Inhibition by rapamycin of leukocyte migration and bronchial hyperreactivity induced by injection of Sephadex beads to guinea‐pigs

Francischi, Janetti Nogueira de; Conroy, Dolores M.; Maghni, Karim; Sirois, Pierré

doi:10.1111/j.1476-5381.1993.tb13973.x

Cited by 17 publications

(8 citation statements)

References 21 publications

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“…In the present study, cyclosporin did not affect either the development o f the early or the longlasting increase in paw volume induced by Sephadex beads, which is in sharp contrast to the effects observed for rapa mycin and dexamethasone. The dose used of rapamycin (5 mg/kg) was previously shown to reduce ex vivo bronchi al hyperreactivity and the increase in leucocyte infiltration induced by Sephadex beads in guinea pigs [4], Therefore, our results reinforce the hypothesis of the participation ofT lymphocytes in the modulation of the Sephadex-induced in flammatory response. However, the mechanisms involved in such a modulation deserve further study.…”

Section: Discussionsupporting

confidence: 79%

“…superfine, Pharmacia) were sterilized under UV light for 15 min and suspended in sterile physiological saline (NaCl, 0.9%) to obtain the following concentrations: 3.30 and 55 mg/ ml. The highest concentration of beads was previously shown to in duce ex vivo bronchial hyperreactivity and infiltration o f leucocytes to the lungs o f guinea pigs [4].…”

Section: Preparation O F Sephadex Suspensionsmentioning

confidence: 99%

“…Castor oil injection did not per sc significantly alter the inflammatory effect o f Sephadex beads (5.5 mg/paw) injected into rat paws compared to saline-injectcd animals. Rapamycin at 5 mg/kg has previously been shown to inhibit leucocyte lung infiltration and ex vi vo hyperreactivity induced by Sephadex beads in guinea pigs [4].…”

Section: Administration O F Linmunosuppressor Drugsmentioning

confidence: 99%

“…This re sults suggested the participation of the immune system in the pathophysiology of the response to Sephadex beads in guinea pigs [4]. Sephadex beads are constituted by dextran polymers which were demonstrated to induce oedema in rat paws [6].…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological Characterization of Sephadex-lnduced Oedema in Rat Paws: Predominant Role of Serotonin and Platelet-Activating Factor

Francischi

Dias

Rocha

et al. 1996

Int Arch Allergy Immunol

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An intravenous injection of Sephadex beads has been used to induce lung inflammation and bronchial hyperreactivity in small animals. In the present study, we injected Sephadex beads (0.3–5.5 mg/paw) into rat paws and followed the resulting inflammation plethysmometrically. Our results show that Sephadex beads induced a significant and dose-dependent increase in the hindpaw volume at 5 min; it was maximal at 30–60 min and declined at 4 h. However, the paw volume remained significantly increased for up to 21 days. The initial 4-hour-oedema was confirmed by histopathology of the paw tissues, but the persistent increase in paw volume was related to a chronic inflammatory (granulomatous) response. The Sephadex-induced oedema was predominantly due to serotonin (5-HT) release since specific antagonists such as methysergide (1 mg/kg) and pizotifen (0.1–2 mg/kg) administered both systemically and locally were able to inhibit the oedema (10–100 µg/paw) as could pretreatment with compound 48/ 80. In addition, platelet-activating factor (PAF) was also shown to be involved, since systemic pretreatment using the specific PAF antagonist BN 52021 (1 mg/ kg) was able to inhibit the increase in paw volume induced by Sephadex. Effective doses of indomethacin (2 mg/kg), L-NAME (1 mg/kg), pyrilamine (1–2 mg/kg), ondansetron (1 mg/kg) and HOE 140 (1 mg/kg) did not affect the Sephadex-induced oedema, thus ruling out the participation of prostaglandins, nitric oxide, histamine, 5-HT3 receptors and bradykinin in its development. Since the late increases in paw volume induced by Sephadex were reduced by pretreatment of the animals with the immunosuppressive drugs rapamycin and dexamethasone but not cyclosporin, our results also suggested that distinct immunological pathways may be involved in the modulation of the chronic phase of inflammation induced by Sephadex beads in rat paws.

