糖皮质激素受体在小鼠单纯疱疹病毒性面瘫中的表达变化
|
摘要
贝尔面瘫(Bell's palsy)一种急性单侧面神经麻痹,是最常见的面神经瘫痪,其病因不明,每年的发病率为11-40/100000,且大部分为30-45岁的中年人。贝尔面瘫最长见于怀孕及患有糖尿病、流行性感冒、受凉、上呼吸道感染等疾病的患者。尽管大部分患者能够痊愈,但仍有一部分患者出现持续的面部肌肉功能紊乱、造成心理伤害及面部疼痛,因为贝尔面瘫具体的发病机制不清楚,所以治疗只是以面瘫后面神经肿胀等病理生理学为依据。因为1型单纯疱疹病毒(Herpes simplex virus type 1.HSV-1)具有很强的嗜神经性,并且能够从潜伏位置逆行运输到运动神经元,因此很多研究认为大多数的贝尔面瘫的病因是HSV-1在膝状神经节潜伏感染后被激活导致的神经炎性造成。对面神经颞骨段得组织病理学研究发现,贝尔面瘫患者的膝状神经节有大量病毒复制,面神经运动纤维存在脱髓鞘反应。面神经包含运动神经纤维和感觉神经纤维,支配耳廓后部的面神经感觉神经元位于膝状神经节。因此,耳廓背面的搔刮伤引起的免疫抑制反应可以促进在膝状神经节潜伏感染的HSV-1的激活。单纯疱疹病毒-1感染面神经核团附近的血旺氏引起病毒的复制和释放及神经纤维脱髓鞘,导致面神经骨管中面神经的炎性反应,最终导致贝尔面瘫。对于炎症性及免疫性疾病的治疗,糖皮质激素是最有效的治疗药物。糖皮质激素进入细胞后与细胞质中的糖皮质激素受体结合,糖皮质激素受体一旦结合配体后立即与伴侣分子分离,迅速进入细胞核发挥生物学效应。目前对于贝尔面瘫的治疗尚无明确的方案,临床资料表明,糖皮质激素对贝尔面瘫的预后有积极作用,能降低损伤诱发的神经免疫反应,降低神经损伤程度,有利于受损神经功能的恢复。此外,有学者通过实验研究发现糖皮质激素对于神经纤维的再生存在促进作用,且糖皮质激素对神经变性、神经保护和再生过程的影响,很大程度依赖于它们的浓度。但是应用糖皮质激素治疗病毒性面瘫的确切机制仍不明确,其用药时机、药量、疗程等均无较确切的方案,多凭个人经验进行治疗。本研究通过建立单纯疱疹病毒致面瘫的动物模型,探讨糖皮质激素受体在单纯疱疹病毒性面瘫小鼠面部运动皮层及面神经核团中的表达规律,揭示糖皮质激素对病毒性面瘫的治疗作用机制,指导临床上合理应用糖皮质激素治疗贝尔面瘫,防止激素抵抗现象具有指导意义。
目的：
探讨糖皮质激素受体(GR)在面瘫小鼠面部运动皮层及面神经核团中的表达变化规律。
方法：
选取89只4周龄Bulb/c雌性小鼠,质量13-14g。随机分为空白对照组(n=8只)和实验组(n=81只),实验组用26G针头在右耳廓背面近耳根处皮肤连续搔刮后,将25μL HSV-1接种创面上,空白对照组不做处理。分别于面瘫后6、12、24、48、72h、7d取面瘫后小鼠组织。采用蛋白质印迹法(western blot)、RT-PCR法、免疫组织化学技术方法检测小鼠中枢神经系统中糖皮质激素受体的表达变化规律。
结果：
实验组接种HSV-1后,其中44只出现周围性面瘫,面瘫率为54.32%。GR mRNA在面瘫后早期小鼠的大脑面部运动皮层及面神经核团中表达逐渐降低,6h达最低值,与对照组相比差异有统计学意义(P<0.05)。之后逐渐升高,于48h达峰值,与对照组相比差异有统计学意义(P<0.01)。之后又逐渐降低,7d时已接近对照组,但其差异无统计学意义(P>0.05)。GR mRNA表达变化规律与GR蛋白表达变化相一致。免疫组织化学显示在面神经核团中可见糖皮质激素受体阳性细胞表达,并且也存在先降低后升高的变化规律。
结论：
病毒性面瘫后糖皮质激素受体表达水平呈动态变化,提示糖皮质激素受体表达水平与病毒感染致面神经损伤的进展密切相关,对于临床上合理应用糖皮质激素治疗贝尔面瘫,防止激素抵抗现象具有指导意义。
Bell's palsy is an acute unilateral paralysis of the facial nerve, and is considered the most common cause of facial nerve paralysis. Its cause is unknown but it affects 11-40 people per 100 000 in the population per annum, most commonly in the age group 30-45. The condition is most common among pregnant women and people who have diabetes, influenza, a cold or some other upper respiratory ailment. Although most recover, as many as 30% of people recovery with continuing facial disfigurement, psychological difficulties and sometimes facial pain. In the absence of an established pathophysiology:swelling and entrapment of the nerve. Some studies suggested that the mayority of Bell's palsy cases might be caused by reactivation of latent HSV-1 infection in the geniculate ganglion. Since HSV-1 is highly neurotropic, it travels retrogradely along motor nerves to the sensory ganglia where latency is established. Histopathological study of the intratemporal portion of the facial nerve showed that the virus replicated profusely in the neurons of the geniculate ganglion, and that the motor fibers of the facial nerve underwent demyelination in Bell's palsy. Facial nerve consists of motor and sensory fibers. Sensorial neurons of facial nerve, innervating the posterior auricle, are located in the geniculate ganglion. Therefore, it is considered that auricular scratch in combination with immunosuppression promotes the reactivation of the latently infected HSV-1 in the geniculate ganglion. Replicated and released viruses must infect Schwann cells adjacent to the facial motor nerve, causing demyelination. Subsequently, vigorous destruction of the facial nerve, which induces an inflammatory reaction in the