Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Complement C3a”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,207 records · Page 67Linked to original sources
PubMed1994

Activation of complement and kinin systems after thrombolytic therapy in patients with acute myocardial infarction. A comparison between streptokinase and recombinant tissue-type plasminogen activator.

BACKGROUND: We have previously shown that treatment with streptokinase induces abrupt complement activation and transient neutropenia in patients with acute myocardial infarction (AMI). The purpose of this study was to compare the effects of two different thrombolytic agents--streptokinase (SK) and recombinant tissue-type plasminogen activator (rTPA)--on activation of the complement and kinin systems in plasma of patients with AMI. METHODS AND RESULTS: Forty-one patients with AMI who were eligible for thrombolytic therapy were studied. Twenty-three patients were treated with streptokinase (1.5 million IU IV over 60 minutes) and 18 were treated with rTPA (8 with bolus of 10 mg IV, followed by 50 mg infused over 60 minutes and then 40 mg infused over 120 minutes; 10 patients were administered rTPA and heparin according to the accelerated infusion protocol indicated by the GUSTO study). C4a and C3a were measured by radioimmunoassay, soluble terminal complement components (SC5b-9) and anti-SK IgG antibodies were measured by ELISA. Cleaved high molecular weight kininogen (HK) was quantitated in plasma by SDS-PAGE and immunoblotting analysis. C4a levels were significantly and similarly increased in both groups, whereas the levels of C3a and SC5b-9 after rTPA infusion were only slightly elevated and were significantly lower than after SK. No differences were observed between patients treated with slow or accelerated rTPA regimens. The titer of antibodies to SK was highly correlated with the levels of C3a and SC5b-9, whereas a lesser correlation was observed with C4a. Treatment with rTPA did not induce the transient neutropenia observed after SK infusion. The cleavage products of HK were significantly greater after SK than after rTPA infusion. CONCLUSIONS: Our results show that both thrombolytic agents activate the classic complement pathway and that plasmin could be the common trigger for this phenomenon. A significant activation of the complement common pathway (from C3 to terminal components) was observed only with SK infusion and is attributable to the rapid formation of immunocomplexes between SK and anti-SK antibodies present in plasma as a consequence of previous streptococcal infections. The minimal activation of C5 component of the common pathway explains the absence of leukopenia in patients treated with rTPA. Cleavage of HK, larger after SK than after rTPA infusion, represents a condition enhancing the generation of bradykinin by kallikrein. The recent experimental data that indicate a damaging effect of complement activation on the infarcted zone and the contrasting favorable effect consequent to bradykinin formation raise some questions about the clinical importance of the different biological consequences of SK versus rTPA.

Adult↗
PubMed1989

Tertiary structure of human complement component C5a in solution from nuclear magnetic resonance data.

The tertiary structure for the region 1-63 of the 74 amino acid human complement protein C5a in solution was calculated from a large number of distance constraints derived from nuclear Overhauser effects with an angular distance geometry algorithm. The protein consists of four helices juxtaposed in an approximately antiparallel topology connected by peptide loops located at the surface of the molecule. The structures obtained for the helices are compatible with alpha-helical hydrogen-bonding patterns, which provides an explanation for the observed slow solvent exchange kinetics of the amide protons in these peptide regions. In contrast to the peptide region 1-63, no defined structure could be assigned to the C-terminal region 64-74, which increasingly acquires dynamic random coil characteristics as the end of the peptide chain is approached. An average root-mean-square deviation of 1.6 A was obtained for the alpha-carbons of the first 63 residues in the calculated ensemble of C5a structures, while the alpha-helices were determined with an average root-mean-square deviation of 0.8 A for the alpha-carbons. A comparison between the solution structure of C5a and the crystal structure of the functionally related C3a protein, as well as inferences for the interaction of C5a with its receptor on polymorphonuclear leukocytes, is discussed.

Amino Acid Sequence↗
PubMed2005

Normal pregnancy is characterized by systemic activation of the complement system.

