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PubMed1986

The effects of methylprednisolone on complement-mediated neutrophil activation during cardiopulmonary bypass.

Complement-mediated neutrophil activation (CMNA) has been implicated as an important pathophysiologic mechanism contributing to acute microvascular lung injury in the adult respiratory distress syndrome (ARDS). Using cardiopulmonary bypass (CPB) as a clinical model for complement-mediated microvascular injury, we studied the effects of methylprednisolone (MPSS) pretreatment on manifestations of CMNA in 28 pediatric patients undergoing CPB. Six patients not receiving MPSS served as controls. Results demonstrated that MPSS did not prevent complement activation as noted by 4.5- and 7.7-fold increases in plasma C3a des Arg levels during and immediately after CPB, respectively. However, detectable in vivo and in vitro manifestations of CMNA were altered. Neutropenia during CPB was attenuated to 65% of prebypass values compared with 47% in the control group. Neutrophil selective chemotactic desensitization toward C5a/C5a des Arg during the on bypass and postbypass periods was evident in the control group (0.41 and 0.76 cm specific migration, respectively) and prevented in the MPSS group (1.55 and 2.00 cm specific migration, respectively). We conclude that CMNA during CPB is ameliorated and/or prevented by MPSS pretreatment. These findings suggest that MPSS pretreatment may ameliorate complement-mediated microvascular (lung) injury in CPB and ARDS.

Anaphylatoxins↗
PubMedDate not supplied

Thrombolytic treatment and complement activation.

Details of possible complement activation in acute myocardial infarction (AMI) and the in vivo effects of fibrinolytic agents on this activation are not yet known. We measured complement activation in 40 patients with AMI: 20 were treated with streptokinase, and 20 did not receive any fibrinolytic agent. Anaphylatoxin C4a, C3a and membrane attack complexes SC5b-9 increased about 10-fold (p < 0.0001) during streptokinase infusion. There were no increases in complement catabolic products in AMI patients not treated with streptokinase. Significant transient leukopenia (-29.5%, 7.0 SEM, p = 0.001) and a drop in systolic pressure (-29%, 3.4 SEM, p < 0.0001) occurred after 15 min of streptokinase infusion simultaneously with the peak of anaphylatoxins in plasma.

Anaphylatoxins↗
PubMed1992

Perioperative complement activation in neonates under halothane or fentanyl anaesthesia.

We investigated perioperative changes in complement activation in 18 neonates undergoing elective abdominal surgery with or without thoracotomy by measuring plasma concentrations of C3a and C5a, and leucocyte counts in peripheral blood. The 18 neonates, ranging in age from 1 to 17 days, were randomly divided into two groups according to type of anaesthetic procedures; the "halothane group" consisted of nine neonates in whom general anaesthesia was maintained with halothane and nitrous oxide (N2O) in oxygen, while the "fentanyl group" consisted of nine neonates in whom general anaesthesia was maintained with fentanyl and N2O in oxygen. Plasma C3a and C5a concentrations were higher in the fentanyl group than in the halothane group during the perioperative period. We have demonstrated that abdominal surgical trauma caused complement activation even in neonates undergoing the fentanyl rather than the halothane anaesthesia. Further studies are required to elucidate the precise mechanisms and the clinical implication of perioperative complement activation in neonates.

Abdomen↗
PubMed1991

[Diversity of complement activation by lentinan, an antitumor polysaccharide, in gastric cancer patients].

Lentinan, a pure polysaccharide, augments many immune responses in vivo but not in vitro. Therefore reaction with any factor is thought to be required for triggering of immunopotentiation by lentinan. To clarify the role of complement in this effect, we investigated whether lentinan could activate alternative pathway of complement or not and the relation with the immunopotentiation in 13 gastric cancer patients. C3, C3a, C5 and C5a levels as parameters of complement activation and interleukin-2 producing activity as parameter of immunopotentiation were assayed before and immediately after intravenous injection of lentinan. Among these complement components, remarkable change was observed only in C3a level. C3a level elevated to more than 1000ng/ml from less than 300ng/ml. And according to the degree and continuation of the elevation, these patients were classified into 3 types-(1) every time little elevation, (2) first remarkable and thereafter little elevation and (3) continuous remarkable elevation. Such an elevated C3a level returned to the level before lentinan injection within one day. When C3a level elevated to more than 1000ng/ml, leukocyte counts of peripheral blood decreased significantly and interleukin-2 producing activity increased concomitantly. Thus, there was diversity in response to lentinan and complement activation was suggested to have contribution in immunopotentiation by lentinan.

