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PubMed1998

Effect of complement inhibition with soluble complement receptor 1 on pig allotransplant lung function.

BACKGROUND: Lung dysfunction after transplantation continues to be a significant clinical problem. Soluble complement receptor 1 (sCR1) is a potent inhibitor of complement activation. We evaluated the inhibitory effect of sCR1 on complement activation and reperfusion injury in pig lung allografts. METHODS: In a randomized and blinded study, left lung transplantation was performed in 13 pigs. Donor lungs were flushed and then stored for 30 hr at 4 degrees C. Control pigs (n=7) received saline, and the treatment group (n=6) received 15 mg/kg sCR1 1 hr before reperfusion. One hour after reperfusion, the right pulmonary artery was clamped for 10 min to assess the function of the transplanted lung. Pulmonary function was assessed again on day 3. RESULTS: Complement inhibition was 93% in the sCR1 group and returned to baseline (8% inhibition) after 3 days. There was a trend toward a higher partial pressure of oxygen at 1 hr in the sCR1 group compared with the control group (mean +/- SE: 408+/-42 mmHg vs. 288+/-69 mmHg, P = 0.19). Alveolar ventilation was better in the sCR1 group than in the control group (P = 0.01) at 1 hr. Mixed venous saturation was significantly lower in the control group at both 1 hr (P = 0.02) and 3 days (P = 0.001). The wet/dry weight of the lung tissue was lower in the sCR1 group compared with the control group on day 3 (P < 0.05). Chemiluminescence, an index of phagocyte priming, was lower in the sCR1 group when cells were stimulated with complement opsonized zymosan but not when stimulated with zymosan or phorbol myristate acetate. CONCLUSION: sCR1 improves ventilation, reduces pulmonary edema, and may be beneficial in improving posttransplant lung oxygenation.

Animals↗
PubMed1998

Quantitative studies of heteropolymer-mediated binding of inactivated Marburg virus to the complement receptor on primate erythrocytes.

Previous in vitro and in vivo experiments in our laboratory have demonstrated that cross-linked bispecific monoclonal antibody (mAb) complexes (Heteropolymers, HP) facilitate binding of prototype pathogens to primate erythrocytes (E) via the E complement receptor, CR1. These E-bound immune complexes are safely and rapidly cleared from the bloodstream. In order to generate a robust bispecific system for HP-mediated clearance of real pathogens such as Filoviruses, we have developed the necessary methodologies and reagents using both inactivated Marburg virus (iMV) and a recombinant form of its surface envelope glycoprotein (rGP). We identified mAbs which bind rGP in solution phase immunoprecipitation experiments. HP were prepared by chemically cross-linking an anti-CR1 mAb with several of these anti-Marburg virus mAbs and used to facilitate binding of iMV and rGP to monkey and human E. These HP mediate specific and quantitative binding (> or = 90%) of both antigens to monkey and human E. Binding was also demonstrable in an indirect RIA. E with bound Marburg virus were probed with 125I labeled mAbs to the Marburg surface glycoprotein and more than 100 mAbs are bound per E. It should be possible to adapt this general approach to other pathogens, and experiments underway should lead to an in vivo test of HP-mediated clearance of Marburg virus.

Animals↗
PubMedDate not supplied

Complement receptors and regulatory proteins in human atherosclerotic lesions.

Complement activation in human atherosclerotic lesions is indicated by the presence of C5b-9 terminal complexes. By using monoclonal antibodies to the complement C3b receptor (CR1) and the iC3b receptor (CR3), it was observed that approximately 20% of the cells in complicated human carotid lesions express CR1 and CR3 antigens. One to five percent of complement receptor-positive cells stained for smooth muscle cell-specific myosin, and the remainder were determined to be predominantly macrophages, based on their reactivity to anti-LeuM3 (CD14) monoclonal antibody. No C3dg receptor (CR2)-positive cells were observed in any of the eight lesions examined. The complement regulatory glycoprotein decay accelerating factor (DAF) was widely distributed extracellularly, in addition to being present on 20% to 60% of the total cell population. Factor H, a plasma protein that regulates alternative pathway C3 convertase formation, was observed extracellularly in 70% of the lesions examined. C1 inhibitor was present in a few plaque specimens, was relatively sparse, and appeared largely cell associated. Terminal C5b-9 complement complexes were pervasive in all lesions. Both the complement regulatory proteins and the activation products were limited to the area of lesion involvement and were absent from normal arterial wall. The results demonstrate that molecules involved in complement regulation and complement ligand binding are present in atherosclerotic lesions, where they may function to modulate the activities of complement.

