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Relaxant effect of N-formyl-methionyl-leucyl-phenylalanine on rabbit vascular strips.

Some types of rabbit isolated blood vessels precontracted with phenylephrine relaxed when exposed to the chemotactic peptide N-formyl-Met-Leu-Phe (FMLP). The thoracic aorta was unresponsive whereas the portal vein and pulmonary artery exhibited concentration-dependent relaxing responses to FMLP (1-100 nM). FMLP-induced relaxations developed over several minutes and occurred after a latency of 30 to 40 sec. An inconsistent, brief and small contractile phase preceded the relaxations in some tissues. Stable responses to FMLP could be obtained repeatedly at 1.5-hr intervals. On both the portal vein and the pulmonary artery, the structure-activity relationship of peptides related to FMLP was similar to the one reported for activating phagocytic leukocytes. The peptide Boc-Phe-D-Leu-Phe-D-Leu-Phe behaved as a competitive antagonist of FMLP-induced relaxations with a calculated pA2 of 7.5 on both types of responsive vessels. Indomethacin inhibited the relaxations completely on the pulmonary artery and partially on the portal vein. FMLP-induced vasorelaxations were unaffected by a platelet-activating factor antagonist, BN 52021, or a 5-lipoxygenase inhibitor, L-651,392. Removal of the endothelium did not prevent the relaxant response to FMLP. The release of 6-keto-prostaglandin F1 alpha in the bathing fluid of portal vein and pulmonary artery exposed to FMLP was demonstrated using a radioimmunoassay. FMLP relaxed rabbit vascular strips in a blood-free environment by releasing secondary mediators tentatively identified as prostaglandins; however, a component of the relaxation in the portal vein was not mediated by cyclooxygenase products.

6-Ketoprostaglandin F1 alpha↗

[The reactivity of pulmonary and hepatic macrophages in normal and prestimulated animals].

The rate of blood clearing of colloidal carbon increased two-fold as compared to the controls 5 days after prodigiosin injection. This was attended by intensified recruitment of macrophages into the alveoli and increase in the number of phagocytizing macrophages in the interstitium of the lungs by 1.5 times above normal. After administration of zymosan granules, the rate of colloid carbon clearance increased 1.5-fold in 5 days and 2.5-fold on the 9th day; the recruitment of macrophages into the alveoli and the number of phagocytizing macrophages in the interstitium of the lungs increased two-fold. At the same time, granuloma-type mononuclear infiltrates formed in the lungs and liver. Prodigiosin injection increases the rate of blood clearance 1.2-fold in animals stimulated by zymosan granules, while the volume of mononuclear infiltration, which acquires a diffuse character, increases 2.5-fold as compared to the value in zymosan stimulated animals. The effects of phagocyte reconciliation may be directly related to exacerbations of chronic inflammatory diseases of different localization.

Animals↗

Respiratory burst oscillations in human neutrophils and their correlation with fluctuations in apparent cell shape.

Neutrophils pretreated with phorbol 12-myristate 13-acetate (1-10 nM) and stimulated with low concentrations of chemotactic agonists (1-10nM) exhibited a marked increase in respiratory burst activity that was characterized by regular oscillations. These were accompanied by parallel oscillations in turbidity having the same phase and period. Four different agonists, f-Met-Leu-Phe, complement fragment C5a, platelet-activating factor, and leukotriene B4, induced virtually identical oscillations, with mean periods of 7.9 +/- 0.6 s (respiratory burst) and 7.9 +/- 0.8 s (turbidity) at 37 degrees C. No burst oscillations were observed at high agonist concentrations (50-100 nM) unless the fungal metabolite 17-hydroxywortmannin was added prior to stimulation. In the absence of phorbol 12-myristate 13-acetate, the respiratory burst activity was inhibited by 17-hydroxywortmannin, the protein kinase C inhibitor staurosporine, and calcium depletion, while agonist-dependent turbidity changes including the oscillations were unaffected. Turbidity changes reflect corresponding changes in cell size and/or shape, suggesting that cyclic alterations in morphology such as lamellipod extension and retraction physically affect the catalytic efficiency of the membrane-bound burst enzyme NADPH-oxidase. The oscillations appear to be controlled via receptor-dependent activation mechanisms which do not involve PKC activation or the rise in internal calcium presumably derived from phospholipase C activation.

Androstadienes↗

Neutrophil chemotactic activity produced by normal and activated human bronchoalveolar lavage cells.

