Ibe Basil O, Portugal Ada Mae, Raj J Usha
Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Int Arch Allergy Immunol. 2006;139(3):225-36. doi: 10.1159/000091168. Epub 2006 Jan 27.
Racemic albuterol is a mixture of (R)- and (S)-enantiomers of albuterol. Its pharmacological activity and clinical efficacy reside in the (R)-enantiomer (levalbuterol), but the (S)-enantiomer exacerbates airway reactivity in nonclinical models. The role of albuterols in airway smooth muscle cell (SMC) proliferation is not well understood.
The effect of levalbuterol on human bronchial SMC growth was compared with the effects of racemic albuterol and (S)-albuterol. Cells were fed albuterols and 3H-thymidine in 5% FBS and incubated for 24 h. The effect of (S)-albuterol on levalbuterol actions was also studied and so were the effects of cAMP/PKA, PI-3 kinase, NK-kappaB, and retinoblastoma (Rb) proteins on albuterols and human bronchial SMC proliferation.
Levalbuterol inhibited cell proliferation at low concentrations. The growth-inhibitory effect of levalbuterol occurs via activation of the cAMP/PKA pathway. Addition of (S)-albuterol to levalbuterol decreased the growth-inhibitory effect of levalbuterol, and (S)-albuterol attenuated levalbuterol-induced cAMP release by 65%. Levalbuterol inhibited NF-kappaB and Rb protein expressions. ICI-118551 abrogated the inhibitory properties of levalbuterol. The PAF receptor antagonist CV-3988 inhibited (S)-albuterol-induced cell growth, with no effect on levalbuterol.
Levalbuterol inhibits cell growth by activating the cAMP/PKA pathway and inhibiting PI-3 kinase, NF-kappaB and Rb protein expression, and (S)-albuterol induces cell growth by activating PAF-receptor-mediated cell signaling.
消旋沙丁胺醇是沙丁胺醇的（R）-和（S）-对映体的混合物。其药理活性和临床疗效存在于（R）-对映体（左沙丁胺醇）中，但（S）-对映体在非临床模型中会加剧气道反应性。沙丁胺醇在气道平滑肌细胞（SMC）增殖中的作用尚未完全了解。
比较了左沙丁胺醇与消旋沙丁胺醇和（S）-沙丁胺醇对人支气管SMC生长的影响。在含有5%胎牛血清的培养基中加入沙丁胺醇和3H-胸腺嘧啶核苷，培养细胞24小时。还研究了（S）-沙丁胺醇对左沙丁胺醇作用的影响，以及cAMP/PKA、PI-3激酶、NK-κB和视网膜母细胞瘤（Rb）蛋白对沙丁胺醇和人支气管SMC增殖的影响。
左沙丁胺醇在低浓度时可抑制细胞增殖。左沙丁胺醇的生长抑制作用是通过激活cAMP/PKA途径实现的。在左沙丁胺醇中加入（S）-沙丁胺醇可降低左沙丁胺醇的生长抑制作用，且（S）-沙丁胺醇可使左沙丁胺醇诱导的cAMP释放减少65%。左沙丁胺醇可抑制NF-κB和Rb蛋白表达。ICI-118551可消除左沙丁胺醇的抑制特性。PAF受体拮抗剂CV-3988可抑制（S）-沙丁胺醇诱导的细胞生长，对左沙丁胺醇无影响。
左沙丁胺醇通过激活cAMP/PKA途径并抑制PI-3激酶、NF-κB和Rb蛋白表达来抑制细胞生长，而（S）-沙丁胺醇通过激活PAF受体介导的细胞信号传导来诱导细胞生长。
