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PubMed2005

Inflammation and tissue damage in crystal deposition diseases.

PURPOSE OF REVIEW: The crystal-induced arthropathies are characterized by self-limiting episodes of acute inflammation and chronic tissue damage. This review summarizes recent advances in the understanding of the cellular responses to monosodium urate, calcium pyrophosphate dihydrate and basic calcium phosphate crystals. RECENT FINDINGS: Factors such as the myeloid related proteins, endothelin-1 and the complement membrane attack complex have been recently identified as mediators of acute crystal-induced inflammation. In addition, signalling pathways involved in both acute inflammation and tissue damage in crystal arthropathies have been further clarified. The potential of macrophage-derived transforming growth factor beta1 to play a key role in the resolution phase of acute gout has also been demonstrated. SUMMARY: Recent work has provided new insights into the regulation of both acute and chronic articular responses to inflammatory microcrystals. Further analysis of these responses may identify potential therapeutic targets for management of the crystal-induced arthropathies.

Calcium Phosphates↗
PubMed1991

The role of lipopolysaccharide in complement-killing of Aeromonas hydrophila strains of serotype O:34.

The role of lipopolysaccharide (LPS) in the susceptibility of Aeromonas hydrophila strains of serotype O:34 to non-immune human serum was investigated using isogenic mutants (serum-sensitive), previously obtained on the basis of phage resistance, and characterized for their surface components. The classical complement pathway was found to be principally involved in the serum-killing of these sensitive strains. LPS preparations from serum-resistant or serum-sensitive strains, or purified core oligosaccharides (low-molecular-mass LPS) inactivated both bactericidal and complement activity of whole serum, while the O-antigen molecules (high-molecular-mass LPS) did not. The results indicate that LPS core oligosaccharide composition contributes to complement resistance of A. hydrophila strains from serotype O:34 with moderate virulence.

Aeromonas hydrophila↗
PubMed1997

Response of SCC-12F, a human squamous cell carcinoma cell line, to complement attack.

We studied the response of a human squamous cell carcinoma cell line, SCC-12F, to human complement attack and found that the cells were completely resistant to complement lysis. In the absence of lysis, there was significant C3 deposition and C5b-9 deposition on the cells. Removal of the lipid-linked complement regulatory proteins CD59 and decay-accelerating factor (DAF) by treatment of the cells with phosphatidylinositol-specific phospholipase C (PIPLC) resulted in increased C3b and C5b-9 deposition on the cells and a slight increase in cell death. Treatment of the cells with complement caused them to release membrane vesicles containing the terminal complement proteins. In addition, complement induced SCC-12F to produce significant amounts of prostaglandin F2alpha (PGF2alpha). We conclude that CD59 and DAF are important in the resistance of SCC-12F to complement and that these cells produce membrane vesicles and PGF2alpha in response to complement attack. These responses, in the absence of cell death, may be important in the pathogenesis of inflammatory skin disease in which complement is deposited.

Animals↗
PubMed2004

Complement activation in prestorage leucocyte-filtered plasma.

Complement activation and generation of pro-inflammatory cytokines occur during storage of blood components. Prestorage leucocyte filtration of platelet concentrates and red cells diminishes the accumulation of leucocyte-derived cytokines during storage, however, transfusion reactions are not eliminated. We investigated inflammatory mediator release during storage of plasma and whole blood and the effect of prestorage leucocyte filtration of plasma. Twenty-four blood units were collected from healthy blood donors and stored for 35 days. Eight units were stored as whole blood, eight units as plasma and eight units as prestorage filtered plasma. Samples were collected weekly for analyses of potassium, leucocytes, free plasma haemoglobin, complement activation (C3a and SC5b-9) and pro-inflammatory cytokines [interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-alpha]. Elevated levels of C3a and SC5b-9 were registered in filtered plasma, from the beginning of storage. C3a levels increased during storage. There was a higher rate of change during storage in C3a (P < 0.01) and SC5b-9 (P < 0.05) in plasma compared with filtered plasma. Interleukin (IL)-8 is released in whole blood. The cytokine levels generated in plasma and filtered plasma were low. Complement activation is present in whole blood, plasma and filtered plasma during storage. Prestorage filtration of plasma activates the complement cascade but does not influence cytokine generation.