Adjuvants, Immunologic↗
PubMed2000

Evaluation of leukocyte-depleted platelet concentrates obtained by in-line filtration.

BACKGROUND AND OBJECTIVES: The use of leukocyte-depleted platelet concentrates (PCs) is justified, yet questions remain regarding their properties. We have assessed the in vitro quality of WBC-reduced PCs obtained by using a new in-line filter. MATERIALS AND METHODS: Twenty blood units were randomized for standard component preparation, or for processing including in-line leukodepletion of platelet-rich plasma using an ATS(TM) PL Pall filter. The resultant PCs were compared during storage for several in vitro platelet quality parameters, content of cytokines and anaphylatoxins, and coagulation markers. RESULTS: In-line filtration of platelet-rich plasma through ATS PL was highly efficient rendering PCs with 99.93% less white blood cells (WBCs) than standard PCs. During storage for up to 9 days, leukocyte-depleted units displayed platelet content, biochemical parameters, and platelet surface expression of glycoproteins Ibalpha, IIb/IIa, CD62 and CD63, similar to those of standard units. However, in-line leukocyte-reduced PCs displayed no significant accumulation of IL-6 and IL-8 during storage in contrast to standard units. Moreover, while storage promoted complement activation with C3a and C4a liberation in both WBC-reduced PCs and standard units, the concentration of these anaphylatoxins after the 9-day storage period was higher in the former group. Finally, all units, standard and leukocyte-reduced, displayed a similar storage-promoted rise in TGF-beta(1), and a mild prolongation of activated partial thromboplastin and prothrombin times. CONCLUSION: In-line filtration during component preparation appears as an easy and effective procedure for obtaining prestorage leukocyte-depleted PCs. During subsequent blood bank storage, these WBC-reduced PCs display, in comparison with standard PCs, normal in vitro platelet properties, decreased accumulation of cytokines IL-6 and IL-8, and increased complement activation.

Anaphylatoxins↗
PubMed2001

C5a and C5a(desArg) enhance the susceptibility of monocyte-derived macrophages to HIV infection.

Mononuclear phagocytes, which include circulating blood monocytes and differentiated tissue macrophages, are believed to play a central role in the sexual transmission of HIV infection. The ability of HIV to productively infect these cells may be influenced by action of exogenous or host-derived substances at the site of viral entry. Given the potent capacities of inflammatory mediators to stimulate anaphylatoxic and immunomodulatory functions in mucosa, the effects of complement-derived anaphylatoxins on the susceptibility of monocytes and monocyte-derived macrophages (MDM) to HIV-1 infection were examined. In our in vitro system, the susceptibility to infection was up to 40 times increased in MDM that had been exposed to C5a or C5a(desArg), but not to C3a or C3a(desArg), for 2 days before adding of virus. By contrast, the treatment with complement anaphylatoxins did not affect HIV replication in fresh monocytes. Stimulatory effect of C5a and its desArg derivative on HIV infection correlated with the increase of TNF-alpha and IL-6 secretion from MDM. All these functional effects of C5a and C5a(desArg) were reversible by treatment of cells with the mAb that functionally blocks C5aR. Taken together, these results indicate that C5a and C5a(desArg) may increase the susceptibility of MDM to HIV infection through stimulation of TNF-alpha and IL-6 secretion from these cells.

Adjuvants, Immunologic↗
PubMed1976

On the nature of the defect in cystic fibrosis.

