Corticosteroids are potent anti-inflammatory agents, but the specific molecular 1 mechanisms accounting for their therapeutic efficacy in the treatment of asthma remain to be identified. Long-standing clinical observation suggests that glucocorticoids may@, act synergistically to potentiate the airway relaxant response to beta-adrenergic I agonists, and emerging evidence indicates that corticosteroids can regulate various cellular proteins that determine the degree of airway smooth muscle relaxation. This information, combined with independent observations that the airway's response to relaxant beta-adrenergic agents varies during post-natal development, raises two interrelates hypotheses: I. That corticosteroids modulate specific beta-adrenergic receptor-coupled and post-receptor transduction mechanisms regulating airway smooth muscle relaxation; and II. That the influence of glucocorticoids on these mechanisms varies in an age-dependent manner. In addressing these hypotheses, the influence of corticosteroids on airway beta-adrenergic function will be assessed in tissues isolated from newborn and adult rabbits. To determine whether corticosteroids modulate airway beta-adrenergic responsiveness, steroid effects will be examined with respect to modulation of: 1) responsiveness to beta-adrenoreceptor stimulation in tissues treated acutely (i.e., 1-6 hrs) or chronically (i.e., 24-48 hrs) with corticosteroids; 2) degradation pathways of beta-adrenergic agonists; 3) beta-adrenoreceptor radioligand-binding density and pharmacologic receptor reserve; 4) affinity of beta-adrenergic agonists to the receptor; 5) post-receptor mediated activation of adenylate cyclase; 6) the influence of inhibitory (G1) and stimulatory (G) guanine regulatory proteins, assayed both functionally and by specific labelling techniques; 7) the relative contribution of the electrogenic Na(+)-K(-) - pump coupled to beta-adrenoreceptor stimulation; and 8) synthesis of beta-adrenoreceptor and Na(+)-K(-) pump proteins, as indicated by changes in specific MRNA levels measured by Northern blot analysis. In separate studies, the influence of post-natal maturation on corticosteroid-induced modulation of airway smooth muscle relaxation will be further examined with respect to age-related changes in the above mechanisms. Collectively, the proposed studies will yield significant new insights into the mechanisms underlying corticosteroid-induced modulation of airway beta-adrenergic responsiveness and, thereby, ultimately provide a scientific basis for a more directed approach to the treatment of the bronchospasm in asthma.
| Omlor, G J; Quinn, L M; Schramm, C M (1996) Ontogeny of beta-adrenergic desensitization in rabbit tracheal smooth muscle. Pediatr Pulmonol 22:255-62 |
| Varlotta, L; Schramm, C M (1994) Maturation of catecholamine response and extraneuronal uptake in rabbit trachea. Am J Physiol 266:L217-22 |
| Schramm, C M; Grunstein, M M (1992) Assessment of signal transduction mechanisms regulating airway smooth muscle contractility. Am J Physiol 262:L119-39 |
| Schramm, C M; Chuang, S T; Grunstein, M M (1992) Maturation of inositol 1,4,5-trisphosphate receptor binding in rabbit tracheal smooth muscle. Am J Physiol 263:L501-5 |