BACKGROUND: The complement system, a major component of innate immunity, has recently been implicated in the mechanisms of fetal loss and placental inflammation in the anti-phospholipid antibody syndrome. Inhibition of complement has been proposed as an absolute requirement for normal pregnancy. Yet, pregnancy is characterized by a generalized activation of the innate immune system. This study was conducted to determine whether or not normal pregnancy is associated with complement activation in the maternal circulation. METHODS: Anaphylatoxins (C3a, C4a and C5a) were determined in the plasma of normal pregnant (20-42 wks; n=134) and non-pregnant women (n=40). These complement split products (C3a, C4a and C5a) were measured using specific immunoassays. Non-parametric statistics were used for analysis. RESULTS: 1) The median plasma concentrations of C3a, C4a and C5a were significantly higher in normal pregnant women than in non-pregnant women (all p<0.001); 2) the concentration of C3a, C4a and C5a did not change with gestational age (p>0.05); and 3) the median plasma concentration of C3a had a positive correlation with the plasma C4a and C5a concentrations (r=0.36, p<0.001 and r=0.35, p<0.001, respectively). CONCLUSION: 1) Normal human pregnancy is associated with evidence of complement activation, as determined by higher concentrations of the anaphylatoxins C3a, C4a and C5a in the maternal circulation; and 2) we propose that physiologic activation of the complement system during pregnancy is a compensatory mechanism aimed at protecting the host against infection.

Adolescent↗
PubMed1987

C5a-specific modulation of phagocyte functions in patients with localized bacterial infections.

Chemotaxis, enzyme release and superoxide-anion (O2-) generation of purified peripheral blood neutrophils (PMN) and monocytes were studied in a total of 87 patients suffering from localized bacterial infections. Shortly after disease onset, single or several PMN functions became non-responsive to the complement split product C5a. Functional activities elicited by the synthetic peptide f-met-leu-phe or leukotriene B4 remained unaltered. C5a-specific impairment lasted one to several days and returned to normal with the subsidence of the disease. C5a elicited release of beta-glucuronidase as well as generation of superoxide-anions was seen more often to be impaired as compared to chemotactic migration. In contrast to PMN, monocytes from the same patients failed to show paralleling C5a-specific functional alterations. There was no correlation between impairment of PMN functions and plasma levels of the complement split-products C3a and C4a as determined by RIA. It is concluded that in acute infectious disease a graded C5a-specific modulation of PMN functions may be present. This phenomenon is transient and not paralleled by functional alterations of monocytes or changes in plasma complement levels.

Bacterial Infections↗
PubMed1997

Phenotypic alterations in circulating monocytes induced by open heart surgery using heparinized and nonheparinized cardiopulmonary bypass systems.

In this study of 31 patients with coronary bypass surgery, we used flow cytometry to compare heparin-coated and noncoated cardiopulmonary bypass systems on leukocyte activation. We found significant differences between the groups during bypass, with activation of the complement system, measured as elevated levels of C3a desArg, upregulation of granulocyte beta2 integrin (CD11b), and a loss of circulating monocytes when noncoated systems were used. In both groups an early increase in the monocyte cell surface CD62L expression was obvious while the percentage of human leukocyte antigen (HLA)-DR positive monocytes did not alter. The morning after the operation, leukocytosis was present, together with a highly significant reduction in the monocyte expression of CD11b and HLA-DR, indicating the recruitment to the peripheral blood of cells with altered phenotypes. This alteration in phenotype on potent inflammatory cells may be one part of the impaired function of the immunological system reported after major surgery.

Adult↗
PubMed1999

Possible mechanism for in vitro complement activation in blood and plasma samples: futhan/EDTA controls in vitro complement activation.

