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PubMed1982

In vivo clearance and tissue distribution of C5a and C5a des arginine complement fragments in rabbits.

We have previously shown a marked difference in the inflammatory response to human C5a or C5a des arginine (Arg) instilled in rabbit lungs. These studies raised the question of where C5a and C5a des Arg are processes in vivo and what role neutrophils may play in the tissue distribution of these two mediators. After intravenous injection of purified, biologically active 125I-C5a or 125I-C5a des Arg, adult rabbits were serially bled and then killed at various time intervals. Although greater than 50% of the injected radioactivity was cleared from the circulation within 2 min for both mediators, C5a des Arg persisted in the circulation longer than C5a. C5a instillation caused an acute neutropenia, whereas C5a des Arg caused a less severe and more prolonged neutropenia, preceding a neutrophilic response observed with both mediators. Clearance of the mediators was primarily seen in the highly vascularized organs: the lung, spleen, liver, and kidney. A time-dependent accumulation was seen initially in the lung, followed by the spleen, liver, and kidney. Histologic examination showed a marked increase in the number of neutrophils within the lung and spleen. Depletion of circulating neutrophils by nitrogen mustard pretreatment of rabbits showed no change in the amount of labeled mediator bound in the lung, whereas splenic accumulation was dependent on the presence of neutrophils. These results indicate that C5a and C5a des Arg are rapidly removed from the circulation by specific accumulation in vascularized tissues. Clearance by the lung was not affected by neutrophil depletion, whereas clearance by the spleen was dependent on neutrophils. These experiments further suggest there are neutrophil-dependent and neutrophil-independent mechanisms involved in the removal of C5a and C5a des Arg from the circulation and that binding of C5 fragments in the pulmonary vasculature may precede and then induce neutrophil sequestration.

Animals↗
PubMedDate not supplied

Effects of cigarette smoking on blood levels of leukotrienes and plasma levels of complements C3a and C5a in healthy volunteers.

We reported previously that cigarette smoking induces bronchoconstriction. In the present investigation we measured the level of peripheral venous blood leukotrienes, which are known to cause marked bronchoconstriction, and plasma complement C3a and C5a, which are known to have chemotactic and anaphylatoxic activities. All of these showed a significant increase after cigarette smoking. These data may suggest that the activation of complement induces the release of leukotrienes, and that these leukotrienes cause bronchoconstriction. It appears likely, therefore, that cigarette smoking induces an increase in peripheral venous blood leukotrienes and complement C3a and C5a, and that such an increase may elicit bronchoconstriction.

Adult↗
PubMed1975

Quantification of mouse macrophage chemotaxis in vitro: role of C5 for the production of chemotactic activity.

Delineation of the mechanisms of macrophage accumulation at local tissue sites will further our understanding of immunologically mediated host resistance to infectious and neoplastic diseases. Since mice are frequently used for the study of immune function, we developed a method for the quantification of mouse macrophage chemotaxis in vitro. By this method it was found that the fifth component of complement is necessary for the production of chemotactic activity in mouse serum by inflammatory agents such as endotoxin or aggregated gamma globulin. The majority of macrophage chemotactic activity produced by these agents in mouse serum can be attributed to a low-molecular-weight (ca. 15,000) chemotactic factor. The data suggest that this factor is the biologically active cleavage product of the fifth component of complement, C5a.

Animals↗
PubMed2026

Qingfei Dayuan granules alleviate the inflammatory response in lipopolysaccharide-induced acute lung injury mice by inhibiting the Nf-κB signaling pathway and regulating the complement pathway.

OBJECTIVES: The study aimed to explore the effects and mechanisms by which Qingfei Dayuan granules (QFDY) mitigate pulmonary inflammation in lipopolysaccharide (LPS)-induced acute lung injury (ALI). METHODS: We established an ALI mouse model by intraperitoneal injection of LPS. HE, Transmission electron microscopy, ELISA assay of inflammatory cytokines, and immunohistochemistry (IHC) were used to assess the degree of lung injury and inflammation. Utilizing network analysis and proteomics analysis, the potential targets and pathways of QFDY were identified. Western blot, IHC, and qRT-PCR analysis were used to evaluate the potential mechanism of QFDY. Additionally, the chemical composition of QFDY were performed using UPLC-MS/MS. KEY FINDINGS: QFDY reduced the pathologic changes and inflammatory cell infiltration in lung tissue inflammation. Network and proteomic analysis showed that the mechanism of QFDY protection against ALI is closely related to the Nuclear factor-kappa B (NF-κB) signaling pathway and complement pathway. Animal experiments showed that Qingfei Dayuan granules (QFDY) significantly reduced the levels of IL-1β, IL-6, TNF-α, and lung tissue F4/80-positive alveolar macrophages. Additionally, western blot and qRT-PCR analyses showed the inhibition of the NF-κB pathway. Notably, the levels of mannose-binding lectin (MBL2) were significantly increased, while complement C3a and complement C5a proteins were reduced in the QFDY group compared to the LPS group. CONCLUSIONS: QFDY suppressed the inflammation in LPS-induced ALI by inhibiting the NF-κB and complement pathway.