Arteriosclerosis↗
PubMed1987

Quantification of the complement receptor function on polymorphonuclear leukocytes: its significance in patients with systemic lupus erythematosus.

The function of complement receptors (CR1) on polymorphonuclear leukocytes (PMN) was assessed by C3b mediated binding of immune complexes (IC) to PMN. The binding of IC to CR1 on PMN depends on the activation of the classical complement pathway and was inhibited by the antibody to CR1 or C3b. CR1 function of PMN from patients with systemic lupus erythematosus was reduced compared with those from normal controls or patients with rheumatoid arthritis.

Antibodies, Monoclonal↗
PubMed1983

T cell prolymphocytic leukemia. 2 cases having a postthymic helper phenotype with complement receptors and 14q+ chromosome abnormality.

We describe 2 elderly patients with splenomegaly and progressive bone marrow failure due to infiltration by leukemic prolymphocytes with a single prominent nucleolus. In each case the leukemia cells had a unique helper T cell phenotype with complement receptors and contained coarse blocks of acid alpha-naphthyl butyrate. A 14q+ chromosome was among the abnormalities that marked one abnormal T cell clone. Histology of the spleen showed mainly red pulp infiltration merging with periarteriolar regions and different from the pseudonodular pattern described in many cases of B cell prolymphocytic leukemia (PLL). Ultrastructurally, leukemia cells contained dense lysosomes, perinuclear clusters of 10-nm microfilaments but no distinctive cytoplasmic inclusions previously described in (B cell) PLL. We suggest that early phenotyping of leukemia cells may enable consideration of monoclonal antibody therapy in elderly patients with bone marrow failure resistant to chemotherapy.

Aged↗
PubMed1998

Escherichia coli bound to the primate erythrocyte complement receptor via bispecific monoclonal antibodies are transferred to and phagocytosed by human monocytes in an in vitro model.

We have prepared cross-linked, bispecific mAb complexes (heteropolymers) that facilitate rapid and quantitative binding of a prototype pathogen, Escherichia coli, to the complement receptor (CR1) on primate erythrocytes. Incubation of the erythrocyte-heteropolymer-E. coli complexes with freshly isolated human mononuclear cells leads to rapid removal of the E. coli from the erythrocytes, and phagocytosis and killing of the bacteria. The erythrocytes are not lysed or phagocytosed during this transfer reaction, but both heteropolymer and CR1 are removed from the erythrocytes along with the E. coli. These findings parallel observations made in previous in vivo experiments in which heteropolymers were used to facilitate clearance of innocuous prototype pathogens in a monkey model. It should now be possible to extend the heteropolymer paradigm to a live pathogen in a primate model.

Animals↗
PubMed1998

Recombinant human erythropoietin modulates erythrocyte complement receptor 1 functional activity in patients with lupus nephritis.

Deposition of immune complexes (IC) is an important step in the pathogenesis of lupus nephritis. Impairment of IC-clearance contributes to the accumulation of IC. It may be partly attributed to decreased complement containing immune complex (ICC) binding by erythrocytic complement receptor 1 (ECR1). Stimulating erythropoiesis with recombinant human erythropoietin (rHuEPO) may enhance the IC-clearance as increasing ECR1 expression and/or functional activity. Ten anemic patients with lupus nephritis were treated with 50 IU rHuEPO (Eprex) per kg body weight three times a week during a five week period. ICC-binding capacity of ECR1 was determined with 125I-labelled, C3ib containing BSA-anti-BSA complexes. In addition to effective correction of anemia, indicated by increased red blood cell count (RBC), hemoglobin concentration and reticulocyte ratio, rHuEPO significantly improved decreased ECR1 functional (ICC-binding) activity in patients with lupus nephritis. This improvement correlated with the increase in reticulocyte ratio. Although patients were kept on their previous therapy during Eprex administration, their clinical condition also improved. That was shown by a decrease in Westergreen ratio, serum creatinine concentration and anti-dsDNA level and also by an increase in creatinine clearance. Results suggest a beneficial immune modulatory effect of rHuEPO in lupus nephritis.

Adolescent↗
PubMed2002

Mice deficient in complement receptors 1 and 2 lack a tissue injury-inducing subset of the natural antibody repertoire.

