Biomedical subjects

M M Teixeira

Publications and source records attributed to M M Teixeira.

At least 91 records · Page 5Linked to original sources

PubMed1997

Chemokine-induced eosinophil recruitment. Evidence of a role for endogenous eotaxin in an in vivo allergy model in mouse skin.

Selective eosinophil recruitment into tissues is a characteristic feature of allergic diseases. Chemokines are effective leukocyte chemoattractants and may play an important role in mediating eosinophil recruitment in various allergic conditions in man. Here, we describe a novel mouse model of eosinophil recruitment in which we have compared the in vivo chemoattractant activity of different C-C chemokines. Furthermore, we describe the use of antibodies to chemokines and receptor blockade to address the endogenous mechanisms involved in eosinophil recruitment in a late-phase allergic reaction in mouse skin. Intradermal injection of mEotaxin and mMIP-1alpha, but not mMCP-1, mRANTES, mMCP-5, or mMIP-1beta, induced significant 111In-eosinophil recruitment in mouse skin. Significant 111In-eosinophil recruitment was also observed in an active cutaneous anaphylactic reaction. Pretreatment of skin sites with antieotaxin antiserum, but not an antiMIP-1alpha antibody, suppressed 111In-eosinophil recruitment in this delayed-onset allergic reaction. Similarly, desensitization of the eosinophil eotaxin receptor CCR3 with mEotaxin, or blockade of the receptor with metRANTES, significantly inhibited 111In-eosinophil recruitment in the allergic reaction. These results demonstrate an important role for endogenous eotaxin in mediating the 111In-eosinophil recruitment in allergic inflammation, and suggest that blockade of the CCR3 receptor is a valid strategy to inhibit eosinophil migration in vivo.

Anaphylaxis↗

PubMed1997

Pertussis toxin shows distinct early signalling events in platelet-activating factor-, leukotriene B4-, and C5a-induced eosinophil homotypic aggregation in vitro and recruitment in vivo.

The present study was performed to investigate the early signalling events responsible for eosinophil activation in response to platelet-activating factor (PAF), C5a, and leukotriene B4 (LTB4). We evaluated the effect of pertussis toxin (PTX) on eosinophil aggregation in vitro and cutaneous eosinophil recruitment in vivo. Further studies using the protein kinase inhibitors Ro 31-8220 and staurosporine were performed in vitro to assess in more detail the early signalling events induced by these three mediators. Our results show that C5a and LTB4 signal predominantly or exclusively through a PTX-sensitive G protein that is negatively modulated by protein kinase C, possibly at the level of phospholipase C-beta. In contrast, PAF activates eosinophils independent of Gi by a mechanism that is abolished by Ro 31-8220, a selective protein kinase C inhibitor. In addition, these results show for the first time that a receptor-operated event on the eosinophil is essential for chemoattractant-induced eosinophil recruitment in vivo.

Animals↗

PubMed1997

Evidence that the eosinophil is a cellular target for the inhibitory action of salmeterol on eosinophil recruitment in vivo.

Systemic administration of agents which elevate cyclic AMP (e.g., phosphodiesterase inhibitors, prostanoids, beta-adrenoceptor agonists) effectively modulates eosinophil recruitment in vivo. The present study was undertaken to evaluate whether the eosinophil itself is a cellular target for the inhibitory action of these drugs in vivo. We chose to use the long-acting beta 2-adrenoceptor agonist salmeterol to test this hypothesis. Eosinophils were pretreated with salmeterol (10(-6) M) before washing and testing in two salmeterol-sensitive systems, namely eosinophil aggregation and 111In-eosinophil accumulation in guinea-pig skin. Pretreatment with salmeterol inhibited by 65% and 43% eosinophil aggregation induced by platelet-activating factor (PAF) and human recombinant C5a, respectively. Similarly, 111In-eosinophil accumulation induced by PAF and zymosan-activated plasma, a source of guinea-pig des-Arg-C5a, was inhibited by 55% and 45%, respectively. In contrast, the level of circulating 111In-eosinophils at 1 h was enhanced by 35% in animals which received salmeterol-pretreated 111In-eosinophils. Our results suggest that the eosinophil itself is one of the cellular targets of the inhibitory action of systemically administered salmeterol on eosinophil recruitment in vivo.

Adrenergic beta-Agonists↗

PubMed1997

Phosphodiesterase (PDE)4 inhibitors: anti-inflammatory drugs of the future?

