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PubMed2006

Identification of a complement receptor 1 peptide for inhibition of immune hemolysis.

Complement sensitization of red blood cells (RBCs) can cause life-threatening hemolytic anemias. We have previously shown that complement receptor 1 (CR1) derivatives specifically the N-terminal region with decay accelerating activity (DAA) for inactivation of a key enzyme in the complement cascade can reduce complement-mediated RBC destruction in vitro and in an in vivo mouse model of hemolytic transfusion reaction. In the present study, we have modeled the N-terminal CR1 molecule based on the X-ray crystal structure of decay accelerating factor and the NMR structure of a homologous CR1 domain. Based on the homology model, we identified a 34-mer peptide encompassing the putative DAA which in vitro reduced hemolysis, C3a release and surface C3 deposition. More importantly, this peptide at 0.6 mM was effective in prolonging survival of transfused incompatible RBCs in vivo. Our results indicate that CR1-based structure-function studies may provide insights for developing structure-derived transfusion therapeutics in the future.

Amino Acid Sequence↗

PubMed1990

Activity of type 1 erythrocyte complement receptors in uremia and after renal transplantation.

The effect of uremia on the activity of the erythrocyte complement receptors type 1 (CR1), and the changes occurring after renal transplantation, were studied. The complement receptor activity was measured by immune adherence utilizing a rosette technique. Patients with terminal kidney failure on the hemodialysis program exhibited significantly lower values of the erythrocyte CR1 activity in comparison with healthy controls. The circulating immune complexes did not affect erythrocyte CR1 activity. After successful renal transplantation, irrespective of the immunosuppressive program used, a significant increase in erythrocyte CR1 activity appeared, similar to control group values. However, the activity of erythrocyte CR1, in the graft recipients under cyclosporin A treatment, was significantly higher than in the patients receiving azathioprine with prednisone. Therefore, it is possible that cyclosporin A, transported in the erythrocytes, modifies the complement receptor function.

Adult↗

PubMed1986

A partial genomic DNA clone for the alpha subunit of the mouse complement receptor type 3 and cellular adhesion molecule Mac-1.

A genomic clone coding for the alpha subunit of the mouse complement receptor type 3 and the cellular adhesion molecule Mac-1 has been isolated directly from a genomic library using synthetic oligonucleotide probes based on the amino-terminal amino acid sequence of the protein. The identity of the clone has been established by DNA sequencing and in vitro translation of hybrid-selected mRNA. The gene is present in a single copy in the murine genome. The region containing the amino-terminal exon has been sequenced. RNA gel blotting shows that the Mac-1 alpha-subunit mRNA is 6 kilobases in length. Mac-1 alpha-subunit mRNA is present in macrophages but not T lymphoma or L cells. During gamma interferon-stimulated maturation of the mouse premyelocytic cell line M1, Mac-1 alpha-subunit mRNA is induced. This corresponds with the tissue distribution of the Mac-1 alpha subunit, showing expression is regulated at least partially at the message level.

Animals↗

PubMed1996

A soluble deletion mutant of the human complement receptor type 1, which lacks the C4b binding site, is a selective inhibitor of the alternative complement pathway.

The human complement receptor type 1 (CR1, CD35), is a single-chain glycoprotein consisting of 30 repeating homologous protein domains known as short consensus repeats (SCR) followed by transmembrane and cytoplasmic domains. The SCR themselves, considered in groups of seven, form long homologous repeats (LHR) which have been designated LHR-A, -B, -C, and -D for the most common human allotype of CR1. A soluble deletion mutant of CR1 which lacks the first seven N-terminal SCR (LHR-A) as well as the transmembrane and cytoplasmic domains was produced and characterized. The resulting protein, designated sCR1[desLHR-A], lacks the C4b binding site found in LHR-A, but retains the two C3b binding sites found in LHR-B and -C, respectively. The functional activities of sCR1[desLHR-A] were quantitatively compared in vitro to those of soluble complement receptor type 1 (sCR1) which has been shown to retain all known functions of the native cell surface receptor. sCR1[desLHR-A] and sCR1 competed equally for the binding of dimeric C3b to erythrocyte CR1. sCR1[desLHR-A] and sCR1 were similar in their capacity to serve as a cofactor in the factor I-mediated degradation of the C3b and C4b alpha chains. sCR1[desLHR-A] and sCR1 were comparable in their capacity to inhibit erythrocyte lysis and anaphylatoxin production mediated by the alternative complement pathway. sCR1[desLHR-A], however, was significantly less effective an inhibitor of erythrocyte lysis and anaphylatoxin production than sCR1 under conditions which allow classical pathway activation. These results demonstrate sCR1[desLHR-A] to be a selective inhibitor of the alternative complement pathway in vitro.

