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PubMed1996

Recombinant human eotaxin induces oxygen radical production, Ca(2+)-mobilization, actin reorganization, and CD11b upregulation in human eosinophils via a pertussis toxin-sensitive heterotrimeric guanine nucleotide-binding protein.

The novel human CC-chemokine Eotaxin is a potent and selective chemotaxin for eosinophils. Here, the biological activities and the activation profile of Eotaxin were further characterized and compared with those of other eosinophil chemotaxins such as complement fragment C5a (C5a), platelet-activating factor (PAF), and RANTES in human eosinophils. Eotaxin stimulated the production of reactive oxygen metabolites as shown by lucigenin-dependent chemiluminescence and superoxide dismutase-inhibitable cytochrome C reduction. Furthermore, Eotaxin induced upregulation of the integrin CD11b. In addition, fluorescence measurements with Fura-2-labeled eosinophils in the presence of EGTA indicated Ca(2+)-mobilization from intracellular stores by Eotaxin. Flow cytometric studies showed rapid and translent actin polymerization on stimulation with Eotaxin. At optimal concentrations, the changes induced by Eotaxin were comparable with those obtained by C5a, PAF, and RANTES. Call responses elicited by Eotaxin were inhibited by pertussis toxin, indicating coupling of its putative receptor to heterotrimeric guanine nucleotide-binding proteins. These results indicate that Eotaxin is a strong activator of eosinophils with biological activity comparable with those of the eosinophil chemotaxins C5a, PAF, and RANTES. These findings point to a role of Eotaxin in the pathogenesis of eosinophilic inflammation as a chemotaxin as well as an activator of proinflammatory effector functions.

Actins↗
PubMedDate not supplied

Removal of anaphylatoxins C3a and C5a and chemokines interleukin 8 and RANTES by polyester white cell-reduction and plasma filters.

BACKGROUND: A few bedside polyester white cell (WBC)-reduction filters have been shown to scavenge C3a anaphylatoxin from stored blood components. One has been shown to remove the chemokines interleukin (IL)-8 and RANTES, but not the proinflammatory cytokines IL-1, IL-6, and tumor necrosis factor alpha. Removal by any filter of the anaphylatoxin C5a or the soluble membrane attack complex (SC5b-9) has not been studied. Further, the ability of other filters to scavenge these biologic response modifiers (BRM) is not known. Four WBC-reduction filters and one plasma filter were studied for their ability to remove IL-8, RANTES, IL-1 beta, C3a, C5a, and SC5b-9. STUDY DESIGN AND METHODS: Plasma was obtained either as freshly thawed fresh-frozen plasma, fresh-frozen plasma thawed and stored for 5 days, or platelet-poor supernatant. Cell-poor plasma was obtained and samples were taken before and after filtration through the various filters Levels of IL-1 beta, IL-8, RANTES, C3a, and SC5b9 were quantitated by enzyme immunoassay. To evaluate filter scavenging of C5a, an in vitro model was developed to generate high levels of C5a in plasma by activating plasma with zymosan. RESULTS: Levels of C3a, C5a, IL-8, and RANTES were reduced by filtration through two bedside platelet WBC-reduction filters, a plasma filter, and a prestorage red cell WBC-reduction filter, but not following filtration through a prestorage platelet WBC-reduction filter. For some BRMs and filters, however, evidence of filter saturation was seen. IL-1 beta was not removed by any of the filters tested. CONCLUSION: Some, but not all, bedside polyester filters and prestorage polyester filters can remove IL-8, RANTES, C3a, and C5a from units of plasma or platelets. Improved biomaterial engineering of these and other filters could maximize scavenging of BRMs and potentially diminish the adverse reactions associated with their infusion during transfusion.

Blood Component Removal↗
PubMed2001

Relationship between pancreatitis and lung diseases.