Activated macrophages can secrete a number of mediators that can attract inflammatory cells and enhance secretion of phlogistic substances from these cells. The ultimate effect of activated bronchoalveolar lavage (BAL) cells may be fibrotic lung injury. Inasmuch as pulmonary sarcoidosis is a disease associated with spontaneous activation of macrophages and lymphocytes among BAL cells, cells obtained from patients with sarcoidosis were compared with normal cells. We report that adherent BAL cells in culture from patients with sarcoidosis (n = 21) release during a resting period in vitro more chemotactic activity for neutrophils (PMNs) than do BAL cells from normal individuals (n = 14). After density fractionation of the respiratory cells by albumin gradient, cells from high-density fractions in the group with sarcoidosis secrete more chemotactic activity for neutrophils than cells from less dense fractions. The PMN chemotactic activity spontaneously released in vitro by BAL cells from patients with sarcoidosis correlates with the percentage of PMNs recovered by BAL. Immunochemical bioassay and high-performance liquid chromatographic (HPLC) analysis of BAL cell supernatants revealed a complex pattern of chemotactic factors to be present. Generally, three peaks of chemotactic activity were noted on HPLC 1-60 separations at greater than 20 kd, 8 to 10 kd, and less than 1 kd apparent molecular weights. Significantly, interleukin-1 was present in these supernatants, whereas complement components and leukotriene B4 were absent. Sarcoid BAL cells, principally alveolar macrophages, are activated in vivo as manifested by spontaneous secretion of chemotactic factors for PMNs in vitro. Interleukin-1 and other less well characterized molecules were detected. The presence of PMNs among the lavage cells of some patients with sarcoidosis appears to be an in vivo biologic correlate of this activation. These data provide additional criteria of BAL cell activation in patients with pulmonary sarcoidosis and provide further evidence concerning factors that attract inflammatory cells into the lung.

Bronchoalveolar Lavage Fluid↗

Complement activation and vascular injury in systemic lupus erythematosus.

The deposition of immune complexes within blood vessel walls results in the potential for complement activation and the release of chemotactic factors, such as fragments of C5 (C5fr). The generation of C5fr results in the intravascular aggregation of neutrophils with subsequent leukostatic occlusion of the pulmonary arterioles. The generation of C5fr may contribute to the pathogenesis of adult respiratory distress syndrome and other diseases. Studies were undertaken to determine the role of circulating complement derived peptides and intravascular neutrophil activation in systemic lupus erythematosus.

Antigen-Antibody Complex↗

High-altitude pulmonary edema. Characteristics of lung lavage fluid.

To evaluate the cellular and biochemical composition of bronchoalveolar fluid in high-altitude pulmonary edema (HAPE), we performed bronchoalveolar lavage in three climbers with HAPE in a research facility at 4400 m on Mount McKinley. Three healthy climbers were used as controls. The HAPE fluids contained marked increases in high-molecular-weight proteins, erythrocytes, and leukocytes, most of which were alveolar macrophages. The HAPE fluids also contained detectable amounts of leukotriene B4 and other lipoxygenase products of arachidonic acid metabolism, complement fragments (C5a), inhibitors of neutrophil chemotaxis, and acid proteases but not hydroxyproline, a constituent of collagen. The data from this study indicate that HAPE involves a transient "large pore" leak in the pulmonary circulation. Despite the presence of two potent mediators of inflammation, leukotriene B4 and C5a, HAPE is not characterized by the intense neutrophil accumulation that is typical of other forms of acute lung injury.

Adult↗

Non-IgE antibody mediated mechanisms in food allergy.

Food sensitivity or intolerance is not necessarily based on the Type I allergic reaction. Non-IgE antibody reactions, complement-dependent reactions, enzyme deficiencies such as lactase and non-immunologic histamine release (such as with some sea foods) have been described. Even the detection of specific antibodies on their own does not necessarily indicate that a given symptom is due to that antibody. Food allergy nevertheless exists. It is important that those observers fortunate enough to see many cases document their observations carefully and eventually publish them for the education of their less fortunate colleagues. Is food allergy more common in infants and young children? What happens as they grow older? How often is atopic eczema due to food allergy? Why are some foods more likely to be implicated than others? Does a negative RAST result eliminate the diagnosis or a positive one confirm it? Until the answers to these and other questions are known, the mainstay of diagnosis will be the history, and that of treatment will be the elimination diet.

Animals↗