in rats and pigs following the administration of LEH or liposomes, which changes include pulmonary vasoconstriction with decreased cardiac output. In light of the proposed use of LEH as an emergency blood substitute, the latter impairment of cardiopulmonary function may warrant particular circumspection as it could aggravate the clinical state of trauma patients who are prone to develop respiratory distress partly as a consequence of C activation by the injury. Our studies on rats and pigs suggest that the above acute side effects of LEH, including the cardiopulmonary distress, can be efficiently inhibited with soluble complement receptor type I, a specific inhibitor of C activation.

关键词：血液代用品/药理学心排血量/药物作用补体激活/药物作用药物载体血红蛋白类/药理学脂质体/药理学受体补体/代谢血管收缩/药物作用动物人类大鼠

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Application of oligo-(14-amino-3,6,9,12-tetraoxatetradecanoic acid) lipid conjugates as steric barrier molecules in liposomal formulations

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BIOCONJUGATE CHEMISTRY 1999年第4期10卷 653-666页

作者： Ansell, SM Kojic, LD Hankins, JS Sekirov, L Boey, A Lee, DK Bennett, AR Klimuk, SK Harasym, TO Dos Santos, N Semple, SC Inex Pharmaceut Corp Burnaby BC V5J 5J8 Canada

Lipid conjugates of oligo-(14-amino-3,6,9,12-tetraoxatetradecanoic acid) (ATTAn) were synthesized as monodisperse analogues of poly(ethylene glycol) (PEG) derivatives used in liposomal drug delivery systems. The new lipids were shown to be at least equivalent to MePEGA-2000-DSPE in assays designed to evaluate the effectiveness of polymers as steric barrier molecules in liposomes. Liposomes containing 1-5% of ATTA8-DSPE (octamer) showed comparable long circulation behavior relative to PEG-2000-DSPE analogues. Surprisingly, the shorter ATTA4-DSPE (tetramer) appeared to be quite effective in reducing clearance. Liver enzyme levels and systemic single dose tolerability of ATTA8-DSPE liposomes were comparable to controls, suggesting that the new materials are nontoxic. Prolonged exposure of ATTA8-DSPE liposomes to splenocytes in vitro showed no evidence of mitogenicity relative to controls or MePEGA-2000-DSPE liposomes. ATTA8-DSPE was as effective as MePEGC-2000-DSPE in preventing complement activation by cationic liposome systems. Repeat dosage in vivo regimes in ICR mice using DSPC/cholesterol liposomes, with and without 5% ATTA8-DSPE and MePEGC-2000-DSPE, showed no evidence of enhanced clearance on successive doses. Splenocytes recovered after repeat doses showed no significant evidence of mitogenicity on restimulation with liposomes. Cellular differentiation and activation marker levels in splenocytes recovered after the fourth in vivo administration were at normal levels. These results suggest that ATTAn oligomers do not induce an immune response in isolation. It was demonstrated that ATTA8-DSPE could be used to replace PEG-lipids in the formulation of doxorubicin, plasmid DNA and oligonucleotides using a variety of formulation techniques. The study demonstrates that ATTAn oligomers can be safely and effectively used in place of poly(ethylene glycol) as well-defined biomaterials in liposomal applications where reproducible behavior is critical.

关键词：抗生素类抗肿瘤/投药和剂量补体激活/药物作用细胞因子类/化学多柔比星/投药和剂量药物载体/化学酶联免疫吸附测定荧光染料/化学指示剂和试剂脂类/化学脂质体/化学小鼠近交BALBC 有丝分裂原/毒性肉豆蔻酸类/化学肉豆蔻酸类/毒性寡核苷酸类反义/化学有机化学品药物附加剂/化学表型聚乙烯二醇类/化学动物女(雌)性小鼠

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C3-ACTIVATION BY MONOSODIUM URATE MONOHYDRATE AND OTHER CRYSTALLINE MATERIAL

