Dexamethasone Inhibits Respiratory Glycoconjugate Secretion from Feline AirwaysIn Vitroby the Induction of Lipocortin (Lipomodulin) Synthesis

Abstract

The effect of glucocorticoids on respiratory glycoconjugate (RGC) secretion was studied in a cat tracheal organ culture system. Dexamethasone (10(-5) to 10(-9) M) added to culture medium for 24 h caused a dose-related reversible inhibition of RCG of as much as 40% with a peak effect at 24 to 60 h after initiation of dexamethasone treatment. A monoclonal antilipocortin antibody added to the cultures blocked the inhibitory effect of dexamethasone on RGC secretion and accelerated the reversal of the dexamethasone effect after discontinuation of dexamethasone treatment. A control antibody without antilipocortin activity had no effect on RGC secretion or dexamethasone-induced inhibition of RGC secretion. Measurement of the concentration of lipocortin in airways revealed a 220% increase after treatment with dexamethasone for 24 h. We conclude that dexamethasone inhibits RGC secretion through the induction of lipocortin synthesis.

Production of lipocortin‐like proteins by cultured human tracheal submucosal gland cells

“…This is the first evidence that lipocortin-like proteins can be produced and released by human airway submucosal secretory cells. This finding is consistent with a previous study [19] demonstrating that lipocortin is a possible mediator of the suppressive effect of dexamethasone on respiratory glycoconjugate secretion. Airway gland cells are known to be targets for glucocorticosteroids [20].…”

“…In airways, it is now becoming clear that human tracheal epithelial cells can produce several cyclooxygenase products such as 15-HETE and prostaglandin E2 [12][13][14][15], and may be partly responsible for the inflammatory diseases of the lung such as asthma. The anti-inflammatory actions of glucocorticoids include the inhibition of the release of arachidonic acid derivatives and the increase of lipocortin levels [40] associated with a significant reduction in respiratory glycoconjugate secretion [19]. Lipocortins are presumed to be responsible for the antiinflammatory effect of the corticosteroids (see [41] for refs).…”

“…Organ cultures (explants) of human [8] and cat [11] trachea, as well as human tracheal epithelium-cell cultures [12][13][14][15] generate numerous metabolites of arachidonic acid, predominantly prostaglandin E2 and 15-hydroxyeicosatetraenoic acid (15-HETE) which have powerful stimulatory effects on respiratory glycoconjugate secretion [8,9]. Glucocorticoids have been shown to inhibit secretion of mucus in asthmatic airways [16,17] and in in vitro experiments using human and cat airway explants [18,19]. Lundgren et al [19] speculated that the inhibitory action of dexamethasone on mucus glycoprotein secretion is mainly due to the inhibition of arachidonic acid product for-mation through the induction of lipocortin synthesis.…”

“…Glucocorticoids have been shown to inhibit secretion of mucus in asthmatic airways [16,17] and in in vitro experiments using human and cat airway explants [18,19]. Lundgren et al [19] speculated that the inhibitory action of dexamethasone on mucus glycoprotein secretion is mainly due to the inhibition of arachidonic acid product for-mation through the induction of lipocortin synthesis. Nevertheless, using whole airway explant cultures, it is impossible to know the cell types or tissues (surface ciliated cells, goblet cells, submucosal gland cells, migratory cells, vessels) responding to glucocorticoid treatment.…”

Detection of Lipocortin 1 in Human Lung Lavage Fluid: Lipocortin Degradation As a Possible Proteolytic Mechanism in the Control of Inflammatory Mediators and Inflammation

“…Our in vitro studies suggest that this degradation could be caused by one or more products of the PMN, while studies with a specific antibody indicate that this partially degraded Lc 1 lacks the N-terminal portion that we believe to be essential for full anti-inflammatory function in vivo and in cellular systems in vitro (Flower et al, unpublished observation). In previous studies, lipocortins have been detected in lung tissue from the rat (6), from cattle (7) and in feline tracheal rings (19). The most likely source of the Lc 1 detected in our lung lavage fluids is the AM, since studies in the rat (5,20) and on cell lines from various species (6) show that monocytes and macrophages are frequently rich sources of lipocortins.…”