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PubMed1983

In vivo complement activation by polyanion--polycation complexes: evidence that C5a is generated intravascularly during heparin--protamine interaction.

In vitro studies have established the complement-activating potency of polyanion-polycation interaction. By transferring the heparin-protamine model to an animal (rabbit) system that picks up ongoing intravascular complement activation by documenting acute granulocytopenia due to margination, evidence that intravascular polyanion-polycation complexing leads to instantaneous activation of the C system in vivo that goes beyond C1, C4, and C2, and results in generation of biologically highly reactive products, such as C5a, is provided. Dependence of the phenomenon on an activable complement system is documented by its complete abolishment when animals were complement depleted by cobra venom factor administration. Therefore, activation of the complement system may play a causative role for untoward effects following heparin neutralization by protamine under clinical conditions. Furthermore, these studies suggest an in vivo role of nonimmune generation of inflammatory mediators by interaction of naturally occurring polyions.

Agranulocytosis↗
PubMed1988

Neutrophil accumulation and cutaneous responses in experimental cutaneous candidiasis of genetically complement-deficient mice.

Mice deficient in the fifth component of complement were studied for their ability to respond to and clear experimental cutaneous Candida albicans infections. The complement-deficient animals took longer to clear the infections and developed a significantly greater delayed hypersensitivity response to Candida than did normal animals. However, although the serum of the complement-deficient animals was incapable of generating in vitro chemotactic activity for neutrophils after appropriate stimulation, the epidermal neutrophilic infiltrate in the Candida-infected skin of these animals was equivalent to that in the normal animals. The progression of the infection, including the early relocation of the invading Candida pseudohyphae to a more superficial site in the stratum corneum and the thickening of the epidermis itself, was also similar in the complement-deficient and normal animals. Therefore, although mice lacking the fifth complement component cannot generate complement-derived serum chemotactic factors and are somewhat less efficient in clearing experimental cutaneous candidiasis, the accumulation of neutrophils in the Candida-infected skin of these animals and their initial cutaneous responses to the infections are normal.

Abscess↗
PubMed1992

Immunological evaluation of late complement component-deficient individuals.

The possible contribution of additional immunologic variables to the susceptibility of late complement component-deficient individuals to meningococcal disease has not been systematically examined in previous studies. Thus, we studied three groups of patients: (1) 24 healthy individuals, (2) 8 complement-sufficient individuals with a history of recurrent bacterial meningitis, and (3) 19 complement-deficient individuals with prior meningococcal infection. No statistical differences were noted among the three groups for the following parameters: the absolute number and the percentage of lymphocytes; CD3+, CD4+, CD8+, CD20+, and CD16+ cells; and the CD4+/CD8+ ratio. The concentration of C4 and circulating immune complexes was also similar among the groups. The concentrations of IgG, IgM, and IgA were slightly, but significantly, decreased in the complement-deficient individuals. Of interest, the coefficient of spontaneous and lipopolysaccharide-stimulated activation of neutrophils was significantly depressed in the deficient individuals. We hypothesize that the terminal complement components may participate in maximal neutrophil activation.

Adolescent↗
PubMed1982

Production of cyclooxygenase products and superoxide anion by macrophages in response to chemotactic factors.

Mononuclear phagocytes are known to play a key role in various phlogistic reactions by synthesizing and releasing products that may potentiate or inhibit inflammatory processes. The expression of these products appears to be dependent on the source of the macrophage population as well as the stimulus employed. We have studied superoxide anion (O-2) production as well as the generation of PGE2, PGF2 alpha, and TXB2 from resident, oil-elicited and thioglycollate-induced peritoneal macrophages in mice in the presence and absence of chemotactic peptides. Production of O-2, occurred only in elicited macrophages stimulated with high concentrations of FMLP or C5a; resident cells stimulated with either of the chemotactic peptides were completely unresponsive. Although resident peritoneal macrophages incubated with chemotactic peptides did not generate O-2, these cells did secrete significant levels of PGE2, PGF2 alpha, and TXB2 in response to C5a. FMLP had no stimulatory effect. Elicited macrophages generated increased levels of PGE2 and PGF2 alpha when incubated with C5a. However, production of TXB2 was not stimulated. FMLP was inactive in stimulating PGE2, PGF2 alpha, and TXB2 in all types of macrophages studied. These studies indicate a heterogeneity in the production of inflammatory mediators from various macrophage populations in response to chemotactic factors.

Animals↗
PubMed1988

Atopic dermatitis: influence of bacterial infections on human monocyte and neutrophil granulocyte functional activities.