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ARTHRITIS AND RHEUMATISM 1979年第6期22卷 571-578页

作者： HASSELBACHER, P DARTMOUTH COLL SCH MED HANOVER NH 03755 USA UNIV PENN SCH MED PHILADELPHIA PA 19174 USA

Monosodium urate monohydrate (MSUM) is a potent activator of the complement [C] system, as measured by electrophoretic conversion of .beta.1C to .beta.1A. Activation of C3 in human serum by MSUM was time- and dose-dependent. The sensitivity of the assay allowed detection of C3 activation by as little as 0.2 mg/ml of MSUM. C3 activation was Ca dependent and eliminated by EDTA and EGTA [ethylene glycol bis tetraacetic acid], demonstrating the major role of the classic pathway of C activation. Excess Ca or Mg alone inhibited C3 activation by MSUM in accord with the inhibitory effect of these cations on sensitized sheep cell hemolysis by C. Heating of MSUM at ***. C for 2 h removed the water of crystallization so that heated crystals may no longer be considered MSUM. Such treatment had a variable effect on C3 activation. Of the crystals and other material studied, only zymosan was more potent than MSUM in activating C3. Calcium pyrophosphate dihydrate and hydroxyapatite activated significant amounts of C3. Asbestos, glass wool or a variety of microcrystalline steroids activated little or no C3. [Urate induced inflammation and the presence of C split products and low C activity of component protein in acute gout patients were discussed.].

关键词：钙/药理学补体激活/药物作用补体C3 依地酸/药理学依他酸/药理学热温度免疫电泳双向镁/药理学尿酸/药理学人类

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Hemodynamic effects of methylprednisolone in patients undergoing cardiac operation and early extubation

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ANNALS OF THORACIC SURGERY 1999年第4期67卷 1006-1011页

作者： Chaney, MA Nikolov, MP Blakeman, BP Bakhos, M Slogoff, S Loyola Univ Med Ctr Dept Anesthesiol Foster G McGaw Hosp Maywood IL 60153 USA Loyola Univ Med Ctr Dept Thorac & Cardiovasc Surg Foster G McGaw Hosp Maywood IL 60153 USA

Background. Whether or not methylprednisolone is beneficial during cardiac operation remains controversial. This study examines the effects of the drug on complement activation and hemodynamics in patients undergoing cardiac operation and early extubation. Methods. Patients undergoing cardiac operation were randomized to receive either intravenous methylprednisolone (group MP) or intravenous placebo (group NS). Complement 3a (C3a) levels and hemodynamic parameters were obtained perioperatively. Extubation was accomplished at the earliest clinically appropriate time. Results. Both groups exhibited equivalent increases in C3a levels after exposure to bypass. Group MP exhibited increased cardiac index, decreased systemic vascular resistance, and increased shunt flow when compared to group NS. More group MP patients required hemodynamic support and group MP patients had prolonged extubation times. Conclusions. Methylprednisolone was unable to attenuate complement activation and led to hemodynamic alterations (primarily vasodilation) that may hinder early extubation in patients after cardiac operations. (Ann Thorac Surg 1999;67:1006-11). (C) 1999 by The Society of Thoracic Surgeons.

关键词：补体激活/药物作用补体C3a/分析冠状动脉分流术双盲法糖皮质激素类/药理学插管法气管内/方法甲泼尼龙/药理学前瞻性研究血管阻力/药物作用成年人老年人女(雌)性人类男(雄)性中年人

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CONVERSION OF C-3 AND CONSUMPTION OF HEMOLYTIC COMPLEMENT BY EXTRACTS OF AIRBORNE GRAIN DUST

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CHEST 1979年第2期75卷 225-227页

作者： OLENCHOCK, SA MULL, JC MAJOR, PC NIOSH DIV RESP DIS STUDIESIMMUNOL SECTMORGANTOWNWV 26505

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C-type lectins and galectins mediate innate and adaptive immune functions: their roles in the complement activation pathway