Phosphodiesterase type 4 (PDE4) plays a major role in modulating the activity of virtually all cells involved in the inflammatory process. Inhibitors of this enzyme family display impressive anti-inflammatory and disease-modifying effects in a variety of experimental models. In this review, Mauro Teixeira, Robert Gristwood, Nicola Cooper and Paul Hellewell examine the capacity of PDE4 inhibitors to exert anti-inflammatory actions in vivo and discuss the potential of this class of drugs to take their place as novel therapeutic agents for a variety of inflammatory diseases.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1997

Tumor necrosis factor and steroid metabolism in chronic heart failure: possible relation to muscle wasting.

OBJECTIVES: We sought to assess the possible relations between clinical severity of chronic heart failure and catabolic factors, specifically tumor necrosis factor (TNF), soluble TNF receptors 1 and 2 (sTNFR-1 and sTNFR-2), cortisol, testosterone and dehydroepiandrosterone (DHEA). BACKGROUND: Chronic heart failure is associated with loss of muscle bulk that may be related to alteration of the balance between catabolism and anabolism. METHODS: Sixty-three patients (average age +/- SD 60.4 +/- 11.3 years) with stable chronic heart failure and 20 control subjects aged 52.8 +/- 11.4 years were studied. We measured body mass index (BMI) and obtained maximal incremental exercise testing with metabolic gas exchange measurements and measurements of venous levels of TNF, sTNFR-1 and sTNFR-2, cortisol and DHEA. RESULTS: There was no difference in total TNF-alpha levels between patients and control subjects (9.76 +/- 8.59 vs. 6.84 +/- 2.7 pg/ml). sTNFR-1 (128.9 +/- 84.5 vs. 63.6 +/- 23.3 pg/ml, p < 0.003) and sTNFR-2 (250.1 +/- 109.5 vs. 187.9 +/- 92.2 pg/ml, p = 0.03) were higher in patients. DHEA was lower in patients (9.88 +/- 6.94 vs. 15.64 +/- 8.33 nmol/liter, p = 0.004). The ratio of log cortisol to log DHEA correlated with log TNF level (r = 0.50, p < 0.001 for the patients alone; r = 0.48, p < 0.001 for the group as a whole). Peak oxygen consumption correlated with both sTNFR-1 and sTNFR-2 (r = -0.51, p < 0.001 and r = -0.39, p < 0.001, respectively). There was a negative correlation between BMI and TNF levels (r = -0.43, p < 0.001 for the patients) and the cortisol/DHEA ratio (r = -0.32, p = 0.01 for the patients). CONCLUSIONS: There is an increase in TNF and its soluble receptors in chronic heart failure. This increase is associated with a rise in the cortisol/DHEA (catabolic/anabolic) ratio. These changes correlate with BMI and clinical severity of heart failure, suggesting a possible etiologic link.

Aged↗

PubMed1997

The effect of the selectin binding polysaccharide fucoidin on eosinophil recruitment in vivo.

1. In order to accumulate at sites of inflammation, leukocytes initially roll on endothelial cells of postcapillary venules before becoming firmly attached. This process of rolling is mediated by selectins which bind to carbohydrate counter-ligands present on the surface of both leukocytes and endothelial cells. The polysaccharide fucoidin has been previously shown to inhibit leukocyte rolling in the mesenteric circulation and to reduce neutrophil accumulation in the skin and meninges in experimental inflammation. 2. In the present study we have assessed the effects of fucoidin on eosinophil function in vitro and eosinophil accumulation at sites of inflammation in guinea-pig skin. 3. At concentrations of up to 1200 micrograms ml-1, fucoidin inhibited phorbol myristate acetate (PMA)-induced eosinophil homotypic aggregation by up to 60% but had no inhibitory effect on PMA-induced eosinophil adhesion to serum-coated plates. 4. Fucoidin effectively reduced the binding of the anti-L-selectin mAb MEL-14 to guinea-pig eosinophils. Binding of a P-selectin-IgG chimera to eosinophils was also partially inhibited by fucoidin, but binding of an anti-CD18 or an anti-VLA-4 mAb were unaffected. 5. When given systemically to guinea-pigs, fucoidin suppressed 111In-labelled eosinophil recruitment to sites of allergic inflammation. 111In-labelled eosinophil accumulation induced by platelet-activating factor (PAF) and zymosan-activated plasma (as a source of C5a des Arg) was also inhibited. 6. These results demonstrate a role for fucoidin-sensitive selectins in mediating eosinophil recruitment in vivo.