Binding, Competitive↗

PubMed1991

Analysis of Epstein-Barr virus-binding sites on complement receptor 2 (CR2/CD21) using human-mouse chimeras and peptides. At least two distinct sites are necessary for ligand-receptor interaction.

The predicted amino acid sequence of human complement receptor 2 (CR2, CD21, C3d,g/Epstein-Barr virus receptor) and its genetic murine homologue are approximately 70% identical. The sequence of each consists of a linear array of 60-70 amino acid repeats designated short consensus repeats (SCRs). Although they share significant sequence identity, a major difference in the activities of these two proteins has been believed to be the ability of human, but not mouse, CR2 to mediate Epstein-Barr virus (EBV) infection of B lymphocytes. In order to formally address this question and to directly compare the activities of the CR2 protein of each species, we have expressed recombinant mouse CR2 (rMCR2) in a human K562 erythroleukemia cell line background. We have found that rMCR2 reacts with two previously described rat anti-MCR2 monoclonal antibodies (mAbs), 7G6 and 7E9, but not mAb 8C12, which recognizes only mouse complement receptor 1. rMCR2 rosettes with erythrocytes bearing mouse and human C3d,g and binds glutaraldehyde cross-linked human C3d,g with a similar Kd as human CR2 (HCR2). rMCR2 does not bind EBV. By using this observation and constructing chimeras bearing portions of MCR2 on a HCR2 background, we have been able to define unique sequences in HCR2 SCRs 1 and 2 important in the interaction with both mAb OKB7, which blocks EBV binding and infection, and with EBV. In addition, by using blocking peptides derived from HCR2 sequence, we have identified a second distinct region in SCR2 important in EBV binding. Therefore, within the first two SCRs of HCR2 are multiple distinct sites of interaction with EBV and with mAb OKB7.

Amino Acid Sequence↗

PubMed1986

Solubilization of active complement receptor type 1 (CR1) from human erythrocyte stroma with trypsin and its purification.

Mild trypsinization of human erythrocyte stroma solubilized CR1 (complement receptor type 1, C3b/C4b receptor) without significant loss of decay-accelerating activity to C5 convertases on hemolytic intermediate cells (EAC 1-3b, P). The solubilized CR1 was purified using DEAE-Sephacel, C3-Sepharose, and anti-CR1-Sepharose column chromatographies. The purified material showed a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis under non-reducing conditions, and its molecular weight was determined to be 175K, about 20K smaller than native CR1. Because the purified sample was separated into the several segments by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions, the molecule is considered to be nicked and those segments are associated by disulfide bonds. These results mean that a large portion of the CR1 molecule is present outside of the plasma membrane of erythrocytes, and the intramembranous and cytoplasmic domains are not necessary for decay-accelerating activity.

Chromatography↗

PubMed2003

Genetic and structural polymorphism of complement receptor 1 in normal Indian subjects.

The human complement receptor 1 (C3b/C4b receptor, CD35, CR1), a polymorphic membrane bound glycoprotein, is differentially expressed on erythrocytes, eosinophils, monocytes, B and T-lymphocytes, dendritic cells and kidney podocytes. It also occurs in the plasma as soluble CR1 (sCR1) and in urine as urinary CR1 (uCR1). Different population studies have suggested the functional and physiological significance of the structural (CR1-A/190, CR1-B/220, CR1-C/160 and CR1-D/250 kDa) and genomic (HH, high erythrocyte CR1 expression, HL, intermediate and LL, low expression) polymorphisms in health and disease. However, simultaneous study on the structural and genomic polymorphism in the same group of study subjects is lacking. This is the first study on both quantitative and structural polymorphism in 101 healthy volunteers from different parts of India by random sampling. In our study, AA phenotype was found to be expressed in 84.2% of individuals and 14.8% carried AB phenotype. One individual (0.9%) was found to possess BB phenotype. Homozygous BB pattern was identified for the first time in Indian subjects. The relative gene frequencies for A and B allele were found to be 0.916 and 0.084, respectively. Pertaining to quantitative polymorphism, percentage distribution for HH, HL and LL phenotypes was found to be 23.7, 54.45 and 21.79%, respectively and the gene frequencies were 0.51 and 0.49 for H and L allele, respectively. The observations for quantitative as well as structural polymorphism showed a good probability of fitness with Hardy-Weinberg equilibrium, thus proving that both the types of CR1 polymorphic forms are encoded by autosomal co-dominant alleles. We found a higher frequency of HL and AA phenotypes in the study subjects. Our findings are unique as we found that gene frequencies for structural and quantitative polymorphism in our study subjects were a combination of those found in Caucasian and Oriental populations.