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DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 1999年第4-5期23卷 401-420页

作者： Vasta, GR Quesenberry, M Ahmed, H O'Leary, N Univ Maryland Ctr Marine Biotechnol Inst Biotechnol Baltimore MD 21202 USA

In recent years, a 'new' pathway for complement activation mediated by the mannose-binding lectin (MBL) has been described as a key mechanism for the mammalian acute phase response to infection. This complement activation pathway is initiated by a non-self recognition step: the binding of a humoral C-type lectin [mannose-binding lectin (MBL)] to microbial surfaces bearing 'foreign' carbohydrate determinants. The recognition factor, MBL, is associated with a serine protease [MBL-associated serine protease (MASP)] which, upon MBL binding to the microbial ligand, activates the complement component C3, leading to either (a) phagocytosis of the opsonized target via the complement receptor, or (b) humoral cell killing via assembly of the membrane attack complex. Galectins (formerly known as S-type lectins) modulate activity of the complement receptor 3 (CR3), the macrophage membrane receptor for complement components C3b and iC3b, downstream products of the MBL pathway which are covalently bound to 'target' cells. Galectins also mediate macrophage- and dendrocyte-adhesion to lymphocytes activated by signaling through another C-type lectin, the L-selectin, leading to immunoglobulin-mediated responses. Thus, the functional interplay of MEL, galectins and L-selectin in the acute phase response neutralizes the microbial challenge, and lead to further adaptive immunity. Although the observation of various components of the lectin pathway in different invertebrate species demonstrates the high conservation and ancient roots of the components of innate immunity, there has previously been no evidence supporting the possibility that the integral lectin-mediated complement activation pathway is present in invertebrates. We now have evidence for the coexistence of homologs of all the pathway's key components (MBL, MASP: C3, and galectin) in the protochordate Clavelina picta, suggesting the lectin-mediated pathway of complement activation preceded the immunoglobulin pathway in evolut

关键词：氨基酸序列载体蛋白质类/化学载体蛋白质类/免疫学胶凝素类补体激活/药物作用补体激活/免疫学补体C3b/代谢补体C3c/化学半乳糖凝集素类血凝素类/化学血凝素类/免疫学 L选择素/免疫学外源凝集素类/免疫学外源凝集素类 C型分子序列数据植物凝集素类受体补体3d/代谢序列比对丝氨酸内肽酶类/代谢动物人类

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Complement activation after oxidative stress -: Role of the lectin complement pathway

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AMERICAN JOURNAL OF PATHOLOGY 2000年第5期156卷 1549-1556页

作者： Collard, CD Väkevä, A Morrissey, MA Agah, A Rollins, SA Reenstra, WR Buras, JA Meri, S Stahl, GL Harvard Univ Brigham & Womens Hosp Sch MedCtr Expt Therapeut & Reperfus Injury Dept Anesthesiol Pain & Perioperat Med Boston MA 02115 USA Univ Helsinki Dept Bacteriol & Immunol Helsinki Finland Univ Helsinki Cent Hosp Helsinki Finland Alex Pharmaceut New Haven CT USA Boston Univ Sch Med Dept Clin Pathol Boston MA 02118 USA Harvard Univ Brigham & Womens Hosp Sch Med Dept Emergency Med Boston MA USA

The complement system plays an important role in mediating tissue injury after oxidative stress. The role of mannose-binding lectin (MBL) and the lectin complement pathway (LCP) in mediating complement activation after endothelial oxidative stress was investigated, iC3b deposition on hypoxic (24 hours;1% O-2)/ reoxygenated (3 hours;21% O-2) human endothelial cells was attenuated by N-acetyl-D-glucosamine or D-mannose, but not L-mannose, in a dose-dependent manner. Endothelial iC3b deposition after oxidative stress was also attenuated in MBL-deficient serum. Novel, functionally inhibitory, anti-human MBL mono-clonal antibodies attenuated MBL-dependent C3 deposition on mannan-coated plates in a dose-dependent manner. Treatment of human serum with anti-MBL monoclonal antibodies inhibited MBL and C3 deposition after endothelial oxidative stress. Consistent with our in vitro findings, C3 and MBL immunostaining throughout the ischemic area at risk increased during rat myocardial reperfusion in vivo. These data suggest that the LCP mediates complement activation after tissue oxidative stress. Inhibition of MBL may represent a novel therapeutic strategy for ischemia/reperfusion injury and other complement-mediated disease states.