BACKGROUND: Ongoing in vitro complement (C) activation in citrate or EDTA plasma has prevented an accurate analysis of C-activation products generated in vivo. The aim of this study was to characterize handling and storage conditions required to prevent in vitro C activation in blood and plasma samples collected with Futhan/EDTA. METHODS: Biotrak(TM) RIAs were used to quantitatively measure C3a and C4a in blood and/or plasma samples from healthy individuals (controls) and from liver transplant patients. Blood samples were routinely drawn into either EDTA (1 g/L) tubes or into tubes containing both EDTA (1 g/L) and Futhan (0.1 g/L) and immediately centrifuged at 2000g for 15 min at 4 degrees C. RESULTS: In controls, C4a, but not C3a, in fresh samples (time 0) was higher in EDTA plasma than in Futhan/EDTA plasma (n = 20; P = 0.002). Futhan/EDTA prevented C3a and C4a generation in blood and plasma samples held at room temperature (22-23 degrees C) for 1 h and in plasma held for 24 h at 4 degrees C or -70 degrees C. The mean C3a concentration (1.76 mg/L; n = 19) at time 0 in EDTA plasma samples from liver transplant patients was significantly higher than for controls (0.34 mg/L; n = 11). In these patients, the mean C3a in EDTA samples increased to 13.8 mg/L after 60 min at room temperature, but there was no change in the C3a concentration of an EDTA plasma from a control. In the patients, C3a concentrations were lower in Futhan/EDTA plasma than in EDTA at time 0 and after 60 min at room temperature (1.40 and 2.02 mg/L, respectively). The mean patient C4a was 4.02 mg/L in EDTA plasma at time 0 vs 0.24 mg/L for controls; it increased to 16.9 mg/L after 60 min at room temperature compared with 0.76 mg/L for controls. The mean patient C4a was 0.83 mg/L in Futhan/EDTA plasma at time 0 vs 0.1 mg/L for controls. Neither patient nor control C4a concentrations increased vs time in Futhan/EDTA. CONCLUSION: The combination of Futhan (0.1 g/L) and EDTA (1 g/L) eliminates in vitro C activation.

Adult↗
PubMed1994

Biocompatible membranes in acute renal failure: prospective case-controlled study.

The mortality of critically ill patients with acute renal failure has been halved through intervention by haemodialysis. However, several reports suggest that the course of the disorder may be prolonged by this procedure. Our prospective randomised study was done to see whether the generation of inflammatory mediators by bio-compatible membranes has an adverse effect on the outcome of acute renal failure. 52 patients, similar in age, severity of acute renal failure, general disease status (APACHE II), and management of acute renal failure or its related conditions, were divided into two groups. Haemodialysis was done with cuprophane or polyacrylonitrile membranes. Cuprophane membranes induced intense activation of the complement system (as judged by measurement of C3a) and lipooxygenase pathway (leukotriene B4) resulting in alterations of neutrophil kinetics and function. The cuprophane group had a lower survival rate (38 vs 65%), a higher proportion of patients dying from sepsis (71 vs 40%), required more haemodialysis sessions (12 vs 9), and demonstrated delayed resolution and recovery from acute renal failure than the polyacrylonitrile group. The difference in mortality regarding lethal sepsis as cause of death was statistically significant. Our observations indicate that the outcome of critically ill patients with acute renal failure may be influenced by bio-incompatibility reactions to the dialysis membrane. These results have direct implications for such patients on haemodialysis.

Acrylic Resins↗
PubMed2005

Inflammation, complement activation and endothelial function in stable and unstable coronary artery disease.