Animals↗

PubMed1997

Characterization of the prostanoid receptors mediating inhibition of PAF-induced aggregation of guinea-pig eosinophils.

1. Prostanoids induce a wide range of biological actions which are mediated by specific membrane-bound receptors. We have recently shown that the E-type prostaglandins, PGE1 and PGE2, effectively inhibit eosinophil aggregation induced by platelet-activating factor (PAF). In an attempt to determine which prostanoid receptor(s) were involved, we investigated the effects of a range of selective prostanoid agonists and antagonists on eosinophil homotypic aggregation induced by PAF. 2. Both PGE1 and PGE2 (10(-10) to 10(-6) M) induced a concentration-related inhibition of the aggregation response induced by PAF. PGE1 was more effective than PGE2 but PGE2 was slightly more potent than PGE1 (approximate IC50 values for PGE1 and PGE2 of 1.5 x 10(-8) M and 5 x 10(-9) M, respectively). 3. The EP2-selective agonists, 11-deoxy-PGE1, butaprost and AH13205, and the EP2/EP3-selective agonist, misoprostol, also inhibited PAF-induced aggregation. The rank order of potency for EP2-selective agonists was 11-deoxy-PGE1 > misoprostol > butaprost = AH13205. The protein kinase A inhibitor, KT5720 (10(-6) M), reversed the inhibitory effects of 11-deoxy-PGE1 (10(-6) M) and AH13205 (10(-5) M). 4. The EP1/EP3-selective agonist, sulprostone, and the EP1-selective agonist, 17-phenyl-omega-trinor PGE2, had no significant inhibitory activity when tested at concentrations up to 10(-6) M. The EP4-receptor antagonist, AH23848B, had no effect on PAF-induced aggregation and did affect the inhibitory activity of PGE1. 5. The IP-selective agonist, cicaprost (up to 10(-6) M), and the IP/EP1-receptor agonist, iloprost (up to 10(-5) M), had no significant effect on PAF-induced eosinophil aggregation. However, iloprost significantly augmented the inhibitory effects of a maximally inhibitory concentration of PGE2. 6. PGD2 (10(-5) M) had no effect on eosinophil aggregation and the inhibitory activity of PGE1 on PAF-induced eosinophil aggregation was not altered by the DP-selective receptor antagonist, BWA868C. 7. The results presented here suggest that the inhibition of PAF-induced eosinophil aggregation by prostanoids is mediated by the occupation of EP2-receptors. It is important to note that the effects of naturally occurring prostanoids, such as PGE2, on eosinophil aggregation occur at low concentrations highlighting a potential role for EP2 receptors in regulating eosinophil function in vivo.

Alprostadil↗

PubMed1997

A novel murine model of allergic inflammation to study the effect of dexamethasone on eosinophil recruitment.