Blood↗
PubMed2004

C-reactive protein and complement depositions in human infarcted myocardium are more extensive in patients with reinfarction or upon treatment with reperfusion.

BACKGROUND: Impaired perfusion of the heart induces a local inflammatory response, which involves deposition of C-reactive protein and complement activation products C3d and C5b-9. We investigated whether reperfusion or reinfarction enhances these phenomena in humans. MATERIALS AND METHODS: Depositions of C-reactive protein and complement were quantified in tissue samples of infarcted myocardium from 76 patients who had died after acute myocardial infarction. The extent of depositions in patients treated with reperfusion or suffering from reinfarction was compared with that in patients who had no reperfusion or reinfarction. RESULTS: Patients with reinfarction had significantly more extensive depositions of C-reactive protein and complement (C3d and C5b-9) in the infarcted myocardium than patients without reinfarction. Similarly, patients who received reperfusion therapy had more extensive depositions also than those who had not received this therapy. CONCLUSIONS: Both reinfarction and reperfusion therapy significantly increase the extent of C-reactive protein and complement depositions in human myocardial infarcts.

Aged↗
PubMed2006

Autophagic vacuolar myopathy in twin girls.

Hereditary autophagic vacuolar myopathy (AVM) may occur in several diseases including the rimmed vacuolar myopathies, acid maltase deficiency, Danon disease, infantile autophagic vacuolar myopathy and X-linked myopathy with excessive autophagy (XMEA). In the latter three conditions the vacuoles are lined by membranes with sarcolemmal features. We present two unusual cases of autophagic vacuolar myopathy in twin girls born at term with no family history of neurological disease. After initial normal developmental milestones they developed progressive leg weakness and wasting with contractures from the age of 12 years. Investigations showed raised CK, normal female karyotype, normal acid maltase activity, normal nerve conduction and myopathic EMG features. Frozen sections of skeletal muscle were stained using routine tinctorial and histochemical methods. Immunohistochemical staining for spectrin, merosin, dystrophin, complement membrane attack complex and sarcoglycans was performed and ultrastructural examination undertaken. Direct sequence analysis of the lamp-2 gene using genomic DNA extracted from lymphocytes was performed. Histological analysis of the muscle biopsies demonstrated myofibres with vacuoles lacking glycogen and lipid many of which were delineated using immunohistochemistry for merosin, dystrophin and sarcoglycans. Ultrastructural examination showed duplication of the myofibre basal lamina with associated autophagic material. Vacuoles within myofibres were either membrane bound containing autophagic material or lined by plasma membrane and basal lamina. Intermyofibrillar glycogen was increased. Sequence analysis of the coding region and intron/exon boundaries of the lamp-2 gene was normal. This is the first report of female cases of AVM with sarcolemmal features. We suggest that these patients may represent manifesting carriers of XMEA, or alternatively, a new form of disease with a similar phenotype having autosomal recessive inheritance.

Adolescent↗
PubMed2004

Effects of vitamin E on the cinnamaldehyde-induced apoptotic mechanism in human PLC/PRF/5 cells.