BACKGROUND: Endothelial dysfunction plays an important role in the pathogenesis of coronary artery disease (CAD). Apart from traditional risk factors complement activation and inflammation may trigger and sustain endothelial dysfunction. We sought to assess the association between endothelial function, high sensitivity C-reactive protein (hs-CRP) and markers of complement activation in patients with either stable or unstable coronary artery disease. METHODS: We prospectively recruited 78 patients, 35 patients with stable angina pectoris (SAP) and 43 patients with unstable angina pectoris (UAP). Endothelial function was assessed as brachial artery reactivity (BAR). Hs-CRP, C3a, C5a and C1-Inhibitor (C1 inh.) were measured enzymatically. RESULTS: Patients with UAP showed higher median levels of hs-CRP and C3a compared to patients with SAP, while BAR was not significantly different between patient groups. In UAP patients, hs-CRP was significantly correlated with cholesterol (r=0.27, p<0.02), C3a (r=0.32, p<0.001) and C1 INH.(r=0.41, p<0.003), but not with flow mediated dilatation (r=0.09, P=0.41). Hs-CRP and C1 INH.were found to be independent predictors of UAP in a backward stepwise logistic regression model. CONCLUSIONS: We conclude that both hs-CRP, a marker of inflammation and C3a, a marker of complement activation are elevated in patients with UAP, but not in patients with SAP.

Aged↗
PubMed1988

Complement activation and the toxicity of stroma-free hemoglobin solutions in primates.

The toxicity of hemoglobin solutions was studied in the context of their ability to activate serum complement (C). Three bovine polymerized hemoglobin solutions (BPHSs) with different degrees of purity were used for experiments in vitro and in vivo. BPHS-1 contained bacterial endotoxins (E) (5 EU/ml) and stromal phospholipids (PLs) (1.2 mg/dl), BPHS-2 contained only PLs (2.0 mg/dl), while BPHS-3 was completely free of both contaminants. C-activation was studied by the direct measurement of C3a, C4a, and C5a des Arg fragments, using commercially available RIA kits. During 1 hour of incubation with fresh monkey plasma, BPHS-1 and -2 activated both pathways of C, while BPHS-3 caused no activation of any factor. In vivo, Hb solutions were used to replace one-third of blood volume in three groups of six Coebus monkeys each, while fresh homologous plasma was used in a control group of four animals. Impure solutions activated the alternative pathway of C and caused significant reactions of the circulating blood (thrombocytopenia, leukopenia, and disseminated intravascular coagulation) associated with multiorgan dysfunction (cardiac arrhythmias, hypoxemia, reduction of renal clearance of endogenous creatinine, and elevation of liver enzyme SGPT). The pure solution neither activated C nor caused any reaction in the circulating blood. However, it caused a moderate degree of direct tissue injury, evidenced by transient reduction of creatinine clearance and elevation of SGPT. These observations suggest that impure and pure Hb solutions carry separate mechanisms of toxicity. Complement, activated by toxic impurities, plays an active role in the toxicity of impure solutions. C-activation in vitro could be used as a screening test of biocompatibility.

Animals↗
PubMedDate not supplied

Activation of the complement pathway: comparison of normal pregnancy, preeclampsia, and systemic lupus erythematosus during pregnancy.

To evaluate a flare of systemic lupus erythematosus (SLE) during pregnancy and to differentiate it from diseases of pregnancy, serological parameters are often utilized. However, there are conflicting reports regarding the merit of conventional measurements of complement and activation products. While in normal pregnancy the levels of serum C3, C4, and CH50 gradually rise, a decline in these levels occurs during the course of pregnancy in selected SLE patients. There is controversy regarding whether such falls represent decreases in the overall synthesis of complement or activation, the former theory being supported by a report of normal levels of the C1s-C1 inhibitor complex. During normal pregnancies, increases of complement split products, such as plasma C3a, may occur, and these correlate positively with elevations of C3. In pregnancies complicated by lupus, increases of C3a are often accompanied by a decline in total C3 and CH50. In a minority of non-SLE patients, preeclampsia has been associated with elevations of a variety of complement split products. Ba, C3a, C4d, SC5b-9, indicating activation of both the classical and alternative pathways. The CH50 levels tend to remain normal in these patients. In contrast, elevations of complement split products frequently accompany disease flares in patients with SLE. A high ratio of CH50/Ba may differentiate patients with preeclampsia from those with active SLE. A decline in conventional measures of C3, C4, or CH50 which is accompanied by elevations of complement split products appears to differentiate a lupus flare from non-SLE diseases of pregnancy.