Sera and lymphocyte culture media derived from cystic fibrosis (CF)-affected and carrier subjects contain ciliary dyskinesia factor (CDF) detected by our rabbit tracheal bioassay. In addition, we also find CDF in fibroblast media from these same donors and in amniotic fluid cell media derived from CF carrier or affected fetuses. In these latter instances, the media were inactive in the bioassay, but became active when mixed with purified IgG. In all instances, CDF activity was eliminated by the addition of anti-IgG. We have separated a low molecular weight fraction, between 1,000 and 10,000 M.W., from CF sera and culture media which is inactive in the bioassay until IgG is added. Presumptive and indirect evidence indicates that this fraction behaves similarly to the complement derived anaphylatoxin C3a. In addition, we have found activity in sera from CF patients and, to a lesser extent, carriers that induces degranulation of cytochalasin-B-treated human polymorphonuclear leukocytes. Since this activity appears to be in a different molecular species from that containing CDF, we postulate that the primary defect in CF is the deficiency of an enzyme whose substrates include a family of membrane-active molecules.

Amniotic Fluid↗
PubMed1997

Activation of the alternative pathway of complement by a phosphorothioate oligonucleotide: potential mechanism of action.

Intravenous infusion of high doses of phosphorothioate oligonucleotides in monkeys has been associated with transient alterations in hematologic and hemodynamic parameters, which appear to be secondary to complement activation. ISIS 2302, a phosphorothioate oligonucleotide specific for human intracellular adhesion molecule-1, was used to further characterize complement activation in monkeys. Complement activation occurred selectively through the alternative pathway resulting in increased plasma concentrations of the complement split products Bb, C3a and C5a. Marked fluctuations in circulating neutrophil counts and reductions in cardiac output were closely associated with peak production of anaphylatoxins C3a and C5a. Changing both dose and infusion duration revealed that complement activation is related to plasma levels of oligonucleotide, and that there is a minimum threshold concentration of approximately 50 micrograms/ml of ISIS 2302 that is required to activate complement. Dose regimens in which plasma concentrations do not exceed this threshold do not result in complement activation. Further investigation reveals that plasma concentrations of a key regulatory component of the alternative pathway, Factor H, were also decreased after administration of ISIS 2302. Decreases in Factor H levels are suggestive of a possible mechanism of complement activation. Direct interaction between ISIS 2302 and Factor H was demonstrated in a competition assay, where increasing concentrations of ISIS 2302 eluted Factor H from a heparin-sepharose column. These data demonstrate a clear correlation between plasma oligonucleotide concentrations and complement activation. Interactions between ISIS 2302 and Factor H may lead to activation of the alternative complement pathway.

Animals↗
PubMed2002

Novel anti-factor D monoclonal antibody inhibits complement and leukocyte activation in a baboon model of cardiopulmonary bypass.