Patients with acute pancreatitis may develop acute lung injury, manifest clinically as the adult respiratory distress syndrome. Most patients who die during the early stages of severe acute pancreatitis die either with or as a result of this lung injury. To explore the events which couple acute pancreatitis to lung injury, a number of recent studies have been performed in the author's laboratory using a variety of experimental models and interventions including gene-targeted deletion of chemokines, cytokines, specific receptors, and adhesion molecules. These studies have indicated that adhesion molecules such as intracellular adhesion molecule-1 (ICAM-1), neutrophils, platelet activating factor (PAF), substance P, and chemokines acting via the CCR-1 chemokine receptor play a pro-inflammatory role while complement factor C5a plays an anti-inflammatory role in pancreatitis and lung injury. Future studies will build on these observations to expand the list of pro- and anti-inflammatory coupling factors and explore the mechanisms by which they act to cause or prevent lung injury in acute pancreatitis.

Acute Disease↗
PubMed1999

Diapedesis across mammary epithelium reduces phagocytic and oxidative burst of bovine neutrophils.

The effect of diapedesis on the phagocytic and oxidative burst activity of polymorphonuclear neutrophil (PMN) was examined, using an in vitro cell culture model consisting of a monolayer of primary mammary epithelial cells. Isolated blood PMN from 10 cows were added to the basal side of the epithelial cell monolayer. Diapedesis was induced by the addition of complement factor C5a to the apical side of the monolayer. PMN phagocytosis of Staphylococcus aureus and oxidative burst were measured before diapedesis on PMN that were non-activated and activated by incubation with C5a and on PMN after diapedesis, using flow cytometry. The percentages of PMN fluorescing due to phagocytosis of S. aureus and oxidative burst were reduced by 21.2 and 14.4%, respectively, after diapedesis. Pre-incubation in the presence of C5a had no effect on percentage PMN fluorescing due to phagocytosis or oxidative burst. The capacity for individual migrated PMN to phagocytose S. aureus and to produce an oxidative burst, as measured by the intensity of fluorescence, decreased by 34.2 and 30.3%. Activation of PMN with C5a increased intensity due to the oxidative burst, but had no effect on intensity due to phagocytosis. These data show that PMN diapedesis across mammary epithelium results in decreased phagocytosis and oxidative burst of the PMN.

Animals↗
PubMed1994

Effect of a selective protein kinase C inhibitor, Ro 31-8425, on Mac-1 expression and adhesion of human neutrophils.

The role of protein kinase C (PKC) in mediating up-regulation of macrophage 1 adhesion protein (Mac-1) and adhesion of neutrophils in response to physiological agonists is not clear. Previous studies have relied on use of phorbol esters to activate PKC directly or on results obtained with non-selective inhibitors of protein kinases. 3-[8-(Aminomethyl)-6,7,8,9-tetrahydropyridol[1,2-a]-indol-10-yl]-4 -(1- methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride (Ro 31-8425) is a potent and highly selective inhibitor of PKC (Bit et al. J. Med. Chem. 1993. 36: 21). In these studies Ro 31-8425 has been used to define, more definitively, the role of PKC in mediating complement fragment C5a (C5a)-stimulated up-regulation of Mac-1 and adhesion of neutrophils to endothelial cells and to bovine serum albumin (BSA)-coated plastic. Phorbol 12, 13 dibutyrate (PBu2) increased surface expression of Mac-1 and stimulated adhesion of neutrophils to endothelial cells and to BSA-coated plastic. This confirms previous reports that activation of PKC can stimulate these responses. The PKC inhibitor, Ro 31-8425, inhibited the PBu2-stimulated responses, which confirms that Ro 31-8425 was effective in inhibiting PKC in these neutrophils. A more physiological agonist, C5a, also increased surface expression of Mac-1 and adhesion of neutrophils to endothelial cells and BSA-coated plastic. However, the responses to C5a were unaffected by Ro 31-8425. These results suggest that, although activation of PKC can promote up-regulation of Mac-1 and adhesion of neutrophils, this does not appear to be the physiological pathway. A non-selective protein kinase inhibitor, staurosporine, inhibited both PBu2 and C5a-stimulated adhesion. This suggests that a protein kinase other than PKC, possibly a tyrosine protein kinase, is likely to be involved in mediating C5a-stimulated Mac-1 up-regulation and adhesion. These results emphasise the need for caution in interpreting experiments and assuming a role for PKC. Use of a potent and selective inhibitor of PKC, Ro 31-8425, provides more definitive information.