1. We have developed a novel model of allergen-induced eosinophil into mouse air-pouches following sensitization and challenge with ovalbumin (Ova). This model was used to investigate the mechanism(s) underlying the anti-inflammatory action of the glucocorticoid hormone dexamethasone (Dex). 2. Injection of 10 micrograms Ova into 6-day-old dorsal air-pouches of mice sensitized to the same antigen provoked an intense cell accumulation as early as 6 h post-challenge (0.08 +/- 0.03 and 4.0 +/- 1.0 x 10(5) leucocytes in saline and Ova-treated air-pouches, respectively), maximal at 24 h (0.02 +/- 0.01 and 6.0 +/- 0.8 x 10(5) leucocytes in saline and Ova-treated air-pouches, respectively) and persisted up to 48 h. At the 24 h time-point, the cellular infiltrate consisted of 37% eosinophils, 18% neutrophils and 45% mononuclear cells, as assessed by histological examination. The same ratio of eosinophil/neutrophil was obtained by fluorescence-activated cell sorting (FACS) analysis, since 72% of the polymorphonuclear (PMN) population was positive for very-late antigen-4 (VLA-4) expression. 3. Subcutaneous (s.c.) administration of Dex (50 or 100 micrograms per mouse, -1 h) inhibited eosinophil accumulation into Ova challenged air-pouches by about 70% (P < 0.05) and 75% (P < 0.05), respectively, when compared to controls. Cell accumulation measured at 48 h after Ova injection was also significantly reduced (-75%) by Dex administration at the 24 h time-point (n = 12, P < 0.05). 4. Eosinophil numbers in the bone marrow and blood were quantitated. We found that the sensitization protocol induced a 3 fold increase in eosinophil numbers in the bone marrow (naive mice: 2.7 +/- 0.3 x 10(5); sensitized mice: 8.7 +/- 1.7 x 10(5), P < 0.05) and blood (naive mice: 0.5 +/- 0.2 x 10(5); sensitized mice: 1.5 +/- 0.3 x 10(5), P < 0.01). However, 24 h following Ova challenge, the eosinophil numbers in the bone marrow had dropped (3.7 +/- 0.8 x 10(5) with no change in the circulating pool, suggesting an equilibrium within the eosinophil pools had been reached. 5. Dex administration provoked a profound eosinopaenia in the blood of naive (5.2 +/- 1.5 to 0.9 +/- 0.6 x 10(4)) and sensitized mice (1.5 +/- 0.3 to 0.08 +/- 0.02 x 10(5)) at 4 h. This effect was reversed within 24 h. Dex also inhibited the release of eosinophils from the bone marrow in response to Ova challenge. 6. We show for the first time that express the steroid-inducible protein lipocortin 1 (LC1). FACS analysis of eosinophils emigrated into the Ova challenged air-pouches revealed detectable LC1-like immunoreactivity (373 x 10(3)). These data were also substantiated by LC1 detection in circulating eosinophils of interleukin-5 transgenic mice (strain: CBA/Ca). However, s.c. injection of Dex (50 micrograms) did not alter LC1 levels in blood eosinophils, such that 235 +/- 21 x 10(3) LC1-like molecules per cell were measured after vehicle treatment (n = 5), and 224 +/- 8 x 10(3) LC1-like molecules per cell were associated with this cell type 1 h after steroid treatment (n = 5, not significant). Finally, resident eosinophils (in the pleural cavity) were found to have much higher LC1 levels than that found in the blood circulation (2 fold increase, P < 0.05). 7. Passive immunization of mice against LC1 with a validated antiserum (termed LCS3) and protocol failed to modify the anti-migratory activity exerted by Dex towards eosinophil extravasation into Ova-challenged air-pouches. The steroid (50 micrograms s.c., -1 h) produced a similar degree of inhibition of eosinophil accumulation both in control animals (treated with a non-immune sheep serum) the LCS3-treated mice (-56% and 59%, respectively, n = 15-21, not significant). 8. In conclusion, the air-pouch provides a novel and convenient cavity to study allergen-induced cell recruitment which is sensitive to glucocorticoid hormone treatment. The effect of Dex on eosinophil distribution in these experimental conditions has been studied in detail and

Animals↗

PubMed1997

A comparison of the inhibitory activity of selective PDE4 inhibitors on eosinophil recruitment in guinea pig skin.

The elevation of intracellular cyclic AMP by phosphodiesterase (PDE)4 inhibitors in eosinophils is associated with inhibition of the activation and recruitment of these cells. We have previously shown that systemic treatment with the PDE4 inhibitor rolipram effectively inhibit eosinophil migration in guinea pig skin. In the present study we compare the oral potency and efficacy of the PDE4 inhibitors rolipram, RP 73401 and CDP 840 on allergic and PAF-induced eosinophil recruitment. Rolipram and RP 73401 were equally effective and potent when given by the oral route and much more active than the PDE4 inhibitor CDP 840. We suggest that this guinea pig model of allergic and mediator-induced eosinophil recruitment is both a sensitive and simple tool to test the efficacy and potency of PDE4 inhibitors in vivo.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1997

Description of an in vivo model for the assessment of eosinophil chemoattractants in the mouse.

Chemokines (chemoattractant cytokines) induce potent and selective chemotaxis of leukocyte subsets in vitro. Here, we review briefly the chemokines shown to induce eosinophil chemotaxis in vitro and describe a novel model for the study of the ability of chemokines to stimulate eosinophil migration in vivo. Eosinophils were purified from the blood of mice over-expressing the IL-5 gene and labelled with 111In. Only the C-C chemokines, eotaxin and MIP-1 alpha, but not RANTES, MCP-1, MCP-3, MCP-4, MIP-1 beta, KC and MIP-2, effectively induced the recruitment of 111 In-eosinophils in mouse skin. We suggest that this mouse model will be useful in assessing the role of endogenously-generated chemokines in mediating eosinophil migration to sites of allergic inflammation in vivo.