Complement Activation↗
PubMed1988

Relative inefficiency of terminal complement activation.

The efficiency of generation of fluid-phase SC5b-9 and membrane C5b-9(m) complexes relative to cleavage of C3 and C5 was studied. Fluid-phase C activation was induced through addition of purified bacterial Ag to human serum. Sephadex beads were used as particulate activators of the alternative pathway. Rabbit or antibody-coated sheep or human E were used to study formation of cytolytic C5b-9(m) complexes. The molar ratios of C3a:C5a generated in the model systems were found to be in the range of 60 to 200:1 in the case of soluble immune complex activators, and 70 to 150:1 with particulate activators and cells. The efficiency of C5 cleavage relative to C3 cleavage increased on surfaces with the density of antibody and/or C3b-binding sites. With soluble immune complexes, the efficiency of subsequent SC5b-9 generation displayed wide variations dependent on Ag and donor with molar ratios of C5a:SC5b-9 ranging from 30:1 for teichoic acid and sometimes approaching 1:1 for streptolysin-O. In contrast, activation on particles or cells always led to C5a:C5b-9 (calculated as the sum of generated moles SC5b-9 and C5b-9(m] ratios approaching 1:1. Hence, there is an overall inefficiency of terminal sequence activation in the C cascade due first to a dissociation at the level of C5 convertase formation/C5-cleavage and second, to a frequent inefficiency of C5b-utilization in the fluid-phase. The results provide an explanation for the very low levels of SC5b-9 found in plasma of healthy individuals and in patients with C-consuming immune complex disease.

Animals↗
PubMed1981

Isolation of three separate anaphylatoxins from complement-activated human serum.

Recent methodologies used in preparing anaphylatoxins from complement-activated serum are described. Activation of the alternative pathway generates C3a and C5a; however, activation of the classical pathway is required to generate the anaphylatoxin from C4. This article describes an activation scheme that simultaneously generates all three of the anaphylatoxins (e.g., C3a, C4a and C5a) in human serum and outlines a procedure for isolating each as homogeneous products. Purification of intact anaphylatoxins directly from complement-activated serum takes place only if an exopeptidase in serum, known as carboxypeptidase N (SCPN), is properly inhibited. A new series of mercapto derivatives of arginine analogs are introduced as potent and effective inhibitors of SCPN. These inhibitors permit normal complement activation but prevent degradation of the released activation fragments C3a, C4a or C5a. The SCPN inhibitor previously used was 6-aminohexanoic acid (EACA), but it required a 1 M concentration for effective inhibition, the substituted mercapto-guanido compounds prove to be effective in the mM range.

Aminocaproic Acid↗
PubMed1998

The interaction of liposomes with the complement system.

Activation of complement (C) by haptenized liposomes has been utilized for a long time to study the interaction of biological membranes with C proteins, or as a sensitive immunoassay for the measurement of specific antigens, antibodies, or serum hemolytic C levels. However, it has been increasingly recognized that regardless of antigenicity, C activation is an intrinsic property of all charged phospholipid/cholesterol bilayers. Liposome-induced C activation and its biological consequences show significant interspecies and interindividual variation, and critically depend on the properties of vesicles as well. Activation can proceed through both the classical and the alternative pathways, with or without the involvement of antibodies. The practical significance of the phenomenon is twofold: 1) opsonization of the vesicles promotes their clearance from the circulation and 2) the liberation of C3a and C5a can cause numerous, potentially adverse, biological reactions. In fact, many cardiovascular and hematological changes observed following administration of liposomes in vivo can be explained by C activation; a fact that has not yet gained wide recognition in the field of drug-carrier liposomes.

Animals↗
PubMed1990

[Complement activation during storage of preserved blood].