Alkaloids↗
PubMed1991

Dibutyryl cyclic AMP induces formyl peptide receptor expression and chemotactic responses in a human eosinophilic cell line, EoL-1.

We investigated actin polymerization and the increase of cytosolic free calcium concentration ([Ca2+]i) in a human eosinophilic leukemia cell line, EoL-1, in response to stimulation with chemotactic factors; we also investigated the effect of dibutyryl cyclic AMP (dbcAMP) on the responses. EoL-1 cells under normal culture conditions did not show either actin polymerization or an increase in [Ca2+]i when stimulated with formyl-methionyl-leucyl-phenylalanine (fMLP). Expression of formyl peptide receptors was not detectable on untreated EoL-1 cells, either. Dibutyryl cAMP induced the expression of formyl peptide receptors and the responsiveness to fMLP. The responsiveness of EoL-1 cells to the complement fragment C5a and platelet-activating factor (PAF) was also induced or enhanced by dbcAMP. The growth of EoL-1 cells was decreased and the proportion of cells in the G0/G1 phase of the cell cycle was increased by the treatment of EoL-1 cells with dbcAMP. The proportion of eosinophilic granule-containing cells and the content of eosinophil cationic protein (ECP) in EoL-1 cells was also increased when they were stimulated with dbcAMP for a longer period. The responsiveness of EoL-1 cells to fMLP, C5a, and PAF was shown to be regulated independently. EoL-1 cells and dbcAMP seem to be useful for examining chemotactic receptor expression and its signal transduction mechanisms.

Actins↗
PubMed1989

Altered free cytosolic calcium changes and neutrophil chemotaxis in patients with juvenile periodontitis.

Nearly 70-75% of patients with localized juvenile periodontitis (JP) have abnormal polymorphonuclear leukocytic (PMN) chemotaxis. The objective of this study was to determine whether the lower chemotactic response in PMNs from JP patients is associated with a defect in intracellular signal transduction, as measured by stimulus-induced changes in free cytosolic calcium (Ca2+) mobilization. We report that peptide chemoattractants such as N-formyl-methionyl-leucyl-phenylalanine (fMLP) and the complement fragment C5a in direct comparative studies induced lower amounts of initial Ca2+ mobilization in PMNs from JP patients than healthy controls, as monitored by intracellular fura-2 fluorescence. The initial resting levels of free cytosolic Ca2+ in PMNs from JP patients and normal individuals were found to be similar. fMLP and C5a both mobilized Ca2+ in PMNs in a dose-dependent manner. Treatment of PMNs from 0.16 to 20 nM fMLP and 0.2 to 20 nM C5a resulted in elevated levels of free cytosolic Ca2+. However, above 20 nM fMLP and 5 nM C5a concentrations the extent of total Ca2+ mobilization did not differ significantly. Although fMLP and C5a caused Ca2+ mobilization in PMN cells from JP and healthy control subjects, fMLP stimulation induced higher levels of free cytosolic Ca2+ mobilization in PMN cells from healthy control subjects (141.29 +/- 25.55 nM/2 x 10(6) PMNs), than PMNs from JP patients (62.33 +/- 23.76 nM/2 x 10(6) PMNs). Similarly C5a induced higher levels of Ca2+ mobilization in PMNs from healthy control individuals (130.43 +/- 18.26 nM Ca2+/2 x 10(6) PMNs)O, when compared to JP patients (49.92 +/- 14.92 nM Ca2+/2 x 10(6) PMNs).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1983

Procoagulant activity of rabbit alveolar macrophages.