BACKGROUND: Adverse outcomes after cardiopulmonary bypass (CPB) are often related to systemic inflammation triggered by complement and leukocyte activation. To determine how inhibition of the alternative complement pathway affects systemic inflammation and tissue injury, we studied a novel monoclonal antibody (Mab), anti-human factor D murine Mab 166-32, in baboons. METHODS: Fourteen baboons (mean weight, 15 kg) underwent hypothermic CPB. The treatment group (n = 7) received a single injection of anti-factor D Mab 166-32 (5 mg/kg), and the control group (n = 7) was given saline solution. After initiation of CPB, all animals were subjected to 20 minutes of core cooling (rectal temperature, 27 degrees C), followed by 60 minutes of aortic cross-clamping, 25 minutes of rewarming, and 30 minutes of normothermic CPB. Blood samples were collected before CPB, during CPB, and 1, 2, 3, 6, and 18 hours after CPB. To measure neutrophil and monocyte activation, we performed flow cytometry for CD11b expression, ELISA for complement activation (Bb, C3a, C4d, and sC5b-9) and interleukin-6 (IL-6) production, and tissue injury studies for creatine kinase MB isoenzymes (CK-MB), creatine kinase (CK), and lactic dehydrogenase (LDH) levels. RESULTS: Anti-factor D Mab almost completely inhibited plasma Bb, C3a, and sC5b-9 production during CPB (P < .001). CD11b expression on neutrophils (129 +/- 5% vs. 210 +/- 42%; P = .0006) and on monocytes (139 +/- 14% vs. 245 +/- 43%; P = .0002) was also lower in the treatment group during CPB. The treated animals had a significantly smaller increase in plasma IL-6 concentrations than did the control animals (71 +/- 27 pg/mL vs. 104 +/- 54 pg/mL; P = .0002). CK-MB levels were also lower in the treatment group 6 hours after the end of CPB (204 +/- 30 vs. 335 +/- 59 IU/L; P = .003) and 18 hours after the end of CPB (P < .05). Creatine kinase levels (6 and 18 hours after the end of CPB) and LDH levels (3 and 6 hours after the end of CPB) showed patterns similar to those of CK-MB (P < .05). CONCLUSIONS: The alternative complement pathway plays a major role in systemic inflammation during CPB. Inhibition of complement activation via the alternative pathway by anti-factor D Mab 166-32 significantly reduces leukocyte activation and tissue injury in our baboon model.

Animals↗
PubMed2001

Mast cells play a key role in neutrophil recruitment in experimental bullous pemphigoid.

Bullous pemphigoid (BP) is an inflammatory subepidermal blistering disease associated with an IgG autoimmune response to the hemidesmosomal protein BP180. Passive transfer of antibodies to the murine BP180 (mBP180) ectodomain triggers a blistering skin disease in mice that depends on complement activation and neutrophil infiltration and closely mimics human BP. In the present study, we show that mast cells (MCs) play a crucial role in experimental BP. Wild-type mice injected intradermally with pathogenic anti-mBP180 IgG exhibited extensive MC degranulation in skin, which preceded neutrophil infiltration and subsequent subepidermal blistering. In contrast, mice genetically deficient in MCs or MC-sufficient mice pretreated with an inhibitor of MC degranulation failed to develop BP. Further, MC-deficient mice reconstituted in skin with MCs became susceptible to experimental BP. Despite the activation of complement to yield C3a and C5a, in the absence of MCs, accumulation of neutrophils at the injection site was blunted. The lack of response due to MC deficiency was overcome by intradermal administration of a neutrophil chemoattractant, IL-8, or by reconstitution of the injection sites with neutrophils. These findings provide the first direct evidence to our knowledge that MCs play an essential role in neutrophil recruitment during subepidermal blister formation in experimental BP.

Animals↗
PubMed2006

[Immunological aspects of pathogenesis of stomatological constructional materials intolerance].

In blood and the mixed saliva of patients with intolerance of stomatologic constructional materials the maintenance of cytokines, factors of humoral answer were investigated. It was established, that in formation of intolerance the increased sensitivity stomatologic constructional materials which is not connected to allergic reaction of immediate type and is, apparently, pseudoallergic or develops on other type. There is an activation of the local immune answer including local synthesis of proinflammatory cytokines, sIgA and hyperactivation of complement system to formation of C3a component. Toxic and allergic action of stomatologic constructional materials grows in patients having antibodies to Candida albicans in the mixed saliva.

Adult↗
PubMed1989

Improved biocompatibility by modified cellulosic membranes: the case of hemophan.