Adult↗

PubMed1983

Complement receptor expression by neoplastic and normal human cells.

Complement receptor (CR) expression in cell lines derived from Burkitt's lymphoma (BL), Epstein Barr virus-transformed cord blood lymphocytes (CB), and peripheral lymphocytes from patients with infectious mononucleosis (IM) was examined. Red cell intermediates bearing various densities of C4b, C3b, C3bi, or C3d were tested for rosette formation with the cell lines. In addition, a series of studies was performed under conditions that precluded the cleavage of cellbound C3b by Factor I (C3bINA). These conditions did not alter rosetting by the cells that were tested. RAJI cells rosetted with EAC3bi greater than EAC3d greater than EAC3b, but not with EAC4b. EAC3b/RAJI rosette formation required much greater quantities of C3b bound to red cells than did CB and IM lines, which unlike RAJI, also bound EAC4b. All of the BL lines failed to bind EAC4b even at a C4b density of 50,000 molecules/cell, but several lines did form rosettes with EAC3b, and most formed rosettes with EAC3bi and EAC3d. Fluid phase C3b blocked RAJI/EAC3b rosetting while having little effect on RAJI/EAC3bi rosette activity. Moreover, fluid phase C3b, as well as C4b, blocked RAJI/EAC3b rosettes more effectively than CB/EAC3b rosettes. The results indicate that the RAJI cell line has a receptor for C3b, with characteristics that differ markedly from the C3b receptor of cell lines derived from CB lymphocytes and of lymphoblastoid cell lines derived from patients with IM. This receptor is capable of interacting with soluble but not cellbound C4b. In these studies, rosette formation was examined under various ionic conditions. RAJI/EAC3b rosette formation was severely reduced as ionic strength was increased, whereas RAJI/EAC3bi binding was only moderately decreased at physiologic ionic strength. In striking contrast, EAC3bi binding to monocytes, PMN, and human erythrocytes was markedly reduced as ionic strength increased, but EAC3b binding to these cells was less sensitive to changes in ionic strength. Under conditions of physiologic ionic strength, the C3bi receptor of phagocytic cells may be at a functional disadvantage in the binding of C3bi-coated particles. This may have major physiologic implications.

Burkitt Lymphoma↗

PubMed1992

Levels of complement receptor type one (CR1, CD35) on erythrocytes, circulating immune complexes and complement C3 split products C3d and C3c are not changed by short-term physical exercise or training.

The effect of heavy short-term physical exercise on the levels of complement receptor type one (CR1, CD35) on erythrocytes, the concentrations of circulating immune complexes (IC), and the complement C3 split products C3c and C3d were examined in young healthy males. Fourteen untrained volunteers underwent a 60-min bicycle exercise test at 75% of maximal oxygen uptake (VO2max). Six of the volunteers were exercised twice with an interval of at least one month. Before the second bicycle test they received oral indomethacin. With an interval of at least 1 week, 6 also went through a 60-min back-muscle exercise at up to 30% of VO2max. Blood samples were collected before and during the last few minutes of exercise as well as 2 h and 24 h afterwards. The same parameters were examined once in 29 highly trained racing cyclists. There were no consistent or significant exercise-induced changes in the levels of erythrocyte CR1, circulating IC, C3c nor C3d as measured by an enzyme-linked immunosorbent assay, polyethylene glycol precipitation complement consumption method, and by intermediate gel rocket immunoelectrophoresis, respectively. Neither did these parameters differ from controls in the highly trained group. The results indicate that CR1 on erythrocytes, circulating immune complexes and complement cleavage products C3c and C3d in healthy subjects remain unaffected by short-term heavy physical activity and training.

Adult↗

PubMed1997

Complement activation in vitro by the red cell substitute, liposome-encapsulated hemoglobin: mechanism of activation and inhibition by soluble complement receptor type 1.