Animals↗
PubMed1977

Mechanism for the inflammatory response in primate lungs. Demonstration and partial characterization of an alveolar macrophage-derived chemotactic factor with preferential activity for polymorphonuclear leukocytes.

Approximately 4 h after an initial bronchoalveolar lavage (BAL) of a primate's lung, an appreciable number of polymorphonuclear leukocytes (PMNs) were noted to accumulate in respiratory fluids when lavage was repeated. Whereas, alveolar macrophages (90%) and lymphocytes (7%) were the principal respiratory cells recovered initially from lavage fluid, later samples contained 45-90% PMNs To explain the observed ingress of PMNs into lung fluids, concentrated BAL fluid was tested for chemoattractant activity. Such fluid obtained 4 and 24 h after an initial lavage contained material that produced directed migration (chemotaxis) for PMNs and mononuclear cells isolated from peripheral blood of normal donors. Gel filtration chromatography of BAL disclosed two peaks of chemotactic activity in the effluent fractions. Material from the column with an estimated molecular weight of 15,000 daltons was chemotactic for both PMNs and mononuclear cells. Because it was susceptible to inactivation with antiserum against the fifth component of complement, resistant to heating, and unaffected by antiserum against C3, this factor was considered analogous to the cleavage product of the fifth component of complement. C5a. In addition chemotactic activity for PMNs only was contained in an effluent peak having a molecular weight of about 5,000 daltons. This material was heat labile but unaffected by antisera to complement components. To locate the possible source of these factors in respiratory fluid, in vitro cultures of alveolar macrophages were established. These cells, whether stimulated by phagocytosis of opsonized bacteria or merely by attachment to a glass surface, produced chemotactic material which had physical characteristics similar to the small molecular weight material in BAL. Moreover, it induced preferential chemotaxis for PMNs. Thus, in primate lungs, at least two chemotactic substances may generate an inflammatory response; one which is a fragment of the complement component C5 and another small molecular weight factor which is released from alveolar macrophages.

Animals↗
PubMed1985

Endotoxin-induced selective dysfunction of rabbit polymorphonuclear leukocytes in response to endogenous chemotactic factors.

To assess the mechanism and specificity of polymorphonuclear leukocyte (PMN) dysfunction induced by endotoxin, rabbits were injected intravenously with 100 micrograms of Escherichia coli endotoxin, and PMN function was studied 18 to 24 h later. Compared to PMN from normal rabbits, peripheral blood PMN from rabbits injected with endotoxin showed diminished chemotactic responsiveness to two endogenous peptides, C5a (complement) and platelet-derived growth factor, and to two endogenous lipids, leukotriene B4 and platelet-activating factor. The chemotactic response to the synthetic chemotactic peptide, N-formyl-methionyl-leucyl-phenylalanine (FMLP), was unimpaired. In contrast to migration, endotoxin injection resulted in inhibition of the secretory response to the two endogenous peptides but not to the lipids or to FMLP. At a 1:4 (vol/vol) dilution, the plasma either 1 or 24 h after the endotoxin injection inhibited normal PMN chemotactic responses to C5a but not to FMLP. Similarly, at a 1:10 dilution, this plasma inhibited normal PMN chemotactic responses to leukotriene B4. The factor responsible for inhibiting responses to leukotriene B4 was anionic, specific for leukotriene B4 responses, and greater than 12,000 daltons. These data may be relevant to understanding PMN dysfunction during gram-negative sepsis.

Animals↗
PubMed1996

Modulation of the receptor for urokinase-type plasminogen activator in macrophage-like U937 cells by inflammatory mediators.

Macrophages in the tissues have been shown to express receptor for urokinase-type plasminogen activator (uPAR) on their cell surface which plays an important role in cell invasion and attachment. We examined the effects of inflammatory mediators on the expression of uPAR employing U937 cells which have monocyte/macrophage-like characteristics. U937 cells were incubated with various mediators such as interleukins (IL), tumor necrosis factors (TNF), dexamethasone, thrombin, fibrin fragment D, bradykinin, complement C5a, and components of the extracellular matrix. The uPAR expression on the cell surface was then analyzed by radio-ligand binding assay using 125I-scuPA. The strongest enhancement of uPAR was observed in the cells stimulated by TNF alpha and TNF beta. IL-1 beta, IL-6, and C5a also increased the uPA binding sites with various patterns of affinity change. Dexamethasone decreased the uPA binding sites without changing the affinity. Fibrin fragment D and IL-3 reduced the affinity without changing the number of receptors. These findings suggest that the expression of uPAR in inflammatory cells could be modulated by various inflammatory mediators.

