Nongenomic Mechanism For The Rapid Inhibitory Effects Of Glucocorticoids On Airway Smooth Muscle Contractions

Glucocorticoids (GCs), a group of hormones with physiological and pharmacological effects regulating a variety of growth, metabolic, developmental, and immune functions, play a pivotal role in preserving basal and stress-related homeostasis and also represent one of the most widely prescribed anti-inflammatory and immunomodulatory drugs in clinic. However, the molecular mechanism of GCs is still not so clear. Traditionally, it is believed that GCs exert most of their effects by genomical mechanism. Upon ligand binding, glucocorticoids receptor (GCR) translocates into the nucleus of cells, where it modulates the transcriptional activity of glucocorticoid-responsive genes in either of two ways: by binding to specific sequences in the promoter region of target genes, the glucocorticoid-response elements (GREs), or through protein-protein interactions with other transcription factors and several signal transducers and activators of transcription (STATs), that process that usually takes several hours. Recent evidence, however, indicates that GCs can also act at the membrane-level of cells to exert rapid non-genomic effects on various tissues and cells. Non-genomic effects are charactered as short latency and insensitive to inhibitors of DNA transcription or protein synthesis (e.g. actinomycin D or cycloheximide) compared to genomic effects. These phenomena also exist in therespiratory system, as we have reported that GCs can inhibit a pulmonary allergic reaction within 10 minutes.The common disease asthma is characterized by the obstruction, inflammation and increased sensitivity of the airways. Glucocorticoids (GCs) are one of the most potent anti-inflammatory agents available for treating allergic disease. In this study, we report that the GC budesonide (BUD) can rapidly inhibit the agonist-induced contractions of airway smooth muscle in a process mediated by non-genomicmechanisms.1. BUD significantly suppressed the increase in isometric tension induced by agonist in trachea segment rings within 15 min.2. BUD can reduce the histamine-induced shrinking of single ASMCs in 7 min.3. GCs significantly decreased the resting values and peak of [Ca +]i elevation induced by agonist in 10 min.4. GCs can elevate intracellular levels of phospho-PLC|3 (serl 105) in 10 min. Neither the glucocorticoid receptor antagonist RU486 nor the protein synthesisinhibitor cycloheximide could alter the inhibitory effects of glucocorticoids stated above. And RU486, cycloheximide or ethanol alone has not this inhibitory effectOur results demonstrate that glucocorticoids exert rapid inhibitory effects on ASMCs via a new mechanism that is independent of corticosteroid type II receptor occupation or protein synthesis. We infer that these effects may be very important for glucocorticoids' action during asthma therapy besides anti-inflammatory function. The series of signal changes in this process that restrain the peak of [Ca2+]i may be responsible for the rapid nongenomic inhibitory effects of GCs.