Alveolar macrophages are thought to participate in the clearance of fibrin from the injured lung, but their ability to facilitate the conversion of fibrinogen to fibrin (procoagulant activity) has not been described. In order to characterize their procoagulant properties, unstimulated alveolar macrophages obtained from normal rabbits were tested for their ability to accelerate the coagulation of plasma in a one-stage clotting assay. Compared with control assays containing no macrophages (coagulation times greater than 500 s), intact cells (10(6)/ml) were shown to display procoagulant activity (coagulation time, 153.6 +/- 11.3 s mean +/- SEM). Cell lysis caused further procoagulant activity to be expressed (125.6 +/- 11.8 s). Alveolar macrophages that were stimulated in vitro with bacterial lipopolysaccharide (LPS) or the purified complement fragments C5a and C5a des Arg caused further significant (p less than 0.002) reductions in coagulation times (intact cells, 71 to 76 s; lysed cells, 27 to 32 s), representing 5- to 6-fold and 30- to 40-fold increases in the procoagulant activity of intact and lysed cells, respectively. The generation of this material was independent of the presence of lymphocytes. The procoagulant material was identified as a cell-associated tissue thromboplastin, acting via the extrinsic coagulation pathway. These findings show that alveolar macrophages have procoagulant activity that is markedly augmented by LPS and complement fragments. This suggests that alveolar macrophages may contribute to intra-alveolar fibrin deposition in vivo.

Animals↗
PubMed2002

In vitro blood damage by high shear flow: human versus porcine blood.

Devices for modern heart support are minimized to reduce priming blood volume and contact area with foreign surfaces. Their flow fields are partly governed by very high velocity gradients. In order to investigate blood damage, porcine and human blood was passed through a narrow Couette type shear gap applying defined high shear rates within the typical range for devices such as blood pumps or artificial heart valves (gamma = 1800/s to 110,000/s for 400 ms). Traumatization profiles of both blood species were recorded in terms of hemolysis and platelet count. Sublethal damage in terms of platelet (PF4) and complement activation (C5a) was additionally measured for human blood. Results for porcine and human blood were very similar. Hemolysis was not started until critical shear rates of about 80,000/s. Impact on platelets was severe with drops in cell count of up to 65% (at gamma = 55,000/s to 110,000/s) likely to set stronger limits to the design layout of devices than hemolysis. Concentrations of PF4 and C5a clearly increased with shear rate exhibiting stronger gradients where hemolysis started. Due to the similar results of porcine and human blood for hemolysis and platelet drop, porcine blood seems to be suitable for device testing. Selection of blood species would thus depend on handling, availability and analysis demands.

Animals↗
PubMed2000

Opioids suppress chemokine-mediated migration of monkey neutrophils and monocytes - an instant response.

Opioid users having acquired human immunodeficiency syndrome (AIDS) are at a greater risk than non-users of contracting opportunistic infections. Opioid-administered and simian immunodeficiency virus (SIV)-infected rhesus monkeys have been an excellent model for studying AIDS and drug abuse in humans. In this study, chemotaxis of monkey leukocytes was evaluated using the chemokines interleukin-8 (IL-8) and regulated upon activation, normal T cell expressed (RANTES) as the chemoattractants, and the effects of various opioid agonists and antagonists on the efficiency of chemotaxis were examined. Opioids were either incubated with monkey leukocytes or added directly to chemokines, and the number of cells migrating toward IL-8 (for neutrophils) or RANTES (for monocytes) was scored. Inhibition of chemotaxis was seen with both assay conditions, and the inhibition was mediated by opioids binding to mu or kappa receptors. Binding to delta opiod receptors was rarely, if ever, observed. Although opioids themselves may act as weak chemoattractants for monkey leukocytes, addition of opioid agonists to chemokines would reduce the chemoattractant ability of the chemokines. Opioids did not cause the same inhibitory effect on the chemotactic migration of neutrophils when the complement component C5a or the chemotactic peptide N-formyl-MET-LEU-PHE (fMLP) was used as chemoattractant. These studies suggest that the presence of opioids during SIV infection immediately alters chemokine-mediated immune functions.

Animals↗
PubMed1993

Chemoattractant agents and nerve growth factor stimulate human spermatozoal reactive oxygen species generation.