关键词：乙酰葡萄糖胺/药理学缺氧载体蛋白质类/免疫学载体蛋白质类/药理学载体蛋白质类/生理学细胞系胶凝素类补体激活/药物作用补体激活/生理学补体C3b/分析补体C3b/药物作用补体C3b/代谢内皮血管/细胞学内皮血管/药物作用内皮血管/代谢免疫组织化学外源凝集素类/生理学甘露糖/药理学小鼠近交BALBC 心肌再灌注损伤/代谢心肌再灌注损伤/病理学氧化性应激大鼠近交Lew 动物女(雌)性人类男(雄)性小鼠大鼠

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The anti-factor D antibody, MAb 166-32, inhibits the alternative pathway of the human complement system

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TRANSPLANTATION PROCEEDINGS 1999年第5期31卷 2168-2171页

作者： Tanhehco, EJ Kilgore, KS Liff, DA Murphy, KL Fung, MS Sun, WN Sun, C Lucchesi, BR Univ Michigan Dept Pharmacol Sch Med Ann Arbor MI 48109 USA Tanox Biosyst Inc Houston TX 77025 USA

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Effect of intravenous immunoglobulin therapy on plasma complement

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TRANSFUSION SCIENCE 1998年第4期19卷 307-318页

作者： Wegmüller, E Regionalspital Interlaken Dept Internal Med CH-3800 Interlaken Switzerland

The effect of the intravenous immunoglobulin preparation (Sandoglobulin(R)) on the complement system and the formation of circulating immune complexes (CIC) was investigated in 10 patients with primary humoral immunodeficiency and in 12 normal volunteers. Infusion of 9 g of the pH4 treated preparation did not show relevant changes in total hemolytic complement activity, plasma levels of C4, C3, and factor B. C3dg fragments, however, increased markedly in some individuals in both groups immediately after infusion. CIC measured by 125 I-C1q binding were not detectable. Furthermore, the initially low C1q concentrations in immune-deficient patients correlated with the pre-infusion IgG levels (p<0.05) and rose significantly 24 h after therapy (p<0.001). In contrast, in vitro incubation of the immunoglobulin preparation with normal human serum did not reveal spontaneous anticomplementary activity nor did it lead to formation of immune aggregates. The results indicate that immunoglobulin infusions may moderately activate complement in vivo, as evidenced by increased C3dg fragments;in addition, partial C1q deficiency in hypogammoglobulinemia seems to be related to IgG concentration and can be corrected by immunoglobulin substitution. (C) 1998 Elsevier Science Ltd. All rights reserved.

关键词：丙种球蛋白缺乏血症/血液丙种球蛋白缺乏血症/遗传学丙种球蛋白缺乏血症/免疫学丙种球蛋白缺乏血症/治疗抗原抗体复合物/血液普通可变性免疫缺陷/血液普通可变性免疫缺陷/免疫学普通可变性免疫缺陷/治疗补体激活/药物作用补体C1q/缺乏补体C3b/分析补体系统蛋白质类/分析溶血免疫球蛋白类静脉内/药理学肽碎片/分析 X染色体/遗传学丙种球蛋白类/药理学青少年成年人老年人女(雌)性人类男(雄)性中年人

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肝素的抗补体作用

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食管疾病 1983年第1期 62-67页

作者：黄寿吾洛阳医学专科学校附属医院

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