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Section: Discussionsupporting

confidence: 79%

Section: Preparation O F Sephadex Suspensionsmentioning

confidence: 99%

Section: Administration O F Linmunosuppressor Drugsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacological Characterization of Sephadex-lnduced Oedema in Rat Paws: Predominant Role of Serotonin and Platelet-Activating Factor

Francischi

Dias

Rocha

et al. 1996

Int Arch Allergy Immunol

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“…This procedure has previously been shown to induce a marked eosinophil infiltration in guinea pig lung associated with an increase in bronchial hyperresponsiveness (Francischi et al 1993). Eosinophils and eotaxin in lung tissue and BAL fluid were measured as described above for the allergic airways model.…”

Section: Eotaxin Generation and Eosinophil Accu-mulation In A Model Omentioning

confidence: 99%

The role of the eosinophil-selective chemokine, eotaxin, in allergic and non-allergic airways inflammation

Conroy

Humbles

Rankin

et al. 1997

Mem. Inst. Oswaldo Cruz

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Kinetics of eosinophilia and eosinophil activation in the development of non-allergic bronchial hyperresponsiveness in guinea pigs injected with Sephadex beads

et al. 1996

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Eosinophils are believed to play a crucial role in the pathogenesis of airway hyperresponsiveness (AHR). In the present study, the involvement of blood and pulmonary eosinophilia as well as the eosinophil activation in the onset of non-allergic AHR caused by the injection of G-50 Sephadex beads in guinea pigs was investigated. Reactivity of the isolated lower bronchus to histamine was measured ex vivo in a bioassay system. The increase of reactivity of the isolated lower bronchus of Sephadex-injected animals to histamine was observed as early as 3 h after the Sephadex injection and was maximal between 6-24 h. Sephadex-induced blood eosinophilia was characterized by two successive increases of blood eosinophil counts peaking at 3 and 12 h respectively. The recruitment of inflammatory cells into the lungs as measured in bronchoalveolar lavage fluid (BALF) have shown that the neutrophils were initially increased at 3 h whereas the number of eosinophils increased only 6 h after the bead injection; both cell populations were maximal 24 h later. Eosinophil peroxidase (EPO) activity was used as a marker for the apparent number of eosinophils in airways and the degree of activation of eosinophils recovered in BALF. Results have shown that EPO activity in the lower bronchus of Sephadex-injected animals increased at 6 h, decreased at 12 h and was maximal 24 h later. The EPO activity recovered in BALF was maximal between 6 to 24 h after the bead injection in guinea pigs. Correlation between the number of eosinophils and the EPO activity in BALF suggests that BALF eosinophils have been activated and have degranulated in airways. Correlation studies also indicated that both Sephadex induced blood eosinophilia and eosinophil activation were associated to the development of AHR. In contrast, the increase of EPO activity in the lower bronchus and BALF eosinophilia were not correlated to the development of AHR in our model. In conclusion, our results suggest that Sephadex induced non-allergic AHR in guinea pigs could be related, at least in part, to blood eosinophilia and eosinophil activation. Whether blood, airway and BALF eosinophilia as well as eosinophil activation are relevant factors to determine the potential role of eosinophils in the pathogenesis of AHR is discussed.

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Inhibition by rapamycin of leukocyte migration and bronchial hyperreactivity induced by injection of Sephadex beads to guinea‐pigs

Cited by 17 publications

References 21 publications

Pharmacological Characterization of Sephadex-lnduced Oedema in Rat Paws: Predominant Role of Serotonin and Platelet-Activating Factor

Pharmacological Characterization of Sephadex-lnduced Oedema in Rat Paws: Predominant Role of Serotonin and Platelet-Activating Factor

The role of the eosinophil-selective chemokine, eotaxin, in allergic and non-allergic airways inflammation

Kinetics of eosinophilia and eosinophil activation in the development of non-allergic bronchial hyperresponsiveness in guinea pigs injected with Sephadex beads

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