Animals↗

PubMed1997

Ribosomal and kDNA markers distinguish two subgroups of Herpetomonas among old species and new trypanosomatids isolated from flies.

We examined files of various families for the presence of trypanosomatids. Of 592 insects, 113 (19%) were positive. From these insects, we obtained 42 cultures and selected 14 for further analysis. Seven of the cultures had the characteristics of Herpetomonas species, they displayed typical opisthomastigotes, lacked arginase, possessed a Pvu II restriction site at 360 bp from the 5' end of the small subunit ribosomal gene, and did not possess a Hin dIII site at 1,500 bp from the ribosomal alpha-large subunit 5' end. Hybridization with synthetic oligonucleotides complementary to the sequences flanking the Pvu II site in Herpetomonas samuelpessoai and Herpetomonas muscarum, permitted the distribution of the old species and the 7 isolates into 2 subgroups of Herpetomonas spp. Of the remaining 7 cultures, 4 were probably Leptomonas spp., whereas the other 3, together with Herpetomonas roitmani, seem to constitute a novel group with morphological and molecular characteristics quite distinct from those of Herpetomonas spp. or any other genera of Trypanosomatidae. We also studied some trypanosomatid species of questionable taxonomic status, Leptomonas samueli and Phytomonas davidi yielded results identical to those of Herpetomonas spp., thus confirming their already suspected affiliation to this genus. On the other hand, Herpetomonas anglusteri, Herpetomonas dedonderi, and Herpetomonas mcgheei displayed morphological and molecular characteristics incompatible with their placement in the genus Herpetomonas.

Animals↗

PubMed1996

Priming of eosinophil recruitment in vivo by LPS pretreatment.

Eosinophils are important inflammatory cells in allergic diseases. Recent evidence suggests that priming mechanisms in the blood may be important for effective eosinophil recruitment to sites of allergic inflammation. We have investigated whether priming an inflammatory site could enhance eosinophil recruitment in vivo. Pretreatment of skin sites in the guinea pig with a low dose (30 ng) of LPS, which had little effect on eosinophil accumulation alone, enhanced by up to threefold the 111In-eosinophil accumulation in response to a passive cutaneous anaphylactic reaction and to intradermally injected eosinophil chemoattractants (leukotriene B4, PAF, and C5ades Arg). In contrast, LPS pretreatment did not enhance accumulation of 111In-neutrophils. Priming was seen only with a 1-h pretreatment time and was not associated with an increase in local edema or a change in cutaneous blood flow. It was independent of local protein synthesis, as assessed using cycloheximide, and was unaffected by a PAF antagonist, a 5-lipoxygenase inhibitor, and the IL-1 receptor antagonist. The priming response was, however, reduced by co-injection with the LPS of TNFR-IgG, but not of CD4-IgG. Blockade of CD18 showed this adhesion molecule to be critical for eosinophil accumulation, and LPS-primed sites were inhibited as effectively as nonprimed sites. In conclusion, low dose LPS pretreatment of guinea pig skin sites primes for eosinophil accumulation induced by intradermally injected inflammatory mediators and cutaneous anaphylactic reaction. This may be an important process by which eosinophil recruitment is modulated in vivo.

Animals↗

PubMed1996

Adhesion mechanisms involved in C5a-induced eosinophil homotypic aggregation.

During the process of migration into tissues, leukocytes interact primarily with vascular endothelial cells but they have also been shown to interact with each other. In this study we investigated the adhesion mechanisms involved in guinea pig eosinophil homotypic aggregation as assessed by changes in light transmission. The anti-CD18 monoclonal antibody (mAb) 6.5E, at concentrations in excess of those previously shown to abrogate CD18-dependent eosinophil adherence to serum-coated plastic, inhibited C5a-induced eosinophil aggregation to a maximum of 49-68%. In contrast, the anti-intercellular adhesion molecule-1 (ICAM-1) mAb RR1/1, which binds to guinea pig eosinophils and has been shown to block guinea pig ICAM-1 function, had no effect on C5a-induced responses. Similarly, two functionally active anti-very late antigen-4 (VLA-4) mAbs has no effect on eosinophil aggregation and did not affect the CD18-independent component of the aggregation response. The role of L-selectin in eosinophil aggregation was investigated by using heparin, the selectin-binding polysaccharide fucoidin, and the anti-L-selectin mAb MEL-14. Heparin concentration dependently inhibited C5a- and platelet- activating factor- (PAF) induced aggregation but C5a-induced responses were inhibited more potently. Fucoidin, but not the carbohydrate dermatan sulphate, effectively inhibited C5a-induced eosinophil aggregation. PMA- and PAF- induced responses were also inhibited by fucoidin. Moreover, fucoidin and 6.5E were additive in their ability to inhibit C5a-induced aggregation. Similarly, MEL-14 effectively inhibited C5a-induced eosinophil aggregation. In conclusion, we have demonstrated that guinea pig eosinophil homotypic aggregation is mostly dependent on CD11/CD18 and L-selectin present on the eosinophil surface. In addition, VLA-4 plays no role in mediating this aggregation response.