OBJECTIVE: To investigate the ability of N-formyl-methionyl-leucyl-phenylalanine (f-MLP), complement 5a (C5a), and nerve growth factor (NGF) to stimulate human spermatozoal reactive oxygen species generation in fertile and infertile patients. DESIGN: Prospective, controlled study measuring human spermatozoal reactive oxygen species generation after addition of f-MLP, C5a, or NGF. SETTING: A large health maintenance organization. PATIENTS, PARTICIPANTS: The fertile group consisted of 14 men with established fertility and normal bulk semen parameters. The infertile group was comprised of 8 men who were infertile after > 18 months of unprotected sexual intercourse. INTERVENTIONS: The sperm samples were subjected to four test conditions: f-MLP stimulation, C5a stimulation, NGF stimulation, and no stimulation (control). MAIN OUTCOME MEASURE: Reactive oxygen generation was measured over a 15-minute period using the method of chemiluminescence. RESULTS: In both the fertile and infertile groups, reactive oxygen species generation was significantly enhanced by f-MLP, C5a, and NGF compared with controls. No significant difference in f-MLP- and C5a-stimulated reactive oxygen production was demonstrated between the infertile and fertile groups; however, there was a significant difference in reactive oxygen generation between infertile and fertile subjects when stimulated with NGF. CONCLUSIONS: The current study represents the first report of f-MLP-, C5a-, and NGF-stimulated reactive oxygen species generation by human spermatozoa. Nerve growth factor enhanced reactive oxygen species production to a greater extent in infertile subjects compared with fertile subjects. This points to a possible NGF-mediated biochemical defect in the sperm of infertile patients.

Adult↗
PubMed1985

The role of the polymorphonuclear leukocyte in hyperalgesia.

The results of recent studies of the mechanism of leukotriene B4-induced hyperalgesia suggest a dependence on polymorphonuclear leukocytes (PMNLs). In this study, we addressed the contribution of PMNLs to hyperalgesia evoked by the peptide chemotactic factors N-formyl-methionyl-leucyl-phenylalanine (fMLP) and the anaphylatoxin fragment of the fifth component of the complement pathway (C5a). Local injection of glycogen, which attracts but does not activate PMNLs, produced a marked shift to the left (toward lower concentrations) in the concentration dependence curve of fMLP-induced hyperalgesia. In addition, PMNL repletion by transfusion with syngeneic PMNLs reestablished fMLP-induced hyperalgesia in PMNL-depleted rats. Finally, supernatants from rat and human PMNLs, that had been stimulated with fMLP in vitro, produced hyperalgesia in PMNL-depleted rats. Preliminary characterization of the hyperalgesia-inducing activity released by stimulated PMNLs indicated that it is lipid in nature. The nonsteroidal anti-inflammatory indomethacin did not attenuate C5a and fMLP-induced hyperalgesia. Thus, the hyperalgesia produced by fMLP and C5a is similar to that produced by leukotriene B4 in that it is dependent on PMNLs and independent of the cyclo-oxygenation of arachidonic acid. Taken together, these data suggest that structurally diverse PMNL-chemotactic factors produce hyperalgesia by a novel mechanism, involving PMNL-derived factors.

Animals↗
PubMed1987

Human GM-CSF primes neutrophils for enhanced oxidative metabolism in response to the major physiological chemoattractants.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a T cell-derived lymphokine which induces hematopoietic precursor cells to proliferate in vitro and differentiate to neutrophils and macrophages. GM-CSF also inhibits the motility of mature neutrophils (NIF-T activity), and primes neutrophils to enhance oxidative metabolism in response to the bacterial chemoattractant, N-formyl-methionyl-leucyl-phenylalanine (f-MLP). The present study was designed to determine whether this lymphokine also enhances neutrophil oxidative metabolism in response to the other major physiological chemoattractants which include complement-derived C5a, and the 5-lipoxygenation product of arachidonic acid, leukotriene B4 (LTB4). Superoxide anion production was measured as superoxide dismutase-inhibitable cytochrome C reduction. Purified biosynthetic GM-CSF enhanced superoxide anion production by neutrophils in response to f-MLP, C5a desArg, and LTB4. In contrast to several other factors which prime neutrophils, GM-CSF did not prime for an enhanced oxidative response to phorbol myristate acetate (PMA). These results suggest that GM-CSF may be an endogenous regulator of neutrophil inflammatory responses induced by the major physiological chemoattractants.

