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Abstract

Representative glucocorticosteroids (GCS) and phosphodiesterase IV (PDE4) inhibitors were compared in several models of pulmonary inflammation ranging in severity. Lung tissue eosinophil peroxidase (EPO) levels rather than bronchoalveolar lavage fluid (BALF) EPO or eosinophil percentages were used to indicate eosinophil recruitment after intratracheal instillation of sephadex beads in rats or nebulized ovalbumin in sensitized guinea pigs. A single oral or intratracheal administration of a GCS was effective against mild and robust sephadex-induced eosinophilia whereas the PDE4 inhibitors evaluated appeared more effective in the milder sephadex models. The GCS were also more effective against sephadex-induced than ovalbumin-induced eosinophilia. The effectiveness of the GCS and PDE4 inhibitors improved when the severity of the ovalbumin-induced eosinophilia was decreased. Multiple day dosing also improved activity. These studies indicated that activity was influenced greatly by administration protocols, the severity of the inflammatory response and possibly the method used for estimating eosinophil recruitment.

Anti-Inflammatory Mechanisms of Glucocorticoids Targeting Granulocytes

“…In these experiments, dexamethasone was suggested to have its major effects through a mechanism involving c-Jun and the transcription factor AP-1. CCR3 (↓), CXCR4 (↑) [52,53] CD11b (↓) [54] EPO (↓) [46,47] FcRIII (CD16) (↓) [43] FcεRII (CD23) (↓) [44] Formyl-methionyl-leucyl-phenyalanine (↓) [41] IL-8 (↓), MCP-1 (↓) [41,42] LTC 4 (↓), cPLA 2 (↓) [48,49] Neutrophil β 2 integrins (↑), L-selectin (↓) [67] BLT1 (↑) [87] CD11b (↓) [73,74] CD18 (↓) [72] COX-2 (↓) [75] IL-8 (↓), MIP-1α (↓) [77][78][79][80][81] NOS2 (↓) [76] Basophil FLAP (↑) [106] Histamine (↓) [98] IL-4 (↓), IL-5 (↓), IL-13 (↓) [91,93,94] IL-6 (↓), IL-8 (↓) [102] ↑ signifies protein is increased by glucocorticoids, ↓ signifies protein is decreased by glucocorticoids Glucocorticoids can inhibit eosinophil activation by preventing the expression of Fc receptors, degranulation, formation of LTs and the release of eosinophil peroxidase (EPO). Interferon (IFN)γ can induce the expression of FcRIII (CD16) in human eosinophils [43].…”

“…In contrast, budesonide, in vivo, has been shown to reduce eosinophil degranulation [17]. Reduced eosinophil degranulation probably accounts, at least in part, for the reduced levels of tissue EPO seen in animal models of asthma [46] and in asthmatic patients [47]. Systemic prednisone (60 mg/day, 3 days) reduced LTC 4 production from freshly isolated human eosinophils [48].…”