We have provided evidence that during storage of CPD-Al stabilized whole blood factors of the complement cascade get activated. We prospectively measured C3a-desArg, C4a-desArg, and C42C3-activatorcomplex in 30 units of whole blood in the absence and presence of the proteinase inhibitors aprotinin and eglin over a storage period of 28 days. C3a-desArg increased from basic levels of 276 +/- 35 ng/ml to maximal levels of 1922 +/- 218 ng/ml after 2 weeks of storage. Similarly there was an increase in C4a-desArg levels from 172 +/- 16 ng/ml (day 0) to 1483 +/- 221 (day 14), but C4a-desArg levels further increased with time. By contrast C42 C3-activatorcomplex levels increased only moderately from 170 +/- 18 micrograms/ml (day 0) to 207 +/- 13 micrograms/ml (day 28). The addition of aprotinin and eglin could not inhibit the increase in activated complement factors. Our observations might be of clinical importance, especially during massive transfusions, since C3a-desArg in concentrations less than 1 ng/ml enhances the activation of platelets.

Blood Preservation↗
PubMed2001

A new in vitro model for the study of pig-to-human vascular hyperacute rejection.

Studies on vascular hyperacute xenograft rejection (HAR) are usually conducted in vitro on cultured endothelial cells (EC) exposed to human serum, in complex whole organ perfusion models using heparinized blood or in vivo models. Here we describe a new model allowing perfusion of pig vessels with human whole blood without anticoagulants. Segments of the porcine iliac artery were connected to circular polyvinyl chloride (PVC) tubing, whose inner surface was conjugated with immobilized heparin. The vessels were perfused with 7 to 8 ml of fresh, non-anticoagulated human blood by rocking of the tubing device for 5, 15 or 60 min in an incubator at 37 degrees C. Human iliac arteries (n = 4) were perfused with fresh human ABO-compatible blood as controls. Perfusion of human vessels resulted in changes in the blood and plasma parameters similar to those in the PVC control loop. Overall, perfusion of the porcine vessels generated high levels of C3a, sC5b-9 and thrombin-anti-thrombin (TAT). Platelet consumption was near total (97.2 +/- 1.2%; "high" responders) in six of 13 vessels perfused and only moderate (55.8 +/- 9.9%; "low" responders) in the remaining seven vessels. The "high" responder vessel group showed a significantly higher platelet reduction, neutrophil loss and monocyte consumption and higher C3a and TAT factor at 60 min compared with the human vessels. The "low" responder porcine vessel group also generated significantly higher TAT levels at 60 min compared with the human vessels, but lower levels compared with the "high" responder porcine vessel group. Immunohistochemical examination of perfused porcine vessels revealed binding of human IgM, IgG, IgA, C1q, C3, fibrin and platelets at 5 min. The binding of these proteins was even stronger at 15 and 60 min, and at 60 min C9 could also be detected. Addition of soluble complement receptor 1 (sCR1) to the blood resulted in a significant reduction in C3a and sC5b-9 (P = 0.046 and P = 0.046, respectively). However, sCR1 did not reduce C1q, C3c or C5 staining, but did abolish C9 binding to the endothelium. In conclusion, in vitro perfusion of porcine vessel segments with non-heparinized, fresh human blood triggered events characterizing HAR. The small quantity of blood and xenogenic tissue that is needed makes this model ideal for investigations of the mechanisms and treatments of rejections associated with xenogeneic pig-to-human xenotransplantation.

ABO Blood-Group System↗
PubMed1999

Increased complement biosynthesis by microglia and complement activation on neurons in Huntington's disease.