1. Cinnamaldehyde has been shown to be effective in inducing cell apoptosis in a number of human cancer cells. The aim of the present study was to investigate the effect of vitamin E on the apoptotic signalling mechanism induced by cinnamaldehyde in human hepatoma PLC/PRF/5 cells. 2. Using the XTT assay, cinnamaldehyde exhibited a powerful antiproliferative effect on PLC/PRF/5 cells. Apoptosis was elicited when cells were treated with 1 micromol/L cinnamaldehyde, as characterized by the appearance of phosphatidylserine on the outer surface of the plasma membrane. 3. The apoptotic effect induced by cinnamaldehyde could be further supported by the release of cytochrome c, Smac/Diablo and Omi/HtrA2 from mitochondria to the cytosol and activation of caspase 3. Cinnamaldehyde also upregulated the expression of pro-apoptotic protein (Bax) and down-regulated the levels of anti-apoptotic proteins, such as Bcl-2 and the inhibitor of apoptosis protein family (X-linked inhibitor of apoptosis protein (XIAP), cellular inhibitor of apoptosis protein (cIAP)-1 and cIAP-2). 4. Cinnamaldehyde induces the generation of reactive oxygen species (ROS) in cells. Following the pre-incubation of PLC/PRF/5 cells with anti-oxidants, it was found that 100 micromol/L vitamin E significantly diminished the effect of cinnamaldehyde-induced apoptosis, whereas a lesser effect was seen with on 100 micromol/L N-acetyl-L-cysteine. Vitamin E effectively blocked the release of cytochrome c, Smac/Diablo and Omi/HtrA2 from mitochondria to the cytosol in cells treated with cinnamaldehyde. Vitamin E also markedly suppressed caspase 3 activation. The expression of apoptotic inhibitors (XIAP, cIAP-1, cIAP-2) and anti-apoptotic (Bcl-2) and pro-apoptotic (Bax) proteins was affected by vitamin E pretreatment. 5. Taken together, the results suggest that cinnamaldehyde triggers apoptosis possibly through the mitochondrial pathway. Pretreatment with vitamin E markedly prevented cinnamaldehyde-mediated apoptosis, which was associated with the modulation of XIAP, cIAP-1, cIAP-2, Bcl-2 and Bax protein activity.

Acetylcysteine↗
PubMed1983

Membrane changes induced by exposure of Escherichia coli to human serum.

The effect of bactericidal concentrations of lysozyme-free human serum on parameters of membrane integrity has been studied in serum-susceptible and serum-resistant Escherichia coli strains. Serum treatment released all of the alkaline phosphatase from the periplasmic space of two rapidly serum-susceptible strains but did so at different rates. In contrast, no periplasmic enzyme was released from two serum-resistant strains or from one moderately susceptible smooth strain. Lysozyme-free serum and heat-inactivated serum released comparable amounts of 86Rb+ from preloaded cells at comparable rates, regardless of serum susceptibility. Serum decreased the rate of phospholipid biosynthesis in both serum-susceptible and serum-resistant strains. In susceptible but not in resistant strains, intracellular ATP pools were depleted after serum exposure. Outer membranes and cytoplasmic membranes were prepared from serum-treated E. coli, and assays for C3 and C5b-9(m) were performed. With rapidly susceptible strains, C3 deposition on the outer membrane without attachment of C5b-9(m) occurred during the short prekilling phase. Subsequent bacterial killing was accompanied by deposition of C5b-9(m), which was recovered with C3 exclusively in outer membrane fractions with increased density and by eventual total loss of recoverable cytoplasmic membranes. Minimal deposition of complement components, without accompanying cytoplasmic membrane loss, occurred with serum-resistant strains. Loss of recoverable cytoplasmic membrane was not due to the action of either serum or bacterial phospholipase A. The results raise the possibilities that C5b-9(m) primarily damages the outer membrane and that the bacteria themselves actively participate in the ensuing, as yet unclarified, metabolic reactions that finally lead to their death.

Adenosine Triphosphate↗
PubMed1984

Mechanism of bacterial resistance to complement-mediated killing: inserted C5b-9 correlates with killing for Escherichia coli O111B4 varying in O-antigen capsule and O-polysaccharide coverage of lipid A core oligosaccharide.