The rising problem of biocompatibility is encouraging the development of new dialysis membranes, but the high cost of synthetic ones precludes their wide use. The authors compared the biocompatibility of cuprophan (CU), cellulose acetate (CA), and hemophan (HE), evaluating both in vitro and in vivo polymorphonuclear leukocyte (PMN) oxidative metabolism activation by resting chemiluminescence and complement activation by C3a; in vivo PMN counts during dialysis were also performed. The lowest increase in in vitro PMN resting chemiluminescence using HE was + 71.3% with CA, +49.3% with CU, and + 21.4% with HE (p less than 0.001 versus CA and CU); furthermore, HE did not significantly stimulate PMN resting chemiluminescence during in vivo hemodialysis: + 56.6% with CA, + 38.8% with CU, and + 3.7% with HE (p less than 0.01 versus CU and p less than 0.001 versus CA). C3a concentration increased with all membranes both in vitro and in vivo, but HE (in both experimental conditions) showed the lowest increase at any time (p less than 0.001 versus CA and CU). After 15 min of dialysis, PMN count dropped to 20.3% of basal values with CU, to 49.8% with CA, and to 76.5% with HE (p less than 0.001 versus CU and CA). Among cellulosic membranes, HE is the most biocompatible and appears to be an important step in preventing blood-membrane interactions and related complications.

Biocompatible Materials↗
PubMed2000

One-year immunological evaluation of chronic hemodialysis in end-stage renal disease patients.

BACKGROUND: Much research has been devoted to the determination of acute leukocyte activation as well as acute cytokines production during and after blood hemodialysis membrane interaction. In contrast, few studies deal with chronic immunological evaluation of T-cell activation markers in hemodialysis. METHODS: We evaluated different immune parameters using a modified cellulose low-flux hemophan vs. synthetic high-flux polyamide membrane during 1 year in 35 stable chronic hemodialysis patients. Leukocyte counts, lymphocyte subpopulations, T-cell activation markers (CD69, CD25, HLA-DR, CD54, CD62L, CD45RO, CD11a, CD28), complement-activation products (C3a) and serum elastase were measured at 0, 3, 6 and 12 months in the two patient groups and compared to 13 healthy control subjects. RESULTS: Over dialysis time, all patients showed a significant level elevation of CD69/CD3 (p < 0.005) and CD25/ CD3 (p < 0.005) phenotypes. In contrast, HLA-DR and CD45RO remained unchanged suggesting a truncated pattern of activation. T lymphocyte subset analysis showed in both hemodialyzed groups a significant decrease in the expression of CD54 (ICAM-1) when compared to controls (p < 0.005). C3a and elastase measurements showed a significant upward trend with dialysis time in both hemodialyzed groups. CONCLUSION: Although the immunological changes seen in chronic hemodialyzed patients must be interpreted in conjunction with their basal uremic states and the membrane permeability properties, our study suggests that 1-year immunological evaluation of hemodialysis membranes biocompatibility is associated with changes in the pattern of chronic T-cell activation, which is in part related to the use of a particular membrane type. Moreover, some key molecules (CD54) are affected in patients with end-stage renal disease undergoing hemodialysis.

Aged↗
PubMed1996

IL-1 beta does not cause neutrophil degranulation but does lead to IL-6, IL-8, and nitrite/nitrate release when used in patients with cancer.

The use of IL-1 in humans is associated with dose-limiting toxicity which resembles that of TNF-alpha or IL-2. Activation of neutrophils is thought to contribute to the toxicity caused by these two cytokines. We studied the effect of IL-1 in vivo on changes in neutrophil numbers and neutrophil degranulation as well as on the formation of neutrophil agonists, such as complement activation products, and on levels of TNF, IL-6, IL-8, and nitrite/nitrate (as a measure of nitric oxide production). Six patients with metastatic melanoma were treated with 3 ng/kg recombinant human IL-1 beta daily. One hour after the start of the 30-min IL-1 infusion, which caused mild cardiovascular toxicity, plasma levels of IL-6 reached a peak of 25 +/- 9 ng/L (mean +/- SEM), IL-8 reached a peak of 311 +/- 100 ng/L at 2 h, and nitrite/nitrate peaked after 10 h to 89 +/- 27 mumol/L. IL-1 did not induce significant changes in plasma levels of TNF or of the complement activation products C3a and C4b/c. Although IL-1 induced neutrophilia, levels of elastase and lactoferrin did not change. The failure of IL-1 to degranulate neutrophils was confirmed in an ex vivo model with whole blood culture in which doses of up to 100 microgram/L IL-1 beta or IL-1 alpha failed to induce significant elastase or lactoferrin release, whereas TNF, tested as a positive control, was able to do so. These results demonstrate that, unlike TNF, IL-1 does not cause neutrophil degranulation in man, despite its ability to cause neutrophilia and the rapid release of IL-6, IL-8, and nitrite/nitrate.