In this study complement activation and biosynthesis have been analysed in the brains of Huntington's disease (HD) (n = 9) and normal (n = 3) individuals. In HD striatum, neurons, myelin and astrocytes were strongly stained with antibodies to C1q, C4, C3, iC3b-neoepitope and C9-neoepitope. In contrast, no staining for complement components was found in the normal striatum. Marked astrogliosis and microgliosis were observed in all HD caudate and the internal capsule samples but not in normal brain. RT-PCR analysis and in-situ hybridisation were carried out to determine whether complement was synthesised locally by activated glial cells. By RT-PCR, we found that complement activators of the classical pathway C1q C chain, C1r, C4, C3, as well as the complement regulators, C1 inhibitor, clusterin, MCP, DAF, CD59, were all expressed constitutively and at much higher level in HD brains compared to normal brain. Complement anaphylatoxin receptor mRNAs (C5a receptor and C3a receptor) were strongly expressed in HD caudate. In general, we found that the level of complement mRNA in normal control brains was from 2 to 5 fold lower compared to HD striatum. Using in-situ hybridisation, we confirmed that C3 mRNA and C9 mRNA were expressed by reactive microglia in HD internal capsule. We propose that complement produced locally by reactive microglia is activated on the membranes of neurons, contributing to neuronal necrosis but also to proinflammatory activities. Complement opsonins (iC3b) and anaphylatoxins (C3a, C5a) may be involved in the recruitment and stimulation of glial cells and phagocytes bearing specific complement receptors.

Adult↗
PubMed1987

Anaphylatoxin release in association with methylmethacrylate fixation of hip prostheses.

In a prospective study, thirty patients in whom a Charnley hip prosthesis was implanted with cement (methylmethacrylate) and fifteen who received a prosthesis without cement were studied. The activation of complement, as indicated by the release of anaphylatoxins (C3a and C5a), reduced activity of whole complement, and decreased levels of C3, C4, and C5 in plasma, was evaluated. Activation of complement was found when methylmethacrylate was used. In patients in whom components were fixed without cement, no formation of anaphylatoxins occurred, and only slightly reduced whole-complement activity and concentrations of C3, C4, and C5 in plasma were found. A dose-correlated release of the anaphylatoxins was found when monomethylmethacrylate was incubated in fresh serum. One explanation for the hemodynamic instability in these patients might be the biological effects of anaphylatoxins that are released in association with fixation by cement.

Adult↗
PubMed2001

Contribution of anaphylatoxin C5a to late airway responses after repeated exposure of antigen to allergic rats.

We attempted to elucidate the contribution of complement to allergic asthma. Rat sensitized to OVA received repeated intratracheal exposures to OVA for up to 3 consecutive days, and pulmonary resistance was then estimated for up to 6 h after the last exposure. Whereas the immediate airway response (IAR) in terms of R(L) tended to decrease in proportion to the number of OVA exposures, late airway response (LAR) became prominent only after three. Although premedication with two kinds of complement inhibitors, soluble complement receptor type 1 (sCR1) or nafamostat mesylate, resulted in inhibition of the IAR after either a single or a double exposure, the LAR was inhibited after the triple. Premedication with a C5a receptor antagonist (C5aRA) before every exposure to OVA also inhibited the LAR after three. Repeated OVA exposure resulted in eosinophil and neutrophil infiltration into the bronchial submucosa which was suppressed by premedication with sCR1 or C5aRA. Up-regulation of C5aR mRNA was shown in lungs after triple OVA exposure, but almost no up-regulation of C3aR. Pretreatment with sCR1 or C5aRA suppressed the up-regulation of C5aR expression as well as cytokine messages in the lungs. The suppression of LAR by pretreatment with sCR1 was reversed by intratracheal instillation of rat C5a desArg the action of which was inhibited by C5aRA. In contrast, rat C3a desArg or cytokine-induced neutrophil chemoattractant-1 induced cellular infiltration into the bronchial submucosa by costimulation with OVA, but these had no influence on the LAR. These differences might be explained by the fact that costimulation with OVA and C5a synergistically potentiated IAR, whereas that with OVA and either C3a or cytokine-induced neutrophil chemoattractant-1 did not. C5a generated by Ag-Ab complexes helps in the production of cytokines and contributes to the LAR after repeated exposure to Ag.

Airway Resistance↗