Chemotactic Factors↗
PubMed1998

Effects of some anti-asthma drugs on human eosinophil superoxide anions release and degranulation.

BACKGROUND: Eosinophil infiltration of bronchial tissues and subsequent release of inflammatory mediators by them are the hallmarks of bronchial asthma but it has not yet been clarified whether anti-asthma drugs affect these cells directly. In this study, we investigated the direct effects of 8 clinically used anti-asthma drugs [salbutamol, salmeterol, theophylline, denbufylline, disodium cromoglycate (DSCG), azelastine, ketotifen and dexamethasone] on superoxide anions (O2-) and eosinophil peroxidase (EPO) release from human blood eosinophils in vitro. METHODS: Highly purified eosinophils were stimulated for O2- release with platelet-activating factor (PAF) or interleukin-5 (IL-5), while for EPO release complement fragment (C5a) or N-formyl-methionyl-leucyl-phenylalanine (FMLP) was employed. Generated products were assayed by standard techniques. RESULTS: All the drugs, except ketotifen and dexamethasone, inhibited PAF-induced O2- release in a dose-dependent manner. The IC50 values were 0.7, 5.8, 330, 3,500, 4,200 and 6,250 nM for DSCG, denbufylline, salmeterol, azelastine, salbutamol and theophylline, respectively. On IL-5-induced release, the effects were similar except that salbutamol completely failed to inhibit the release induced by this stimulus. In contrast, EPO release was generally poorly inhibited, especially when the release was induced by C5a. Only theophylline and azelastine (both at 10(-4) M or more) were able to inhibit EPO release by both C5a and FMLP. Salbutamol and, to a lesser extent, salmeterol inhibited FMLP-, but not C5a-induced EPO release, while all the other drugs tested were inactive. CONCLUSIONS: The results show that some of the anti-asthma drugs, but not all, do exert direct effects on human blood eosinophils but these effects may be stimulus-dependent and by far more pronounced against O2- release than against degranulation.

Anti-Asthmatic Agents↗
PubMed1982

Release of leukotrienes from guinea pig lung stimulated by C5ades Arg anaphylatoxin.

The complement anaphylatoxins C5a and C5Ades Arg contract guinea pig peripheral airway preparations and trachea by a mechanism largely independent of histamine release. In trachea the contractions are inhibited by FPL 55712, a relatively specific inhibitor of slow-reacting substance of anaphylaxis (SRS-A). SRS-A is now known to be a mixture of leukotrienes C4, D4, and E4 (LTC4, LTD4, LTE4). These data suggest that C5-derived anaphylatoxins stimulate production and release of leukotrienes in pulmonary tissues. To define these observations more precisely, fragments of guinea pig lung were incubated with porcine C5ades Arg, and the supernatant fluids were analyzed for leukotrienes by using both pharmacologic and chemical methods. In addition to histamine, a smooth muscle contracting activity characteristic of SRS-A was released from C5a-treated lung preparations. The contractile substance was identified as a leukotriene based on: 1) the characteristic contraction of guinea pig ileum, 2) inhibition of the contractile activity by FPL 55712, 3) enhanced release of activity in the presence of indomethacin or L-cysteine, 4) chromatographic behavior of ethanol-extracted active material on Amberlite XAD-7 resin, and 5) cochromatography of the active material on reverse-phase, high performance liquid chromatography with standard LTD4. We therefore concluded the humoral factor C5ades Arg induces a leukotriene release reaction in guinea pig lung tissue. This particular response of pulmonary tissue to anaphylatoxin has not been appreciated previously as an immediate effect of complement activation on the pathophysiology of the lung.