Intestinal ischemia-reperfusion (IR) injury is initiated when natural Abs recognize neoantigens that are revealed on ischemic cells. Cr2(-/-) mice, deficient in complement receptors (CR)1 and CR2, demonstrate defects in T-dependent B-2 B cell responses to foreign Ags and have also been suggested to manifest abnormalities of the B-1 subset of B lymphocytes. To determine whether these CRs might play a role in the generation of the natural Abs that initiate intestinal IR injury, we performed experiments in Cr2(-/-) and control Cr2(+/+) mice. We found that Cr2(-/-) mice did not demonstrate severe intestinal injury that was readily observed in control Cr2(+/+) mice following IR, despite having identical serum levels of IgM and IgG. Pretreatment of Cr2(-/-) mice before the ischemic phase with IgM and IgG purified from the serum of wild-type C57BL/6 mice reconstituted all key features of IR injury, demonstrating that the defect involves the failure to develop this subset of natural Abs. Pretreatment with IgM and IgG individually demonstrates that each contributes to unique features of IR injury. In sum, CR2/CR1 play an unanticipated but critical role in the development of a subset of the natural Ab repertoire that has particular importance in the pathogenesis of IR injury.

Animals↗
PubMed1999

Measles: immunosuppression, interleukin-12, and complement receptors.

Measles virus, the first pathogen recognized to cause immunosuppression, induces profound and prolonged abnormalities in cellular immune responses in infected hosts. The ability of measles virus to specifically ablate monocyte/macrophage and dendritic cell production of interleukin (IL)-12 provides a potentially unifying mechanism for many of these in vivo and in vitro abnormalities. Cross-linking of the cellular receptor for measles virus, the complement regulatory protein CD46, is sufficient to inhibit IL-12 production. CD46-mediated downregulation of IL-12 has turned out to be a specific instance of a more general pattern of tight inhibitory control over IL-12 production effected by complement and phagocytic receptors on antigen-presenting cells. Exploitation of these pathways by other intracellular pathogens is likely.

Animals↗
PubMed1989

Reduced numbers of complement receptor type 1 on erythrocytes are associated with increased levels of anticardiolipin antibodies. Findings in patients with systemic lupus erythematosus and the antiphospholipid syndrome.

In several diseases, including systemic lupus erythematosus (SLE) and autoimmune hemolytic anemias, the numbers of complement receptor type 1 (CR1) expressed on erythrocytes of patients are reduced. In patients with SLE, anticardiolipin antibodies (aCL) have been associated with positive results on direct antiglobulin tests. Because of these findings, we investigated whether the reduced expression of erythrocyte CR1 in 61 patients (53 with SLE and 8 with the antiphospholipid syndrome) might be associated with the presence of aCL. A negative correlation was observed between aCL levels and mean numbers of CR1 (rs = -0.43, P = 0.001), and a positive correlation was observed between aCL levels and the levels of erythrocyte C4d and C3d (rs = 0.33 and 0.41, P = 0.01 and 0.001, respectively), but no correlation of aCL levels with serum C4 levels was found. When the results were further analyzed according to the IgG or IgM class of aCL, levels of antibodies of both classes were negatively correlated with CR1 numbers, but only IgM aCL levels were correlated with erythrocyte C4d and C3d numbers. The levels of anti-double-stranded DNA antibodies showed no correlation with erythrocyte CR1, C4d, or C3d numbers but were negatively correlated with serum C4 levels (rs = -0.43, P = 0.002). These data suggest that aCL, or a closely related antibody specificity, may bind to erythrocytes and may be directly involved in the mechanism for reduction of erythrocyte CR1 expression in SLE patients.

Antibodies, Antinuclear↗
PubMed1994

Relationship between immune complex binding and release and the quantitative expression of the complement receptor, type 1 (CR1, CD35) on human erythrocytes.