Adult↗
PubMed1984

Mechanisms of leukocyte regulation by complement-derived factors.

Progress over the past five years has drawn attention to the fact that the anaplylatoxins are important factors in both leukocyte activation and regulation events. The C5 anaphylatoxin has been proposed to play major role in leukocyte aggregation and adherence phenomenon. Influences of C5a on the leukocyte may lead to clinical manifestations such as respiratory distress syndrome after trauma or postpump syndrome after cardiopulmonary bypass, both effects derived from leukocyte sequestration. Many other clinical conditions involving repeated transient sequestration of leukocytes, particularly in the pulmonary vasculature, may eventually be recognized as a complication of systemic complement activation. Dramatic pathologic changes observed in the lungs of animals exposed to either C3a or C5a emphasizes the potential damage that these factors may exert via cellular activation mechanisms (Huey et al., 1983). More recent evidence that the anaphylatoxins are potent immunoregulatory factors under in vitro conditions suggests a physiologic role for these humoral factors in nonspecific modulation of the immune response. It is an attractive hypothesis to suggest that once activated, complement is capable of relaying information to the cellular immune system via the anaphylatoxins. Other components of the complement system have long been known to exert regulatory influences on the immune system, and perhaps molecular description of such entities as the C3d-K fragment will serve to unravel this seemingly more complex effector system. In any case, as our understanding of both the chemical and biologic nature of factors derived from blood complement components advances, it has become apparent that a major function of complement may be to modulate the immune response. We have already demonstrated that these factors are selective both for cell type and for eliciting a variety of cellular responses. From this, one can infer that manipulation of the cellular events will eventually be possible. Hence a therapeutic value may be realized once involvement of these complement factors under in vivo conditions is better characterized.

Anaphylatoxins↗
PubMed1997

Lipopolysaccharide-binding protein and bactericidal/permeability-increasing factor during hemodialysis: clinical determinants and role of different membranes.

The host response to the presence of lipopolysaccharide (LPS) is complex and varied. Two closely related endogenous serum proteins, LPS-binding protein (LBP) and bactericidal/permeability-increasing factor (BPI), regulate delivery of LPS to CD14 antigen on effector cell surfaces and modulate the host response to LPS. In the study presented here, plasma levels of LBP and BPI were measured, predialysis, 15 min into dialysis and postdialysis in patients dialyzed with cellulose, cellulose-tri-acetate (CTA), and polysulfone dialyzers. Further, the association between LBP levels and BPI release during hemodialysis and clinical and laboratory characteristics of patients, complement activation represented by plasma C3a levels, and monocyte cytokine production represented by interleukin-1 receptor antagonist (IL-1Ra) synthesis was also studied. Predialysis plasma levels of LBP were 14,459 +/- 544, 13,889 +/- 1362 and 12,622 +/- 6305 ng/mL, respectively, with cellulose, CTA, and polysulfone dialyzers, and postdialysis levels were 17,834 +/- 861, 20,979 +/- 8485 and 18,177 +/- 1656 ng/mL, respectively. Postdialysis plasma levels of LBP were consistently higher than predialysis levels with all three dialyzers (P < 0.05). However, plasma LBP levels were not significantly different between the three dialyzers either predialysis (P = 0.28) or postdialysis (P = 2.8). There were no significant differences in predialysis BPI levels between the three dialyzers (P = 0.21). BPI levels at 15 min of dialysis with CTA (10.91 +/- 3.65 ng/mL) and polysulfone (10.73 +/- 2.24 ng/mL) dialyzers were significantly greater (P < 0.05) than that observed with cellulose (5.49 +/- 0.66 ng/mL). Similarly, postdialysis levels with CTA and polysulfone were significantly greater (P < 0.05) than that observed with cellulose dialyzers. The percentage change in BPI levels between predialysis and 15 min was 1341 +/- 243%, 2935 +/- 1033%, and 3790 +/- 1151% for cellulose, CTA, and polysulfone dialyzers, respectively. The changes in BPI levels from predialysis to 15 min and between pre- and postdialysis samples were statistically significant for all three dialyzers (P < 0.05). Postdialysis LBP:BPI ratios were 50 +/- 6%, 18 +/- 4%, and 22 +/- 6% of predialysis ratios for cellulose, CTA, and polysulfone dialyzers, respectively. These changes were statistically significant (P < 0.05) for all three dialyzers. There was no significant correlation between baseline clinical or laboratory characteristics and predialysis LBP levels. Similarly, the correlation between BPI levels at 15 min of dialysis with the clinical and laboratory characteristics was also poor, with the exception of serum albumin (r = 0.43, P = 0.008). The correlation between BPI levels at 15 min of dialysis with plasma LBP levels (r = -0.29; P = 0.08), plasma C3a levels (r = -0.1; P = 0.55), peripheral blood mononuclear cells (PBMC) content of IL-1Ra (r = 0.01; P = 0.94), and IL-1Ra production by unstimulated (r = 0.13; P = 0.45), and endotoxin-stimulated PBMC (r = 0.32; P = 0.06) was not statistically significant. The results of this study demonstrate that dialysis with cellulose, CTA, and polysulfone dialyzers results in a significant increase in LBP and BPI levels. BPI release is probably mediated by non-complement factors and may be related to the nutritional status of the patient. The release of BPI during HD and consequent lowering of the LBP:BPI ratio could potentially afford some protection against endotoxin in the dialysate.

