Granulocyte Depletion and Dexamethasone Differentially Modulate Airways Hyperreactivity, Inflammation, Mucus Accumulation, and Secretion Induced by rmIL-13 or Antigen

Abstract

The intratracheal administration of interleukin (IL)-13 to hyperresponsive BP2 mice induces bronchopulmonary hyperreactivity (BHR), eosinophilia, mucus and MUC5AC accumulation, similar to those observed after ovalbumin (Ova) treatment when mice are immunized. mRNAs for IL-4 peaked at 6 h after Ova challenge, then vaned, whereas IL-13 expression was stable for a longer period, suggesting different effects. Inhalation of aerosolized methacholine by immunized mice 72-96 h after Ova reduced epithelial mucus content, and enriched the bronchoalveolar lavage fluid (BALF) mucus. The role of granulocytes for mucus accumulation was studied using vinblastine or the antigranulocyte antibody RB6-8C5, which interfered to a limited extent only with allergen-induced mucus accumulation. By contrast, eosinophilic and neutrophilic inflammation, as well as BHR, were completely suppressed. Granulocytes are thus involved in Ova-induced BHR, whereas mucus accumulation and BHR are unrelated. Granulocytes seem to be more implicated in rmIL-13-induced mucus, which is reduced by the antigranulocyte antibody, whereas BHR is unaffected. The glucocorticosteroid dexamethasone reduced all the parameters evaluated after Ova or after rmIL-13. Because the effects of IL-13 are glucocorticoid-sensitive, they probably involve secondary mechanisms.

Dexamethasone Effects in the Strongyloides venezuelensis Infection in A Murine Model

“…Glucocorticoids also suppress the expression of the arachidonic acid-liberating enzyme, cPLA, 11,14,18,38 that inhibits the production of lipid mediators, such as leukotrienes and prostaglandin. 19 This consequently leads to a decrease in the recruitment of inflammatory cells to the site of infection.…”

“…[11][12][13] Also, glucocorticoids inhibit immunoglobulin G (IgG), IgM, and IgA antibody synthesis, 14 phospholipase A2 enzyme (cPLA2) expression, and production of leukotrienes 15 and prostaglandins. 16 As a consequence, there is reduced neutrophil, eosinophil, and macrophage recruitment to the inflammatory site, impaired cell differentiation and survival, 8,17 decreased nitric oxide (NO) production, reduced expression of the adhesion costimulatory and major histocompatibility complex (MHC) molecules, 16,18,19 lowered pulmonary mucous secretion, 19 and impaired apoptosis. 20,21 However, glucocorticoids increase the expression of certain antiinflammatory proteins, such as lipocortin-1 and IL-10, 9 and the expression of the high-affinity receptor for leukotriene B 4 (BLT1), which increases the antiapoptotic effects of this lipid mediator.…”

Interleukin‐13 and ‐4 expression in the central airways of smokers with chronic bronchitis

“…IL-13 may act indirectly, through the activation of an l epidermal growth factor receptor cascade [7]. According to this hypothesis, SINGER et al [26] recently showed that, in mice, granulocyte depletion inhibited mucus accumulation induced by IL-13, suggesting a supportive role of these cells in mediating the effects of IL-13 on mucus. Mucus hypersecretion is believed to result, at least in part, from inflammation.…”

Stimulation of Airway Mucin Gene Expression by Interleukin (IL)-17 through IL-6 Paracrine/Autocrine Loop

“…In vivo models using transgenic mice (26) and intranasal (14) or intratracheal (27) injections of IL-13 consistently showed increased goblet cells in the airways of mice. However, one limitation of these in vivo experiments was their inability to determine the exact mechanism of how the cytokine affects mucin gene expression.…”