Primate erythrocytes (E) play a central role in clearing potentially pathogenic immune complexes (IC) from the circulation. E capture circulating IC via interaction between C3b and C4b sites, generated on the IC during activation of the complement cascade, and the complement receptor, type 1 (CR1), expressed on E. IC are released from E when C3b and C4b sites on the IC are cleaved by Factor I. The goal of this study was to examine the interactions between human E and model IC in the context of quantitative variations in CR1 expression. IC were prepared by combining murine monoclonal IgG1, IgG2b, or IgG3 anti-dinitrophenyl (DNP) antibodies with DNP-bovine serum albumin. The expression of CR1 on E, obtained from eight healthy donors, was quantified by radioimmunoassay and Scatchard analysis. On the basis of quantitative CR1 expression, preparations of E obtained from different donors at various times were categorized into phenotypic groups expressing high, intermediate, or low numbers of CR1. While there was some variation in the expression of CR1 of individual donors, five of the eight donors remained within the same phenotypic group upon repeated sampling. Surprisingly, when interactions between IC and E were examined in vitro, there was no direct relationship between the number of CR1 per E and the peak magnitude of IC binding to E. When peak binding and release rates were calculated, there was a direct correlation between the number of CR1 per E and the peak binding rate of IC constructed with IgG3 antibodies (IgG3 IC). In addition, there was an inverse correlation between the number of CR1 per E and the peak release rate of IgG2b IC. There was no direct correlation between the quantitative expression of CR1 on E and the peak binding or release rates of IgG1 IC. These data indicate that the quantitative expression of CR1 can affect the interactions between IC and E, but that these interactions are also dependent upon the immunochemical properties of the IC. These findings may be relevant to the pathogenesis of diseases, including systemic lupus erythematosus and AIDS, in which E express reduced numbers of CR1.

Antigen-Antibody Complex↗
PubMed1996

Reactivity of purified complement component 3b with bovine neutrophils and modulation of complement receptor 1.

OBJECTIVE: To study binding of purified complement component C3b to bovine blood and mammary neutrophils (PMN) after various treatments and determine their ability to modulate receptor numbers. DESIGN: Cell isolation, activation, and flow cytometric studies. ANIMALS: Healthy lactating Holstein cattle. PROCEDURE: Complement component C3b (18,300 kd) was isolated from bovine serum by column chromatography, and flow cytometric assays using fluorescein isothiocyanate-labeled C3b were developed to evaluate binding to PMN complement receptor 1. Multiple substances were tested to determine their overall effect on C3b binding to PMN. Blood and milk PMN were isolated by differential centrifugation and exposed to optimal concentrations of recombinant human C5a, formyl-methyl leucyl phenylalanine, recombinant bovine interferon-gamma, variable concentrations of phorbol myristate acetate (0.01 to 100 ng), calcium ionophore A23187, serum-opsonized zymosan, zymosan-activated serum (ZAS), zymosan-activated plasma (ZAP), and hydrocortisone acetate (25 and 70 ng). Additionally, mammary and blood PMN were preincubated in skim milk and whey. RESULTS: Variable concentrations of phorbol myristate acetate caused a dose-dependent increase in percentage of PMN binding C3b, and increased the amount of C3b bound per cell. Significant increases were observed after PMN treatment with calcium ionophore, serum opsonized zymosan, ZAS, and ZAP; conversely, incubation of PMN with hydrocortisone acetate resulted in reduced overall binding of C3b. Mammary PMN consistently bound more C3b, which was attributed to their activation during migration into the mammary gland. Binding of C3b was inhibited by skim milk. Activation of blood PMN with PMA, ZAS, and ZAP elicited larger responses than those observed for mammary PMN. CONCLUSIONS: Modulation of complement receptors on bovine PMN is possible. Additionally, significant difference between the level of binding of C3b to blood and milk PMN, with milk PMN having higher binding, may be attributable to migration of PMN into the mammary gland, causing increased receptor expression. CLINICAL RELEVANCE: Contribution to a greater understanding of the role of complement in bovine immunologic systems, leading to testing for in vivo enhancement of bovine immune responses to invading pathogens.

Animals↗
PubMed1996

Protection of porcine endothelial cells from complement-mediated cytotoxicity by the human complement regulators CD59, C1 inhibitor, and soluble complement receptor type 1. Analysis in a pig-to-human in vitro model relevant to hyperacute xenograft rejection.

Inhibition of complement activation is considered a prerequisite to overcome hyperacute xenograft rejection. In the present study, we investigated the efficacy of C1 inhibitor (C1 inh) and recombinant soluble complement receptor type 1 (rsCR1) to protect xenogeneic cells against complement-mediated cytotoxicity in an in vitro xenotransplantation model. The addition of the soluble complement regulators to human serum led to a dose-dependent inhibition of complement-mediated destruction of aortic porcine endothelial cells (PEC). On a molar base, rsCR1 was more efficient than C1 inh. Transfection of PEC with cDNA of human CD59 resulted in several clones where protection against complement-mediated cell destruction correlated with the expression level of the inhibitor. Addition of low concentrations of C1 inh and rsCR1 to a CD59 (human)-positive PEC clone, expressing a suboptimal level of the membrane-bound regulator, resulted in a significant improvement of protection against complement-mediated cell destruction.