BACKGROUND: Liposome-encapsulated hemoglobin (LEH) has been developed as an emergency blood substitute, yet its effect on human complement has never been explored. Considering that complement activation is a major pathogenic factor in the respiratory distress syndrome that often develops in trauma and shock, LEH-induced complement activation may be a critical safety issue. STUDY DESIGN AND METHODS: Various LEH and corresponding empty liposomes were incubated with normal human sera, and various markers of complement activation (serum levels of C4d, Bb, SC5b-9, and CH50; C5a-induced granulocyte aggregation; membrane deposition of C3b) were measured. Incubations were also performed in the presence of (ethylene-bis[oxyethylenenitrilo]tetraacetic acid) (EGTA) and Mg++ (EGTA/Mg++) and soluble complement receptor type 1. RESULTS: LEH and liposomes activated human complement, as indicated by significant changes in one or more markers. The effect was primarily due to the presence of the phospholipid vehicle; small, unilamellar, highly homodispersed vesicles induced the greatest degree of complement activation. Complement activation was partially inhibited by EGTA/Mg++. The latter finding, together with the parallel increases in serum C4d and Bb, suggests activation of both the classical and alternative pathways. Soluble complement receptor type 1 (0.05-20 micrograms/mL) efficiently inhibited all vesicle-induced complement activation. CONCLUSION: Because of complement activation, the use of LEH for transfusion may require careful evaluation of safety. Soluble complement receptor type 1 may be useful as a prophylactic agent for complement activation-related complications of liposome infusions.

Blood Substitutes↗

PubMed1987

Erythrocytes transfused into patients with SLE and haemolytic anaemia lose complement receptor type 1 from their cell surface.

Erythrocyte complement receptor type 1 (CR1) shows a numerical deficiency in patients with SLE and with haemolytic anaemias. This receptor is a cofactor for the enzymatic degradation of C3b and is believed to play a role in the transport of immune complexes from the circulation to the reticulo-endothelial system. Erythrocyte CR1 was enumerated on cells which had been transfused into patients with SLE and haemolytic anaemias. In three patients with active disease up to 60% of CR1 was lost from erythrocytes during 5 days after blood transfusion and up to 410 molecules of C3 were deposited on these cells. These are the first in vivo data showing that CR1 may be lost from circulating erythrocytes. This acquired deficiency of CR1 on erythrocytes may have pathological consequences in patients with SLE.

Anemia, Hemolytic, Autoimmune↗

PubMed1994

Failure to prevent decompression illness in rats by pretreatment with a soluble complement receptor.

Controversy exists over the role of complement activation in the natural history of decompression illness (DCI), and whether an individual's predisposition to DCI might be influenced by susceptibility to activation of complement by intravascular gas bubbles. Treatment with a soluble complement receptor (sCR-1), which neutralizes activated complement components, is known to be beneficial in other complement-dependent disease processes. This study investigated the effect of treating rats with sCR-1 or saline before decompression from a dive profile known to produce a high incidence of DCI. No statistical difference in the incidence of DCI was observed between the 27 rats treated with sCR-1 and 26 control rats treated with saline. The study was unable to confirm the previously reported observation in rats of a positive correlation between DCI incidence and increasing weight.

Animals↗

PubMed1993

Soluble complement receptor type 1 prevents human complement-mediated damage of the rabbit isolated heart.

The purpose of this study was to determine if recombinant human soluble CR1 (sCR1) could prevent tissue damage associated with the activation of human complement. Directly mediated human complement-dependent myocardial injury was induced in the rabbit isolated heart perfused with a Krebs-Henseleit buffer containing 6% human plasma. There were three study groups: 1) 6% heat-inactivated human plasma (control); 2) 6% normal human plasma (NHP); or 3) 6% normal human plasma + 20 nM sCR1 (NHP + sCR1). Recorded functional parameters of the control group remained stable throughout the duration of the 70-min protocol. Complement activation in hearts perfused with 6% NHP increased the diastolic pressure; decreased developed pressure; and increased coronary perfusion pressure. These alterations were accompanied by a decrease in the maximum positive and negative dP/dt. Complement activation also increased cardiac muscle lymphatic fluid flow rate. The changes were greatest between 20 and 40 min, but persisted for the duration of the protocol. sCR1 (20 nM) in the perfusate containing 6% NHP prevented the complement-mediated alterations in the systolic, developed, and coronary perfusion pressures. sCR1 prevented the decrement in the positive and negative dP/dt, and the increase in the lymphatic fluid flow rate. Values for each of these parameters in hearts perfused with 6% NHP + sCR1 were not altered from those of controls at any time point in the protocol. Ultrastructural changes were present in tissues perfused with 6% NHP along with immunohistochemical evidence for presence of the terminal C5b-9 complex. sCR1 prevented the ultrastructural changes and the formation of the terminal complex. sCR1 offers significant protection against the cytolytic effects resulting from activation of the human complement system.