Anaphylatoxins↗
PubMed1991

Neutrophil chemotactic factors.

Polymorphonuclear leukocytes (neutrophils) are recruited to inflammatory sites by a variety of soluble mediators (chemoattractants) that stimulate neutrophil directed migration (chemotaxis). Many neutrophil chemoattractants such as neutrophil activating proteins, leukotriene B4 (LTB4), platelet activating factor, and complement-derived C5a, are generated endogenously by host cells or enzymatic cleavage of host proteins. Other chemoattractants such as N-formyl peptides are generated exogenously by bacteria that invade the host. Oxidative modification of methionine residues or changes in the amino acid sequence of peptide chemoattractants dramatically alter their chemoattractive properties. Many of the well-defined neutrophil chemotactic factors and studies of their structure-function relationships will be reviewed.

Animals↗
PubMed1993

Increased lower airways responsiveness associated with sinusitis in a rabbit model.

The association between sinusitis and asthma has been clinically recognized, but its precise nature is controversial. We studied the relationship between sinusitis and lower airways function in a rabbit model of sterile maxillary sinusitis induced by the chemotactic complement fragment C5a des arg. Animals kept in a head-up position following experimental sinusitis demonstrated a significant increase in airways responsiveness (AWR) to histamine. In contrast, animals of which the sinuses were injected with a saline diluent and in which no sinus inflammation developed had no increase in AWR. Experiments were subsequently carried out to investigate some of the potential mechanisms for these observations. A group of rabbits in which a distal site of inflammation was induced did not demonstrate increased AWR. Likewise, when sinus inflammation was established but passage of fluid to the lower airways was prevented, either by intubation or by head-down positioning, there was no change in AWR. A fourth experiment was designed to decrease complement factor activity before placing the animals in a head-up position. This led to the same degree of increased AWR. Neither the histology nor the bronchoalveolar lavage data demonstrated significant lower airways inflammation in any group. We conclude that sterile sinusitis can increase lower airways responsiveness to histamine in a rabbit model. The most likely mechanism for this effect is the postnasal dripping of cells or cell products into the lower airway. The role of a nasobronchial reflex or inflammatory mediator absorption could not be demonstrated in this model.

Animals↗
PubMed1987

Antigenic identification of chemotactic factor inactivator in normal human serum and bronchoalveolar lavage fluid.

Several proteins have been described that can modulate the activity of the complement component C5a, a potent chemoattractant for neutrophils. One of these inhibitors has been termed chemotactic factor inactivator (CFI). We hypothesized that CFI was antigenically present in normal human serum and that antigenic levels would correlate with the ability of serum to inhibit C5a. To test this hypothesis, CFI was purified from normal human serum, antibodies to CFI were developed in rabbits, and these reagents were used to develop an enzyme-linked immunoadsorbent assay to measure CFI. Sera from 32 normal volunteers were assayed for CFI and found to contain 77 +/- 29 micrograms/ml (range 17 to 137 micrograms/ml). Partially purified CFI from normal human sera was found to inhibit 61% +/- 9% (range 45% to 75%) of the ability of C5a to attract human neutrophils. Importantly, the ability of CFI to inhibit C5a-induced neutrophil chemotaxis correlated with the antigenic amounts of CFI (r = 0.68, P less than 0.05), suggesting that CFI is a major inhibitor of C5a. This was confirmed by the finding that (1) all C5a inhibitory activity coprecipitated with CFI by ammonium sulfate precipitation (45% to 65% saturation), and (2) depletion of this ammonium sulfate fraction of CFI resulted in a major loss in its ability to inhibit the chemotactic activity of C5a (57% vs. 8% inhibition, P less than 0.01). To determine whether CFI could play a role in the modulation of inflammation at tissue sites, normal bronchoalveolar lavage fluid was evaluated for the presence of CFI. CFI was identified in all fluids (mean 0.50 +/- 0.09 micrograms/mg albumin, range 0.14 to 1.43 micrograms/mg albumin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