Animals↗
PubMed1999

Complement receptor 1 red cell expression is not controlled by the In(Lu) gene.

BACKGROUND: The In(Lu) gene reportedly suppresses several blood group antigens that are not part of the Lutheran system, including the high-incidence antigens of the Knops blood group system. Because complement receptor 1 (CR1), which is known to carry the Knops system antigens, has a red cell (RBC) expression polymorphism, the role of In(Lu) in the expression of the Knops system antigens was reinvestigated. STUDY DESIGN AND METHODS: Blood samples from nine donors having the Lu(a-b-) phenotype were obtained and immediately phenotyped for Lu(b), Kn(a), McC(a), Sl(a), and Yk(a). The samples were also tested for Lu(a), P1, and AnWj. Immunoblots were performed to study both the CR1 and Lutheran glycoproteins from these donors. RBC expression of CR1 was quantified with an enzyme-linked immunosorbent assay, and the genetic inheritance of the high-expression (H) or low-expression (L) allele for CR1 was determined by Southern blot. RESULTS: Lu(b) was demonstrable only by absorption and elution techniques on all nine samples; however, the high-incidence Knops system antigens were readily detectable by hemagglutination. Two Lu(a-b-) donors (sibs) demonstrated weak Lutheran glycoprotein bands of 78 and 85 kDa on immunoblots, while the other seven Lu(a-b-) samples had no detectable glycoprotein. All donors had CR1*1, and one donor also had CR1*2 on immunoblot. Only one donor was homozygous for the L allele, and all had RBC copy numbers of CR1 within the normal range. CONCLUSIONS: Nine donors with the Lu(a-b-) phenotype showed suppression of the Lutheran system antigens but normal expression of CR1 glycoprotein and the Knops system blood group antigens. This suggests that the genes that suppress Lutheran system antigens do not suppress CR1 or its related blood group antigens.

Alleles↗
PubMed1998

Soluble complement receptor type 1 (sCR1) in chronic liver diseases: serum levels at different stages of liver diseases.

Complement receptor type 1 (CR1) is an integral membrane protein of many haematopoietic cells and plays an important role in the clearance of complement-associated immune complexes, favouring their transport to liver and spleen macrophages. A small amount of soluble CR1 (sCR1) is also found in plasma and might originate directly from release of leucocytes and other circulating cells. In previous studies, an increase in serum sCR1 level has been observed in liver cirrhosis and end-stage renal failure. High levels have also been found in patients with some haematologic malignancies. sCR1 serum levels were measured using a specific double sandwich ELISA assay. The present study demonstrates the correlation between mean serum sCR1 concentrations and disease severity in patients with chronic liver disease. In patients with liver cirrhosis, grouped according to the Child-Pugh classification, sCR1 rose as liver function decreased. The presence of neoplastic growth in the liver apparently does not play a role in the increase of sCR1. Serum sCR1 was not elevated in other solid malignancies. Since sCR1 accumulates in liver diseases, evaluation of its serum levels could be useful as a liver function test.

Carcinoma, Hepatocellular↗
PubMed1997

Binding of the 68-kilodalton protein of Mycobacterium avium to alpha(v)beta3 on human monocyte-derived macrophages enhances complement receptor type 3 expression.

Attachment to and uptake by host cells are important early events in the pathogenesis of intracellular organisms such as Mycobacterium avium. Monocyte-derived macrophages (MDM) are known to express multiple surface receptors that play a role in binding to and uptake of M. avium. These include complement receptor type 3 (CR3), fibronectin receptor, mannose receptor, and transferrin receptor. In addition to these, we have previously reported that the integrin receptor alpha(v)beta3 also plays a role in binding to M. avium in a nonopsonic environment. Further, we have shown that a 68-kDa surface protein of M. avium binds to human monocytes and plays a role in attachment of M. avium to MDM. The present study provides direct evidence that this protein mediates attachment of M. avium to MDM by binding to alpha(v)beta3. Using the technique of cell surface enzyme-linked immunosorbent assay, we have shown that the M. avium 68-kDa protein inhibits the binding of monoclonal antibodies (MAb) against alpha(v)beta3 to MDM compared to control proteins such as ovalbumin and laminin (P < 0.05). Dual-labeling studies were performed to demonstrate that after phagocytosis, alpha(v)beta3 is present along with M. avium in phagosomes of M. avium-infected MDM. In addition, we have demonstrated that this interaction between alpha(v)beta3 and the M. avium 68-kDa protein resulted in enhancement of CR3 expression, which is known to play a role in complement-mediated uptake of M. avium. Attachment of MDM to wells coated with the M. avium 68-kDa protein resulted in a twofold increase in CR3 expression compared to attachment of MDM to wells coated with ovalbumin. This enhancement was completely inhibited by pretreatment of MDM with MAb against alpha(v)beta3. In summary, M. avium binds to MDM via alpha(v)beta3 with the help of the M. avium 68-kDa protein, and this ligation enhanced the expression of CR3 on MDM. Since CR3 has been known to play a role in M. avium uptake, enhanced expression of this receptor mediated by M. avium-alpha(v)beta3 interaction indicates a complex mechanism of communication among different receptors that participate in M. avium attachment and uptake. These findings add to current understanding of the roles played by multiple receptor-ligand systems in uptake and pathogenesis of intracellular pathogens such as M. avium.