In 15 patients with atopic dermatitis (AD) and without concomitant viral or bacterial infections, chemotaxis, superoxide-anion (O2-) generation, and beta-glucuronidase release of purified monocytes (MO) and neutrophils (PMN) were determined. Defined receptor-dependent stimulators (i.e., N-formyl-methionyl-leucyl-phenylalanine, C5a, and leukotriene B4, as well as native and opsonized zymosan particles) were used for phagocyte stimulation. PMN functional activities in response to the stimuli tested were found to be normal in patients with AD and without infections. MO from these patients revealed a slight enhancement of O2- production after stimulation with opsonized zymosan and a small increase of N-formyl-methionyl-leucyl-phenylalanine-induced chemotaxis. Other MO functions tested were within the normal range. However, investigations of MO and PMN functions during the course of concomitant bacterial infections of three patients with AD demonstrated striking alterations of cellular responsiveness. These changes ranged from enhanced to decreased phagocyte functions, depending on the activity of the infectious disorder. Chemotaxis of PMN and MO was depressed around the third day after onset of the infectious disease. In the beginning of infection, there was a decreased O2- generation and beta-glucuronidase release in PMNs. In MOs, both parameters were enhanced. The results of these investigations provide evidence that functional abnormalities of phagocytes observed in patients with AD are sequelae of concomitant skin infections and not signs of an intrinsic defect present in MOs and PMNs.

Adolescent↗
PubMed1989

A role of Ia-associated invariant chains in antigen processing and presentation.

Most native antigens require processing in a cellular compartment for efficient presentation to T helper cells. The cellular elements that permit processing are not known. We investigated a possible role of the class II MHC-associated invariant chains in antigen processing. Fibroblast cells that were transfected with class II genes were compared with fibroblasts supertransfected with the invariant chain gene for their capacity to present the fifth component of complement (C5) to C5-specific class II restricted T cell clones or influenza virus protein to a virus-specific T cell clone. Only fibroblasts supertransfected with the invariant chain gene were able to present native antigen, even at very low antigen concentration, whereas both fibroblast types could present cyanogen bromide-fragmented C5 or the virus peptide. Presentation of intact antigen but not of fragmented antigen was totally abrogated by treatment of fibroblasts with chloroquine. The invariant chain gene encodes two polypeptides, li31 and li41. Expression of either li31 or li41 was sufficient to render class II-expressing fibroblasts capable of presenting intact antigen.

Animals↗
PubMed1984

Membrane attack by complement.

Membrane attack by complement involves the self-assembly on membranes of five hydrophilic proteins (C5b, C6, C7, C8 and C9) to an amphiphilic tubular complex comprising approximately 20 subunits. The hydrophilic-amphiphilic transition of the precursor proteins is achieved by restricted unfolding and exposure of previously hidden hydrophobic domains. Restricted unfolding, in turn, is driven by high-affinity protein-protein interactions resulting in the formation of amphilic complexes. Circular polymerization of C9 to a tubular complex (poly C9) constitutes the molecular mechanism for transmembrane channel assembly and formation of ultrastructural membrane lesions.

Animals↗
PubMed1986

Role of the N-terminal regions of hog C3a, C5a and C5a-desArg in their biological activities.

The N-terminal regions of the complement peptides C3a, C5a and C5a-desArg (purified from yeast-activated hog serum) were gradually shortened by incubation with leucine amino peptidase. This treatment led to the following changes in the biological activities of these peptides: the potencies of C5a and C5a-desArg in aggregation of human polymorphonuclear leukocytes and of guinea-pig platelets, and their ability to deactivate these cells were gradually diminished; the chemotactic effect of C5a-desArg on human leukocytes was similarly lowered, while the chemotactic potency of C5a was even increased up to the loss of the first 12 N-terminal amino acids. However, after removal of the whole N-terminal region (i.e. 20 amino acids distal of the first disulfide bridge) the potency of both peptides was decreased to a few percent. In contrast, C3a totally lost its platelet-aggregating as well as deactivating activity already after cleavage of 10-15 N-terminal amino acids by LAP. On leukocytes, on the other hand, C3a retained some activity even after the loss of the whole N-terminal region. These results indicate that the N-terminal regions play an important role for biological activities of the three complement peptides, possibly by stabilizing the optimal conformation of their C-terminal regions which contain the receptor-activating domains.