The interaction of C3 and terminal complement components with three isogenic strains of Escherichia coli O111B4 varying in outer membrane and capsule composition was examined. Strains CL99 and 1-1, which possess O-antigen capsule and 74 to 77% coverage of lipid A core oligosaccharide, were sensitive to killing in pooled normal human serum (PNHS) or magnesium ethylene glycoltetraacetic acid PNHS in the presence but not the absence of antibody, although 1-1 contained 35% more lipopolysaccharide than CL99 and was slightly less sensitive to alternative pathway killing. In contrast, strain 1-2 lacks O-antigen capsule but contains 84% coverage and resists serum killing in the presence and absence of antibody in both PNHS and magnesium ethylene glycoltetraacetic acid PNHS. All three strains consumed C3 and C9 when incubated in PNHS, but consumption was most rapid with 1-2, which also bound the largest number of C3 molecules per CFU. Between 15 X 10(3) and 24 X 10(3) molecules of C9 per CFU bound to CL99 and 1-1 during incubation in 10% PNHS or 10% magnesium ethylene glycoltetraacetic acid PNHS, and binding was relatively stable. Binding and release of 3 X 10(3) to 8 X 10(3) molecules of C9 per CFU was observed for strain 1-2. The majority of C9 bound to CL99 and 1-1 in the presence of antibody distributed with the outer membrane after lysis of the organisms in a French press, whereas only 16.1 to 20.1% of C9 was deposited on these organisms in the absence of antibody, and 31.5 to 39.8% of C9 on strain 1-2 with or without antibody sedimented with the outer membrane. Between 4.6 X 10(3) and 5.5 X 10(3) molecules of C9 per CFU remained bound in a salt- and trypsin-resistant form to the outer membrane of organisms that were killed, whereas fewer than 1.4 X 10(3) molecules of C9 per CFU were bound to the outer membrane of organisms not killed by serum. These results indicate that C5b-9 that is bound to the outer membrane of E. coli O111B4 in a form resistant to salt or protease elution correlates with bacterial killing.

Antigens, Bacterial↗
PubMed1988

Role of immunoglobulin G in killing of Borrelia burgdorferi by the classical complement pathway.

The antibody and complement requirements for killing of Borrelia burgdorferi 297 by normal human serum (NHS) and NHS plus immunoglobulin G (IgG) were examined. B. burgdorferi activated both the alternative and classical complement pathways in NHS. In NHS chelated with 10 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid plus 4 mM MgCl2 (Mg-EGTA) to block classical pathway activation, consumption (activation) of total hemolytic complement, complement component 3 (C3), and C9 by B. burgdorferi was observed. Furthermore, challenge of unchelated NHS with 297 cells resulted in the consumption of C4, in addition to an increase in C3 and C9 consumption over that observed in chelated serum. In spite of complement activation, B. burgdorferi was resistant to the nonspecific bactericidal activity of NHS. The addition of human anti-B. burgdorferi IgG to NHS, however, resulted in the complete killing of 297 cells. Bactericidal activity of this serum was abrogated if NHS was immunochemically depleted of C1, indicating that killing was mediated by the classical pathway. The manifestation of bactericidal activity was accompanied by a large increase in total complement and C3 consumption over that observed in NHS alone. Under similar conditions, only a minimal increase in C9 consumption was observed. No increase in total complement consumption was observed if NHS plus anti-B. burgdorferi IgG was treated with Mg-EGTA prior to challenge. The results of these experiments demonstrate that B. burgdorferi is resistant to the nonspecific bactericidal activity of NHS, in spite of classical and alternative complement pathway activation. B. burgdorferi is sensitive to serum, however, in the presence of IgG, which mediates bacterial killing through the classical complement pathway.

Antibodies, Bacterial↗
PubMed1992

Complement activation by polyclonal immunoglobulin G1 and G2 antibodies against Staphylococcus aureus, Haemophilus influenzae type b, and tetanus toxoid.

To obtain information on effector functions of human immunoglobulin G2 (IgG2), we have measured the complement-activating properties of polyclonal IgG subclass antibodies against bacterial antigens. IgG1 and IgG2 were purified from serum samples from five healthy individuals, and complement activation was measured with different bacterial antigens. We used Staphylococcus aureus Wood 46 (STAW), which is a common antigen, Haemophilus influenzae type b (Hib), which is a common pathogenic microorganism in children, and formaldehyde-inactivated tetanus toxin (TT). Bacteria were incubated with antibodies and then incubated with sera from agammaglobulinemic patients as a complement source, and C3c deposition was measured by enzyme-linked immunosorbent assay. We found that anti-STAW IgG2 activated complement to a level similar to that of anti-STAW IgG1. Anti-Hib IgG1 complement activation was as much as seven times higher than that of anti-Hib IgG2 in four individuals. In one individual, anti-Hib IgG2 was more effective in complement activation than anti-Hib IgG1. Anti-TT antibodies showed patterns similar to those of anti-Hib. Our results indicate that IgG2 antibodies may contribute significantly to antibacterial defense. Also, individual differences in antibody effector functions should be taken into account when evaluating the immune status of patients and during early phase 1 studies of new vaccines.