Acute-Phase Proteins↗
PubMed1987

Complement activation by hydroxyethylmethacrylate-ethylmethacrylate copolymers.

Certain biomaterials, including nylon oxygenator and cellulosic dialysis membranes, are potent activators of human complement. In this study, the effect of polymers containing 2-hydroxyethyl methacrylate (HEMA) on the human complement system was investigated. Copolymers of HEMA with ethylmethacrylate (EMA) varying from 100 to 40% HEMA in the monomer made by radiation initiation were used to coat glass discs. These were equilibrated with human plasma in vitro and the degree of complement activation was quantitated by C3a radio immunoassay. Significant activation was caused by copolymers made from monomers containing 60% or greater HEMA. A direct relationship between the amount of activation and the percentage of HEMA was found. The degree of activation by poly HEMA, when corrected for surface area, was quite similar to that observed for dialysis and oxygenator membranes. Similar observations were made when solid casts of crosslinked HEMA/N-vinylpyrrolidone (NVP) copolymer gels were tested, but the magnitude of activation was much greater. The results are significant because complement activation may play an important role in the response to foreign surfaces, in both extravascular and intravascular settings. A new concept of molecular biocompatibility is proposed in which surfaces eliciting molecular transformations in any of the biological defense systems are deemed nonbiocompatible. By this criterion, the hydrogel poly-HEMA, which has so frequently been thought of as biocompatible, is considered to be a molecularly non-biocompatible material.

Biocompatible Materials↗
PubMed1989

Complement activation and neutrophil dysfunction in burned patients with sepsis--a study of two cases.

The changes in complement components and neutrophil functions were investigated in two cases of flame burn patients who died of multiple organ failure following septic shock. In the period of bacteremia, complement activation was observed in the plasma of both patients, using an immunoblotting method demonstrating C3a-related antigens. Coincidently, reduced neutrophil function and a decrease in the superoxide and leukotriene producing capacity, were also observed. An in vitro study showed that the capacity to produce superoxide and leukotriene became reduced in normal neutrophils after exposure to complement activated serum. These observations suggested that complement activation, probably brought about by massive bacterial infection, induced the impairment of neutrophil functions and resulted in a further breakdown of the host defence system, thereby leading to sepsis.

Adult↗