Bacterial Proteins↗
PubMed2004

Measurement of erythrocyte C4d and complement receptor 1 in systemic lupus erythematosus.

OBJECTIVE: C4-derived activation fragments are the only complement ligands present on the surfaces of normal erythrocytes. The significance of this observation is unknown, and the role of erythrocyte-bound C4 (E-C4) in human disease has not been explored. More than any other human disease, the pathogenesis of systemic lupus erythematosus (SLE) has been characterized by defects in clearance of complement-bearing immune complexes via erythrocytes expressing complement receptor 1 (CR1). This study was undertaken to determine whether these functional defects might be reflected by abnormal patterns of E-C4 and E-CR1 expression on erythrocytes of patients with SLE. METHODS: We conducted a cross-sectional study of 100 patients with SLE, 133 patients with other diseases, and 84 healthy controls. Erythrocytes were characterized by indirect immunofluorescence and by flow cytometry for determination of levels of C4d and CR1. RESULTS: Patients with SLE had higher levels of E-C4d and lower levels of E-CR1 than did patients with other diseases (P < or = 0.001) or healthy controls (P < or = 0.001). The test was 81% sensitive and 91% specific for SLE versus healthy controls and 72% sensitive and 79% specific for SLE versus other diseases, and it had an overall negative predictive value of 92%. CONCLUSION: This is the first report of abnormal levels of E-C4d in human disease. We found that abnormally high levels of E-C4d and low levels of E-CR1 are characteristic of SLE, and combined measurement of the 2 molecules has high diagnostic sensitivity and specificity for lupus. Determination of E-C4d/E-CR1 levels may be a useful addition to current tests and criteria for SLE diagnosis.

Adult↗
PubMed1998

Complement inhibition by soluble complement receptor type 1 improves microcirculation after rat liver transplantation.

BACKGROUND: Recent observations provide evidence that complement is involved in the pathophysiology of ischemia/reperfusion injury. In this study, we assessed the impact of complement inhibition on hepatic microcirculation and graft function using a rat model of liver transplantation. METHODS: Arterialized orthotopic liver transplantation was performed in Lewis rats after cold preservation (University of Wisconsin solution, 4 degrees C, 24 h). Eight animals received the physiological complement regulator soluble complement receptor type 1 (sCR1) intravenously 1 min before reperfusion. Controls received Ringer's solution (n=8). Microvascular perfusion, leukocyte adhesion, and Kupffer cell phagocytic activity were studied 30-100 min after reperfusion by in vivo microscopy. RESULTS: Microvascular perfusion in hepatic sinusoids was improved in the sCR1 group (87+/-0.7% vs. 50+/-1%; P < 0.001). The number of adherent leukocytes was reduced in sinusoids (68.3+/-4.7 vs. 334.1+/-15.8 [adherent leukocytes per mm < or = liver surface]; P < 0.001) and in postsinusoidal venules after sCR1 treatment (306.6+/-21.8 vs. 931.6+/-55.9 [adherent leukocytes per mm < or = endothelial surface]; P < 0.001). Kupffer cell phagocytic activity was decreased in the sCR1 group compared to controls. Postischemic bile production reflecting hepatocellular function was increased by almost 200% (P = 0.004) after complement inhibition. Plasmatic liver enzyme activity was decreased significantly upon sCR1 treatment, indicating reduced parenchymal cell injury. CONCLUSIONS: Our results provide further evidence that the complement system plays a decisive role in hepatic ischemia/reperfusion injury. We conclude that complement inhibition by sCR1 represents an effective treatment to prevent reperfusion injury in liver transplantation.

Animals↗