Animals↗

PubMed1996

Trypanosomatidae: a spliced-leader-derived probe specific for the genus Phytomonas.

We probed DNA from all trypanosomatid genera by slot blot hybridization with an oligonucleotide (SL3') complementary to a sequence of the Phytomonas spliced-leader or mini-exon RNA. The 19-nucleotide probe target site was previously shown to be highly conserved among a limited number of Phytomonas isolates, but diverges in other kinetoplastid genera. Our examination of 84 isolates of various genera of trypanosomatids showed hybridization of this probe exclusively with isolates from plants or insects which could, by morphological, biochemical, and molecular criteria, be considered to belong to the genus Phytomonas. In contrast, no hybridization was observed with flagellates of the genera Blastocrithidia, Crithidia, Endotrypanum, Herpetomonas, Leptomonas, Leishmania, and Trypanosoma. The method detected DNA quantities as low as 50 ng using either radioactive or nonradioactive probes, and was effective with as few as 10(4) intact flagellates. Together, these results suggest that this probe will serve as a convenient marker for taxonomic and epidemiological studies requiring reliable identification of Phytomonas spp. in plants or in putative insect vectors.

Animals↗

PubMed1996

Enhancement of Schistosoma mansoni infectivity by intradermal injections of larval extracts: a putative role for larval proteases.

Extracts of Schistosoma mansoni cercariae caused increased vascular permeability and edema if administered to CBA/Ca mice by intradermal injection. Percutaneous infection with cercariae over the skin site at which cercarial homogenate (CH) had been injected intradermally resulted in a significant increase in the infectivity of S. mansoni compared with that shown by worm recovery from control animals (P < .05). This effect was abrogated by inhibition of protease activity prior to injection. Injection of inflammatory mediators (bradykinin or zymosan-activated plasma) with or without prostaglandin E2 produced a similar amount of edema as did CH. Injection of these mediators did not, however, enhance infectivity of cercariae. Pancreatic elastase was found to induce edema and enhancement of infectivity comparable to those induced by CH. The protease(s) introduced into the site of infection may have facilitated larval migration directly by hydrolyzing host tissue or indirectly by inducing an inflammatory response (or both).

Animals↗

PubMed1996

Effects of dexamethasone and cyclosporin A on the accumulation of eosinophils in acute cutaneous inflammation in the guinea-pig.

1. Eosinophils are thought to play an important role in the pathophysiology of allergic diseases and pharmacological suppression of their recruitment is considered to be of therapeutic benefit. In the present study we have assessed and compared the effects of treatment with dexamethasone and cyclosporin A on the accumulation of 111In-labelled eosinophils and local oedema formation in sites of acute inflammation in guinea-pig skin. 2. When injected locally 150 min prior to i.d. administration of antigen in a passive cutaneous anaphylactic (PCA) reaction, dexamethasone (10(-9) to 3 x 10(-7) mol per site) dose-dependently inhibited oedema formation by up to 50%. Similarly, oedema formation induced by PAF and lipopolysaccharide (LPS), but not by zymosan-activated plasma (ZAP), was significantly inhibited by dexamethasone. In contrast, 111In-eosinophil accumulation measured in response to i.d. injection of PAF, LPS and ZAP or in the PCA reaction was not altered. 3. Systemic treatment with dexamethasone (4 mg kg-1, i.v., 150 min pretreatment period) inhibited both oedema formation and 111In-eosinophil accumulation induced by PAF, ZAP, LPS and in the PCA reaction. 4. The effects of i.d. injection of cyclohexamide (2 x 10(-7) mol per site) on 111In-eosinophil accumulation and oedema formation induced by PAF, ZAP or in a PCA reaction were evaluated in order to assess the dependency of these responses on protein synthesis. Cycloheximide had no effect on the responses measured. In contrast, 111In-eosinophil accumulation, but oedema formation, induced by LPS was inhibited by 30%. 5. Acute (10 mg kg-1, i.v., 15 min pretreatment) or prolonged (10 mg kg-1, s.c. daily for 3 days) systemic treatment with cyclosporin A had no effect on 111In-eosinophil accumulation or oedema formation induced by PAF, ZAP, LPS or in the PCA reaction. 6. In conclusion, we demonstrate preferential inhibitory effects of dexamethasone on 111In-eosinophil accumulation according to its site of administration. In addition we show that dexamethasone inhibits protein synthesis-independent acute inflammation in guinea-pig skin. Finally, our results do not support the concept that eosinophils are an important cellular site of action for the inhibitory effects of cyclosporin A in a guinea-pig model of allergic inflammation.