narrow facial canal in the temporal bone, may exacerbate the paralysis. Glucocorticoids are the most effective anti-inflammation drugs available for the treatment many inflammtory and immune diseases. Glucocorticoids diffuse across the cell membrane and bind to glucocorticoid receptors(GR) in the cytoplasm. Upon ligand binding. GR are activated and released from chaperone proteins and rapidly translocate to the nuleus where they exert their molecular effects. Recently, there is no clear program for the treatment of Bell's palsy. The clinical data indicate that glucocorticoids have a positive effect for the prognosis of Bell's palsy. In addition, some scholars have found that glucocorticoids have large extent dependent of on their concentration for the regeneration of nerve fibers stimulated and nerve degeneration,nerve protection and regeneration. However, the exact mechanism is still not clear for treatment of Bell's palsy, the timing, dose, treatment options of their medication is not precise, more personal experience for treatment. Established animal model of facial paralysis caused by HSV-1, the expression of glucocorticoid receptor is researched in facial motor cortex and facial nucleus in mice infected with HSV-1, and reveal paralysis therapeutic mechanism for action of glucocorticoid on viral facial, and guide rational clinical treatment of Bell's palsy, and prevent the phenomenon of hormone resistance instructive.
Objective To establish an animal model of facial nerve palsy in mice induced by herpes simplex virus type 1 (HSV-1) infection so as to investigate the expression of glucocorticoid receptor (GR) in in the motor cortex and facial nucleus.
Methods A total of 89 four-week-old female Bulb/c mice were selected in this work. These animals were randomly divided into two groups, i.e., the control group without any intervention and the experimental group, in which 25μL HSV-1 was inoculated into the right auricle after scratching the surface of bilateral auricles with a 26 gauge needle. The tissues were taken out at 6 h,12 h,24 h,48 h,72 h, and 7 d after the appearance of facial nerve palsy. Western blot and immunohistochemistry were used to detect the level of GR protein, RT-PCR was used to measure the level of GR mRNA.
Results The incidence of facial nerve palsy was 52.3% among the 81 inoculated animals. GR was localized in facial nucleus.. GR mRNA expression in experimental group was slightly decreased after facial nerve palsy in the motor cortex and facial nucleus, sharply declined at 6 h, showing a significant difference compared with control group (P<0.05). The expression gradually reached a peak at 48 h, having a significant difference compared with control group (P<0.01). The expression eventually returned to the baseline level at and after 7 d, but, not showing a notable difference between the two groups (P>0.05).GR protein expression in experimental group was similar to GR mRNA.
Conclusions GR expression in response to HSV1 infection appears in a time-depend manner, indicating that GR expression level is closely related to the progress in HSV1-induced facial nerve palsy. Our findings may be of import clinic implication in the rational use of glucocorticoid and attenuation of the phenomenon of hormone resistance in treatment of Bell's facial paralysis.