Antibodies, Bacterial↗
PubMed1993

Facilitation of complement-dependent killing of the Lyme disease spirochete, Borrelia burgdorferi, by specific immunoglobulin G Fab antibody fragments.

In the absence of specific antibody, Borrelia burgdorferi is resistant to the bactericidal action of complement, despite the capacity of the spirochete to activate complement. Complement-mediated killing of B. burgdorferi requires the presence of antiborrelial immunoglobulin G (IgG). The effect of bactericidal IgG takes place after formation of the C5 convertase. Therefore, we examined the ability of Fab fragments from bactericidal IgG to mediate killing of B. burgdorferi by complement. The complement-activating domain of IgG, the Fc fragment, was not required for killing of borreliae, as monovalent Fab fragments prepared from immune IgG were also able to mediate killing. However, the killing efficiency of the Fab fragments was less than that of intact IgG, suggesting that the bactericidal activity of IgG is enhanced by divalency. IgG Fab-mediated killing occurred without increased complement activation or C3 fluid-phase consumption. Cell killing proceeded via the classical complement pathway, as no killing of Fab fragment-sensitized cells was observed in human serum deficient in C2. These results demonstrate directly that the bactericidal effect of anti-B. burgdorferi IgG is independent of the complement-activating properties of the antibody.

Animals↗
PubMed1996

Interaction between complement subcomponent C1q and the Klebsiella pneumoniae porin OmpK36.

The interaction between C1q, a subcomponent of the complement classical pathway component C1, and OmpK36, a porin protein from Klebsiella pneumoniae, was studied in a solid-phase direct-binding assay, inhibition assays with the purified globular and collagen-like regions of C1q, and cross-linking experiments. We have shown that the binding of C1q to the OmpK36 porin of the serum-sensitive strain K. pneumoniae KT707 occurs in an in vivo situation and that this binding leads to activation of the complement classical pathway and the subsequent deposition of complement components C3b and C5b-9 on the OmpK36 porin. Scatchard analysis of the binding of [125I]C1q to the OmpK36 porin showed two binding sites with dissociation constants of 1.5 and 75 nM. The decrease of [125I]C1q binding to the OmpK36 porin in buffer with increasing salt concentrations and the pIs of the C1q subcomponent (10.3) and OmpK36 porin (4.5) suggest that charged amino acids are involved in the binding phenomenon. In inhibition assays, only the globular regions of C1q inhibited the interaction between C1q and OmpK36 porin, demonstrating that C1q binds to porin through its globular region and not through the collagen-like stalks.

Bacterial Proteins↗
PubMed2001

Dual signaling by the alpha(v)beta(3)-integrin activates cytosolic PLA(2) in bovine pulmonary artery endothelial cells.

Vitronectin, which ligates the alpha(v)beta(3)-integrin, increases both lung capillary permeability and lung endothelial Ca(2+). In stable monolayers of bovine pulmonary artery endothelial cells (BPAECs) viewed with confocal microscopy, multimeric vitronectin aggregated the apically located alpha(v)beta(3)-integrin. This caused arachidonate release that was inhibited by pretreating the monolayers with the anti-alpha(v)beta(3) monoclonal antibody (MAb) LM609. No inhibition occurred in the presence of the isotypic MAb PIF6, which recognizes the integrin alpha(v)beta(5). Vitronectin also caused membrane translocation and phosphorylation of cytosolic phospholipase A(2) (cPLA(2)) as well as tyrosine phosphorylation of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK) 2. The cPLA(2) inhibitor arachidonyl trifluoromethylketone, the tyrosine kinase inhibitor genistein, and the MAPK kinase inhibitor PD-98059 all blocked the induced arachidonate release. PD-98059 did not inhibit the increase of cytosolic Ca(2+) or cPLA(2) translocation, although it blocked tyrosine phosphorylation of ERK2. Moreover, although the intracellular Ca(2+) chelator MAPTAM also inhibited arachidonate release, it did not inhibit tyrosine phosphorylation of ERK2. These findings indicate that ligation of apical alpha(v)beta(3) in BPAECs caused ERK2 activation and an increase of intracellular Ca(2+), both conjointly required for cPLA(2) activation and arachidonate release. This is the first instance of a tyrosine phosphorylation-initiated "two-hit" signaling pathway that regulates an integrin-induced proinflammatory response.