Animals↗

PubMed1996

Effects of agents which elevate cyclic AMP on guinea-pig eosinophil homotypic aggregation.

1. Eosinophil recruitment and activation in inflamed tissue is thought to play an important role in the pathophysiology of allergic diseases. Experimental evidence suggests that elevating cyclic AMP is an effective means of reducing eosinophil recruitment in vivo and may therefore have therapeutic benefit. In the present study, we have assessed the capacity of cyclic AMP-elevating agents to modulate guinea-pig eosinophil homotypic aggregation, a CD18-dependent process, which may be an important component of eosinophil function in vivo. 2. Prostaglandin E1 (PGE1, 10(-16) to 10(-6) M) inhibited platelet activating-factor (PAF)- and C5a-induced eosinophil aggregation in a concentration-dependent manner. However, PAF-induced responses were more potently and more effectively inhibited by PGE1. The inhibitory effects of PGE1 on PAF-induced aggregation were reversed by pretreatment of eosinophils with the protein kinase A inhibitors H89 and KT5720. 3. The beta 2-adrenoceptor agonists, salbutamol and salmeterol, concentration-dependently inhibited eosinophil aggregation induced by C5a and PAF and, again. PAF-induced responses were more effectively reduced. The inhibitory effect of salmeterol was mediated by beta-adrenoceptors, as assessed by the reversal after pretreatment with propranolol. 4. Rolipram, a selective phosphodiesterase 4 (PDE4) inhibitor, also attenuated PAF- and C5a-induced aggregation and at a low concentration which did not affect aggregation per se, had a synergistic effect with PGE1 and salbutamol to suppress this response. 5. Activation of eosinophils with PAF or C5a induced a small but significant increase in the level of CD18 expression on the eosinophil surface. PGE1 (10(-7) M) decreased PAF- and C5a-induced upregulation of CD18 by 93% and 62%, respectively. 6. These results demonstrate that cyclic AMP-elevating agents effectively inhibit eosinophil aggregation, a CD18-dependent functional response. Because CD18 has been shown to be important for eosinophil recruitment to inflamed tissue in vivo, our findings may be of relevance to the efficacy of cyclic AMP-elevating agents at inhibiting eosinophil trafficking.

Albuterol↗

PubMed1995

Anti-inflammatory effects of a short-acting and a long-acting beta 2-adrenoceptor agonist in guinea pig skin.

The pharmacological modulation of the accumulation and function of eosinophils in tissues may have a significant impact in the treatment of allergic diseases such as asthma, atopic dermatitis and rhinitis. In this study, we have investigated the acute anti-inflammatory effects of a short-acting (salbutamol) and a long-acting (salmeterol) beta 2-adrenoceptor agonist on 111In-accumulation and oedema formation in allergic and mediator-induced inflammation in guinea pig skin. Both salbutamol and salmeterol inhibited 111In-eosinophil accumulation induced by platelet-activating factor and in a passive cutaneous anaphylactic reaction when co-injected with the inflammatory stimuli or when given as a 30 min pretreatment. The inhibition was reversed by DL-propranolol, but not D-propranolol. Systemic treatment with salbutamol inhibited 111In-eosinophil accumulation and oedema formation when given as a 15 min, but not as a 3 h, pretreatment. In contrast, salmeterol was effective when given at both times. We conclude that a long duration of action of beta 2-adrenoceptor agonists is not necessary to demonstrate acute anti-inflammatory effects on eosinophil accumulation in guinea pig skin.

Adrenergic beta-2 Receptor Agonists↗