Animals↗
PubMed1982

5,8,11,14-Eicosatetraynoic acid (ETYA) inhibits binding of N-formyl-methionyl-leucyl-phenylalanine (FLMP) to its receptor on human granulocytes. A note of caution.

Binding of two biochemically chemotactic factors, FMLP and C5a, to their respective receptors on human granulocytes produces a transient several-fold increase in cAMP. To determine if arachidonic acid metabolites were responsible for the increased cAMP concentrations, two inhibitors of arachidonic acid metabolism, indomethacin and ETYA, were incubated with granulocytes prior to FMLP or C5A. ETYA, but not indomethacin, inhibited both the cAMP and superoxide responses to a similar degree. However, the mechanism of this effect was found to be through inhibition of the binding of FMLP to its receptor rather than through inhibition of arachidonate metabolism.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1983

Platelet-activating factor-mediated contraction of rabbit lung strips: pharmacologic modulation.

Synthetic platelet-activating factor (PAF) (1-0-octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine, AGEPC) has been shown to induce a slowly developing contraction of rabbit lung parenchymal strips in an isolated organ bath. The spasmogenic effect of AGEPC appeared to be mediated by specific receptors distinct from H1, H2, cholinergic and C5a anaphylatoxin receptors. Prior exposure to AGEPC induced specific desensitization of lung parenchymal strips. Experiments with several pharmacological agents indicated that AGEPC-induced contraction was independent from cyclooxygenase, but was blocked when phospholipase A2 and lipoxygenase were inhibited and when the Ca++ channels were antagonized. Corticosteroids exhibited an inhibitory effect specific for AGEPC. Intracellular levels of cyclic AMP or cyclic GMP seemed to have a modulatory role in AGEPC-induced contraction of rabbit lung parenchymal strips.

Acetylcholine↗
PubMed1983

Effects of C5a on guinea pig lung: histamine release and mechanism of contraction.

C5a, a product of complement system activation, causes a significant contraction of the isolated guinea pig trachea, and the antihistamine diphenhydramine does not alter the rate, amplitude, or duration of the contraction (Regal et al., 1980). The present study demonstrates that over the range of C5a concentrations investigated, the C5a-induced contractile response of the trachea maximized, whereas the contraction of lung parenchymal strips and the release of histamine from chopped lung did not. In addition, the antihistamines, diphenhydramine and pyrilamine, caused a significant delay in the onset of the C5a-induced contraction of lung parenchymal strips. When parenchymal strips from nonperfused lung were used, the maximum of the contraction was also reduced by pyrilamine. Aspirin and indomethacin effectively inhibited the C5a-induced contraction of lung parenchymal strips, and inhibition by a combination of aspirin and pyrilamine was the sum of the inhibition by aspirin and the inhibition by pyrilamine. The SRS-A antagonist, FPL 55712, caused a more rapid relaxation of the C5a-induced response over control. These studies suggest that products of the cyclo-oxygenase pathway are mediators involved in the C5a-induced contraction of lung parenchyma, with histamine and leukotrienes contributing as well.

Animals↗
PubMed1984

Effects of human anaphylatoxins on guinea pig atria.

Purified human C3a and C5a produce positive inotropic effects on spontaneously contracting atria isolated from guinea pigs. The increased amplitude of contraction induced by C5a has a threshold at 1 X 10(-9)M. This effect is concentration dependent, increasing by 180% at 1.7 X 10(-7)M C5a. The threshold concentration for a C3a-induced effect is four times greater than that for C5a. The C3a-induced effect is also concentration dependent, maximizing at 1 X 10(-7)M. Above that concentration, the increased response to C3a reaches a plateau value at approximately a 70% greater amplitude than that of untreated tissue. Unlike effects induced by anaphylatoxins in other tissues, these positive inotropic responses are not tachyphylactic. The same atrium will respond repeatedly to either C3a or C5a for a period of up to 4 h. Studies with histamine, leukotriene and prostaglandin inhibitors revealed that the anaphylatoxin-induced responses are not solely histamine mediated. Cimetidine partially inhibited the response of isolated guinea pig atria to C5a (e.g. 25%) and failed to affect the response of this tissue preparation induced by C3a. FPL 55712 inhibited the response to both anaphylatoxins by approximately 40%. The atrial response to C3a was inhibited by more than 70% by indomethacin, whereas the response to C5a was unaffected. This is the first report characterizing the specific action of purified C3a and C5a on isolated cardiac tissue. It was concluded that C3a acts primarily via prostaglandins and leukotrienes while C5a affects contractile intensity via vasoamines and leukotrienes.

Alprostadil↗