Animals↗
PubMed1986

Reactive oxygen species: production and role in the kidney.

Reactive oxygen species (ROS) are formed by incomplete reduction of molecular oxygen. They include superoxide anion (O2-.), hydrogen peroxide (H2O2), hydroxyl radical (OH.), and singlet oxygen (1O2). ROS may induce different types of cell injury, particularly lipid peroxidation and membrane damage. ROS have been shown to play an essential role in the mechanisms of experimental models of several renal diseases: ischemic acute renal failure, renal graft rejection, acute glomerulonephritis, and toxic renal diseases. They are produced by the renal cells and also by the inflammatory bone marrow-derived cells invading the renal tissue. ROS, regardless of their origin, may degrade the glomerular basement membrane and alter the glomerular and tubular cell functions. Particularly, they produce an increase in cyclic AMP synthesis and prostaglandin production in the glomeruli. Recent studies have shown that the glomerular mesangial cells themselves generated ROS on stimulation by phagocytosis of foreign particles or exposure to the complement membrane attack complex or platelet-activating factor. Production of ROS is in narrow relationship with the metabolism of arachidonic acid. Conversion of this fatty acid via the lipoxygenase pathway is associated with an increase of ROS, whereas its transformation into prostaglandins via the cyclooxygenase pathway results in the opposite effect. Production of ROS in activated mesangial cells can be inhibited by glucocorticoids via a receptor-mediated mechanism. The fact that some of these characteristics are different in leukocytes suggests the possibility in the future of the more specific pharmacological control of the inflammatory process in the glomerular mesangium.

Acute Disease↗
PubMed2000

Pleural SC5b-9: a test for identifying complicated parapneumonic effusions.

UNLABELLED: BACKGROUND AND OBJECTIVES We have tested whether the complement activation products SC5b-9 and C3a-desArg are useful to distinguish complicated (CPE) from uncomplicated parapneumonic effusions (UPE). DESIGN: A total of 66 patients were enrolled in the study: 5 with empyema, 19 with CPE, 12 with UPE, and 30 transudates who served as controls. SC5b-9 and C3a-desArg were measured by commercial ELISA tests, and their performances were evaluated using receiver operating characteristic (ROC) analysis. RESULTS: Patients with CPE had higher mean levels of pleural SC5b-9 (8,218 microg/l) and C3a-desArg (8,790 microg/l) than those with UPE (2,227 and 3,772 microg/l, respectively; p < 0.0001), whereas concentrations in the latter were comparable with controls for the SC5b-9 test. Empyemas had a wide range of pleural complement activation product values. Pleural SC5b-9 and C3a-desArg showed very high diagnostic accuracy in the diagnosis CPE (90.3 and 77.8%, respectively) when corresponding cutoff points of 2,000 and 4,000 microg/l were used. In a stepwise logistic regression analysis, the combination of SC5b-9 >/=2,000 microg/l, LDH >/=1,000 U/l and a pleural polymorphonuclear percentage >/=85% provided the highest discriminative power for the diagnosis of CPE (area under ROC curve 0.97). CONCLUSION: This pilot study suggests that measurement of pleural SC5b-9 can be useful in the workup of patients with a parapneumonic effusion in order to differentiate CPE from UPE.

Adult↗
PubMed1996

Role of atheroma liposomes and malondialdehyde-modified low-density lipoproteins in complement activation.

We investigated the ability of atheroma-associated liposomes and malondialdehyde (MDA)-modified low-density lipoproteins (MDA-LDL) to activate complement. Complement activation markers C3a, Bb, C4d and SC5b-9 were measured in both normal and complement-deficient sera. We found that MDA-LDL was able to generate C3a and SC5b-9, predominantly by the alternative pathway. High-density lipoproteins modified with MDA were also capable of C3a generation although to a lesser degree. The presence of atheroma-associated liposomes did not result in detectable levels of complement activation markers. We conclude that MDA-modified lipoproteins may represent a possible source for complement activation within atherosclerotic lesions.

Aortic Diseases↗