Bradykinin↗
PubMed1992

TNF-specific deactivation of granulocytes in vivo: a possible mechanism of self-protection.

Granulocytes (PMN) have recently been shown to be specifically deactivated towards tumor necrosis factor (TNF) by preexposure to TNF itself and to other stimuli such as endotoxin and complement C5a in vitro. When TNF (200 micrograms/m2) was infused to a male volunteer, we found ex vivo an almost complete TNF-specific deactivation of PMN adhesion (57 +/- 3* vs 6 +/- 2%**), of exocytosis of secondary granules (37 +/- 1* vs 7 +/- 1%**) and of the respiratory burst as measured by hexose monophosphate shunt activation (74 +/- 1* vs 12 +/- 3** nM/10(7) PMN/45 min). Furthermore, up- and down-regulation, respectively, of the PMN surface adhesion molecules Mac-1 and LAM-1 became TNF-resistant. Similar to the results obtained in vitro, deactivation correlated with a decrease in the number of cellular TNF receptors. In PMN of 4 patients exposed to activated complement during hemodialysis, a state of TNF-specific cross-deactivation could also be demonstrated.

Adult↗
PubMed1979

Involvement of membrane calcium in the response of rabbit neutrophils to chemotactic factors as evidenced by the fluorescence of chlorotetracycline.

We have utilized the fluorescent chelate probe chlorotetracycline to investigate the possible involvement of membrane calcium in the response of rabbit peritoneal neutrophils to chemotactic factors. Two chemotactic factors, the small molecular weight fragment of the fifth component of complement C5a and the synthetic peptide formyl-methionyl-leucyl-phenylalanine (F-Met-Leu-Phe), were tested and found to decrease the fluorescence of cell-associated chlorotetracycline in a manner strongly suggesting stimulus-induced displacement of membrane calcium. The time-course, concentration dependence, and receptor specificity of the calcium redistribution induced by the stimuli are consistent with its early role in the initiation of the various neutrophil functions. F-Met-Leu-Phe and C5a appear to interact with the same pool of membrane calcium and to release it to the cytoplasmic side of the plasma membrane. Intracellular calcium then binds back to the membrane(s) from where it can be displaced by additional stimulation. The release of membrane calcium, experimentally defined here, appears to play a central role in the initiation of the various neutrophil functions.

Animals↗
PubMedDate not supplied

Picogram concentrations of endotoxin stimulate synthesis of IL-1 beta and TNF alpha by human peripheral blood mononuclear cells exposed to recombinant human C5a.

Endotoxemia, complement activation, and the generation of C5a occur in the course of sepsis, trauma, and the adult respiratory distress syndrome, clinical situations in which TNF and IL-1 are thought to play an important role. In the present studies, we examined the effect of picogram concentrations of endotoxin (LPS) on the synthesis of IL-1 beta and TNF alpha by human PBMC exposed to recombinant human C5a (rhuC5a). rhuC5a induced the synthesis of IL-1 beta by PBMC made in response to otherwise substimulatory levels of LPS. In the presence of rhuC5a, LPS concentrations from 10 pg to 1000 pg/ml substantially amplified IL-1 beta synthesis by PBMC compared to LPS alone. Since rhuC5a can induce transcription of IL-1 beta with minimal translation to cytokine protein, these studies support the concept that fM concentrations of LPS can combine with rhuC5a to provide the "second signal" for optimal translation of IL-1 beta mRNA.

Complement C5a↗
PubMed1981

Novel structural determinants of the human neutrophil chemotactic activity of leukotriene B.