Animals↗

PubMed2004

The electrostatic nature of C3d-complement receptor 2 association.

The association of complement component C3d with B or T cell complement receptor 2 (CR2 or CD21) is a link between innate and adaptive immunity. It has been recognized in experimental studies that the C3d-CR2 association is pH- and ionic strength-dependent. This led us to perform electrostatic calculations to obtain a theoretical understanding of the mechanism of C3d-CR2 association. We used the crystallographic structures of human free C3d, free CR2 (short consensus repeat (SCR)1-2), and the C3d-CR2(SCR1-2) complex, and continuum solvent representation, to obtain a detailed atomic-level picture of the components of the two molecules that contribute to association. Based on the calculation of electrostatic potentials for the free and bound species and apparent pK(a) values for each ionizable residue, we show that C3d-CR2(SCR1-2) recognition is electrostatic in nature and involves not only the association interface, but also the whole molecules. Our results are in qualitative agreement with experimental data that measured the ionic strength and pH dependence of C3d-CR2 association. Also, our results for the native molecules and a number of theoretical mutants of C3d explain experimental mutagenesis studies of amino acid replacements away from the association interface that modulate binding of iC3b with full-length CR2. Finally, we discuss the packing of the two SCR domains. Overall, our data provide global and site-specific explanations of the physical causes that underlie the ionic strength dependence of C3d-CR2 association in a unified model that accounts for all experimental data, some of which were previously thought to be contradictory.

Complement C3d↗

PubMed1994

Analysis of the functional domains of complement receptor type 1 (C3b/C4b receptor; CD35) by substitution mutagenesis.

The complement receptor type 1 (CR1; CD35), carrying 30 short consensus repeats (SCRs), has two sites. Site 1 contains SCR-1 and SCR-2 and binds C4b. Site 2 contains SCR-8 and SCR-9 and was reported to bind mainly C3b (Klickstein, L. B., Bartow, T. J., Miletic, V., Rabson, L. D., Smith, J. A., and Fearon, D. T. (1988) J. Exp. Med. 168, 1699-1717). For the functional analysis we used two constructs, each with one site. CR1-4, composed of eight and one-half initial SCRs, carries site 1, binds C4b, and is cofactor for C4b cleavage. CR1-4(8,9), obtained from CR1-4 by converting site 1 to site 2, binds iC3/C3b and, unexpectedly, C4b. It is a cofactor for cleavage of both ligands. Its cofactor activity for C4b cleavage is greater than that of site 1. Analysis of the mutants constructed by interchanging homologous peptides between the two sites identified no sequences necessary for cofactor activity other than those required for binding. In site 2, peptides important for both ligands were found. Some modifications of either site led to higher activity for both ligands. Thus the activity of complement regulators can be increased by changing a few amino acids within SCRs, an important step toward the generation of more effective inhibitors of complement activation. Knowledge of the active sites of CR1 should be applicable to other SCR-containing proteins and should provide insights into the evolution of these proteins.

Amino Acid Sequence↗

PubMed1993

Binding ability of complement receptor CR1 to C3 bound on the surface of M+ group A streptococci.

