Bronchodilator and anti‐inflammatory activities of glaucine: In vitro studies in human airway smooth muscle and polymorphonuclear leukocytes

Abstract

1 Selective phosphodiesterase 4 (PDE4) inhibitors are of potential interest in the treatment of asthma. We examined the eects of the alkaloid S-(+)-glaucine, a PDE4 inhibitor, on human isolated bronchus and granulocyte function. 2 Glaucine selectively inhibited PDE4 from human bronchus and polymorphonuclear leukocytes (PMN) in a non-competitive manner (K i =3.4 mM). Glaucine displaced [ 3 H]-rolipram from its highanity binding sites in rat brain cortex membranes (IC 50 *100 mM). 3 Glaucine inhibited the spontaneous and histamine-induced tone in human isolated bronchus (pD 2 *4.5). Glaucine (10 mM) did not potentiate the isoprenaline-induced relaxation but augmented cyclic AMP accumulation by isoprenaline. The glaucine-induced relaxation was resistant to H-89, a protein kinase A inhibitor. Glaucine depressed the contractile responses to Ca 2+ (pD' 2 *3.62) and reduced the sustained rise of [Ca 2+ ] i produced by histamine in cultured human airway smooth muscle cells (7log IC 50 *4.3). 4 Glaucine augmented cyclic AMP levels in human polymorphonuclear leukocytes challenged with N-formyl-Met-Leu-Phe (FMLP) or isoprenaline, and inhibited FMLP-induced superoxide generation, elastase release, leukotriene B 4 production, [Ca 2+ ] i signal and platelet aggregation as well as opsonized zymosan-, phorbol myristate acetate-, and A23187-induced superoxide release. The inhibitory eect of glaucine on superoxide generation by FMLP was reduced by H-89. 5 In conclusion, Ca 2+ channel antagonism by glaucine appears mainly responsible for the relaxant eect of glaucine in human isolated bronchus while PDE4 inhibition contributes to the inhibitory eects of glaucine in human granulocytes. The very low PDE4/binding site ratio found for glaucine makes this compound attractive for further structure-activity studies.

Neutrophilic airway inflammation and IL‐17

“…These radicals can increase the transcription of IL-8 mRNA, leading to IL-8 protein production, subsequent neutrophil recruitment and bronchial hyperresponssiveness in canine airways (29)(30)(31). This also supports the idea that neutrophils have a functional impact in the airways and lungs.…”

Neutrophils, interleukin-17A and lung disease

“…The production of cytotoxic reactive oxygen species by neutrophils is increased in patients with inflammatory lung diseases [90][91][92][93]. This is of interest as there is experimental evidence in mammals that reactive oxygen species can induce the transcription of the mRNA encoding neutrophil-recruiting cytokines, such as the functionally important neutrophil chemoattractant IL-8, leading to subsequent release of IL-8 and more neutrophil recruitment [94,95].…”

Role of Interleukin-17 and the Neutrophil in Asthma

“…In fact, neutrophils themselves can release IL-8 in response to pro-inflammatory stimuli present in asthmatic airways, such as eosinophil granule major basic protein [14, 15]. Finally, neutrophils can produce an elastase that constitutes one of the most potent secretagogues in airway gland cells known until today, thereby capable of contributing to airway gland hypersecretion in asthma [16, 17, 18, 19]. This elastase can also contribute to bronchial hyperresponsiveness and to tissue remodelling, as indicated in rodent airway models in vivo and in collagen gels in vitro [20, 21, 22, 23].…”