A specific 5(S),12(R)-dihydroxy-eicosa-6,8,10(trans/trans/cis), 14(cis)-tetraenoic acid, designated leukotriene B, is generated by the lipoxygenation and subsequent enzymatic hydration of arachidonic acid in a variety of leukocytes. Leukotriene B elicits a maximal human neutrophil chemotactic response in vitro which is similar in magnitude to those evoked by the chemotactic fragment of the fifth component of complement, C5a, synthetic formyl-methionyl peptides, and 5-hydroxy-eicosatetraenoic acid (5-HETE). The neutrophil chemotactic potency of purified leukotriene B, assessed by the 50% effective concentration of 6 x 10(-9) M, is equivalent to that of C5a, but is up to 100-fold greater than that of 5-HETE and of other natural di-HETE isomers. 5(S),12(R)-di-hydroxy-eicosa-6,8,10(all-trans),14(cis)-tetraenoic acid, which differs from leukotriene B only in having a trans-double bond in place of a cis-double bond in the triene portion of the molecule, and acetyl-leukotriene B are significantly less potent neutrophil chemotactic factors than leukotriene B, which indicates that both the conjugated double bonds and the free hydroxyl-group(s) are functionally critical determinants. The capacity of acetyl-leukotriene B to inhibit competitively and selectively the human neutrophil chemotactic response to equimolar concentrations of leukotriene B suggests the existence of a specific subset of receptors for this potent lipid mediator.

Acetylation↗
PubMed1981

Inhibition of human polymorphonuclear leukocyte function by 2-cyclohexene-1-one. A role for glutathione in cell activation.

2-cyclohexene-1-one and diethyl maleate specifically decrease reduced glutathione (GSH) levels in human polymorphonuclear leukocytes (PMN) by direct conjugation, and by interaction with the glutathione-s-transferase system. Using these two nontoxic reagents we have examined the effect of decreased GSH levels on five parameters of PMN activation: superoxide generation, release of the lysosomal enzymes lysozyme and beta-glucuronidase, and increases in the influx of Na+ and Ca2+. When PMN pretreated with 2-cyclohexene-1-one or diethyl maleate were incubated with formyl-methionyl-leucyl-phenylalanine (FMLP) or the proteolytic fragment of the fifth component membrane of complement, C5a, agents that interact with surface membrane receptors, increases in all five parameters were inhibited in a dose-dependent manner. For O-2 generation and lysosomal enzyme release the ID50 for 2-CHX-1 was 40--90 micrometers corresponding with a 30--50% decrease in intracellular GHS. In contrast stimulation of treated PMN by the divalent cation ionophore A23187 or 5-hydroxyeicosatetraenoic acid was much less sensitive to depressed GSH; the ID50 for 2-cyclohexene-1-one was 1 mM or greater, corresponding with an 80--90% decrease in GSH. The effect of lowered GSH was not the result of decreased binding of FMLP to surface receptors because [3H]-FMLP binding studies demonstrated a two- to three-fold increase in the number of available binding sites. These data indicate that normal GSH levels are necessary for the transduction of the activation signal from the exterior to the interior of the PMN, but once initiated the activation sequence proceeds normally despite markedly lowered intracellular GSH.

Calcium↗
PubMed1991

Differential inhibition and potentiation of chemoattractant-induced superoxide formation in human neutrophils by the cell-permeant analogue of cyclic GMP, N2,2'-O-dibutyryl guanosine 3':5'-cyclic monophosphate.

Human neutrophils possess a superoxide (O2-)-forming NADPH oxidase which is activated by the chemoattractants, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMet-Leu-Phe), complement C5a, platelet-activating factor and leukotriene B4. We studied the roles of cAMP and cGMP in the regulation of O2- formation using the cell-permeant analogues of cyclic nucleotides, N6,2'-O-dibutyryl adenosine 3':5'-cyclic monophosphate (Bt2cAMP) and N2,2'-O-dibutyryl guanosine 3':5'-cyclic monophosphate (Bt2cGMP). Bt2cAMP inhibited O2- formation induced by these chemoattractants to similar extents. Bt2cGMP as low as 10 mumol/l significantly inhibited O2- formation induced by fMet-Leu-Phe at a submaximally effective concentration (50 nmol/l), and Bt2cGMP was more effective in diminishing O2- formation than Bt2cAMP. In contrast, Bt2cGMP did not affect O2- formation induced by fMet-Leu-Phe at a maximally effective concentration (1 mumol/l). Bt2cGMP (0.1 and 1 mmol/l) enhanced O2- formation induced by 0.1 mumol/1 C5a by 23% and 49%, respectively, and Bt2cGMP antagonized inhibition of O2- formation caused by Bt2cAMP. Bt2cGMP inhibited platelet-activating factor-induced O2- formation to a lesser extent than Bt2cAMP and had no effect on that induced by leukotriene B4. Bt2cAMP and Bt2cGMP had no effect on O2- formation induced by NAF, gamma-hexachlorocyclohexane, phorbol myristate acetate, A 23187 and arachidonic acid. Our data suggest that: 1. Bt2cAMP generally inhibits chemoattractant-stimulated O2- formation. 2. Bt2cGMP inhibits fMet-Leu-Phe- and platelet-activating factor-stimulated O2- formation but potentiates C5a-induced O2- formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Bucladesine↗