A previous study demonstrated that although M+ bacteria bound C3, mainly C3b and iC3b, via the classical pathway of complement activation, they were not phagocytosed by polymorphonuclear leucocytes (PMN). To elucidate this mechanism, we attempted to distinguish between the possibilities that M+ bacteria are effectively adhering to PMN but are not being endocytosed, or that the C3 deposited on M+ bacteria is not able to interact with the complement receptors on PMN. In the present study, we studied the interaction of C3-coated M+ bacteria with complement receptor CR1, which was isolated from the stroma of human erythrocytes. We show that the isolated complement receptor CR1 can associate with C3-coated M+ bacteria as well as with C3-coated M- bacteria, and the C3 deposited on M+ bacteria is cleaved and releases a C3 fragment in the presence of factor I and liquid-phase CR1. These results suggest that the C3 bound on the surface of M+ bacteria is able to promote adherence to the complement receptor CR1 on PMN. We also studied the distribution of C3 deposited on M+ bacteria in normal human serum (NHS) or normal human plasma (NHP). By immunofluorescence, we show that the C3 bound to M+ bacteria in NHS was deposited uniformly over the surface of the bacteria. On the other hand, the C3 bound to M+ bacteria in NHP was deposited at both ends between adjacent daughter cocci. The results suggest that an additional factor contained in NHP is related to the enhancement of anti-phagocytic activity of M+ bacteria.

Antibodies↗

PubMed2004

Role of complement receptors 1 and 2 (CD35 and CD21), C3, C4, and C5 in survival by mice of Staphylococcus aureus bacteremia.

Complement-mediated opsonization and phagocytosis of encapsulated serotype 5 Staphylococcus aureus are essential to host defense. We describe the effects of complement depletion and deficiencies of C4, C5, and complement receptors 1 and 2 on mouse survival after intravenous exposure to S aureus. Depletion of complement proteins in C57BL/6 mice with the use of cobra-venom factor decreased survival compared with that of controls after the induction of bacteremia with mucoid (90% mortality), encapsulated (73%), and unencapsulated (59%) S aureus strains. In this model complement is even more important in the control of infection with encapsulated S aureus (80% of clinical isolates) than in the control of infection by unencapsulated strains. C4-deficient mice demonstrated similar mortality from bacteremia caused by encapsulated S aureus compared with controls, suggesting that in the unimmunized animal the alternative complement pathway contributes more to control of bacteremia caused by encapsulated S aureus than the classical complement pathway or mannan-binding lectin pathway. C5-deficient mice (B10.D2-H2(d) H2-T18(c) Hc(0)/oSnJ) showed similar mortality when subjected to bacteremia caused by encapsulated S aureus compared with C5-sufficient (B10.D2-Hc(1) H2(d) H2-T18(c)/nSnJ) mice, suggesting that in this model the anaphylatoxin C5a and the late complement cascade are not critical to survival of bacteremia induced with the use of these strains. However, C5-deficient mice depleted of C3 with the use of cobra-venom factor had 60% decreased survival compared with untreated C5-deficient mice with bacteremia induced by encapsulated S aureus, suggesting that in this model C3 is more critical than C5 in controlling S aureus bacteremia. Complement receptor 1 (CD35) is the primary receptor for the opsonin C3b. Mice deficient in CD35/CD21 showed a 67% decrease in survival compared with normal mice, suggesting that CD35/CD21 is of major importance in the control of S aureus-induced bacteremia.

Animals↗

PubMed1993

Complement inhibition with soluble complement receptor type 1 in cardiopulmonary bypass.

Although complement activation during cardiopulmonary bypass (CPB) is well documented, its pathogenic role in postperfusion organ injury is unproven. In this study, soluble human complement receptor type 1 (sCR1), a potent inhibitor of complement activation, was used to determine the contribution of complement activation to pulmonary injury in a porcine model of CPB. In vitro experiments demonstrated that sCR1 inhibits both classic and alternative complement pathways in the pig. Seven control piglets and 6 piglets treated with sCR1 (12 mg/kg intravenously) underwent 2 hours of hypothermic (28 degrees C) CPB followed by 2 hours of observation. In control piglets, total hemolytic complement activity and functional activities of C3 and C5 declined to 61.3%, 67.8%, and 61.4% of prebypass values, respectively, after 2 hours of CPB. Plasma from animals treated with sCR1 had virtually no hemolytic activity (total hemolytic complement activity < 5% of baseline), demonstrating effective complement inhibition. Similar degrees of neutropenia developed in the two groups during CPB, and there was no difference in post-CPB lung tissue myeloperoxidase level. Two hours after CPB, pulmonary vascular resistance increased 338% in control piglets but only 147% in piglets pretreated with sCR1 (p < 0.05); the alveolar-arterial gradient was not significantly different between controls (331 +/- 52 mm Hg) and piglets receiving sCR1 (290 +/- 85 mm Hg). Histologic examination revealed similar degrees of pulmonary edema in both groups. These data constitute direct evidence that complement activation plays a pathogenic role in lung injury after CPB.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