目的：
探讨糖皮质激素受体(GR)在面瘫小鼠面部运动皮层及面神经核团中的表达变化规律。
方法：
选取89只4周龄Bulb/c雌性小鼠,质量13-14g。随机分为空白对照组(n=8只)和实验组(n=81只),实验组用26G针头在右耳廓背面近耳根处皮肤连续搔刮后,将25μL HSV-1接种创面上,空白对照组不做处理。分别于面瘫后6、12、24、48、72h、7d取面瘫后小鼠组织。采用蛋白质印迹法(western blot)、RT-PCR法、免疫组织化学技术方法检测小鼠中枢神经系统中糖皮质激素受体的表达变化规律。
结果：
实验组接种HSV-1后,其中44只出现周围性面瘫,面瘫率为54.32%。GR mRNA在面瘫后早期小鼠的大脑面部运动皮层及面神经核团中表达逐渐降低,6h达最低值,与对照组相比差异有统计学意义(P<0.05)。之后逐渐升高,于48h达峰值,与对照组相比差异有统计学意义(P<0.01)。之后又逐渐降低,7d时已接近对照组,但其差异无统计学意义(P>0.05)。GR mRNA表达变化规律与GR蛋白表达变化相一致。免疫组织化学显示在面神经核团中可见糖皮质激素受体阳性细胞表达,并且也存在先降低后升高的变化规律。
结论：
病毒性面瘫后糖皮质激素受体表达水平呈动态变化,提示糖皮质激素受体表达水平与病毒感染致面神经损伤的进展密切相关,对于临床上合理应用糖皮质激素治疗贝尔面瘫,防止激素抵抗现象具有指导意义。
Bell's palsy is an acute unilateral paralysis of the facial nerve, and is considered the most common cause of facial nerve paralysis. Its cause is unknown but it affects 11-40 people per 100 000 in the population per annum, most commonly in the age group 30-45. The condition is most common among pregnant women and people who have diabetes, influenza, a cold or some other upper respiratory ailment. Although most recover, as many as 30% of people recovery with continuing facial disfigurement, psychological difficulties and sometimes facial pain. In the absence of an established pathophysiology:swelling and entrapment of the nerve. Some studies suggested that the mayority of Bell's palsy cases might be caused by reactivation of latent HSV-1 infection in the geniculate ganglion. Since HSV-1 is highly neurotropic, it travels retrogradely along motor nerves to the sensory ganglia where latency is established. Histopathological study of the intratemporal portion of the facial nerve showed that the virus replicated profusely in the neurons of the geniculate ganglion, and that the motor fibers of the facial nerve underwent demyelination in Bell's palsy. Facial nerve consists of motor and sensory fibers. Sensorial neurons of facial nerve, innervating the posterior auricle, are located in the geniculate ganglion. Therefore, it is considered that auricular scratch in combination with immunosuppression promotes the reactivation of the latently infected HSV-1 in the geniculate ganglion. Replicated and released viruses must infect Schwann cells adjacent to the facial motor nerve, causing demyelination. Subsequently, vigorous destruction of the facial nerve, which induces an inflammatory reaction in the narrow facial canal in the temporal bone, may exacerbate the paralysis. Glucocorticoids are the most effective anti-inflammation drugs available for the treatment many inflammtory and immune diseases. Glucocorticoids diffuse across the cell membrane and bind to glucocorticoid receptors(GR) in the cytoplasm. Upon ligand binding. GR are activated and released from chaperone proteins and rapidly translocate to the nuleus where they exert their molecular effects. Recently, there is no clear program for the treatment of Bell's palsy. The clinical data indicate that glucocorticoids have a positive effect for the prognosis of Bell's palsy. In addition, some scholars have found that glucocorticoids have large extent dependent of on their concentration for the regeneration of nerve fibers stimulated and nerve degeneration,nerve protection and regeneration. However, the exact mechanism is still not clear for treatment of Bell's palsy, the timing, dose, treatment options of their medication is not precise, more personal experience for treatment. Established animal model of facial paralysis caused by HSV-1, the expression of glucocorticoid receptor is researched in facial motor cortex and facial nucleus in mice infected with HSV-1, and reveal paralysis therapeutic mechanism for action of glucocorticoid on viral facial, and guide rational clinical treatment of Bell's palsy, and prevent the phenomenon of hormone resistance instructive.
Objective To establish an animal model of facial nerve palsy in mice induced by herpes simplex virus type 1 (HSV-1) infection so as to investigate the expression of glucocorticoid receptor (GR) in in the motor cortex and facial nucleus.
Methods A total of 89 four-week-old female Bulb/c mice were selected in this work. These animals were randomly divided into two groups, i.e., the control group without any intervention and the experimental group, in which 25μL HSV-1 was inoculated into the right auricle after scratching the surface of bilateral auricles with a 26 gauge needle. The tissues were taken out at 6 h,12 h,24 h,48 h,72 h, and 7 d after the appearance of facial nerve palsy. Western blot and immunohistochemistry were used to detect the level of GR protein, RT-PCR was used to measure the level of GR mRNA.
Results The incidence of facial nerve palsy was 52.3% among the 81 inoculated animals. GR was localized in facial nucleus.. GR mRNA expression in experimental group was slightly decreased after facial nerve palsy in the motor cortex and facial nucleus, sharply declined at 6 h, showing a significant difference compared with control group (P<0.05). The expression gradually reached a peak at 48 h, having a significant difference compared with control group (P<0.01). The expression eventually returned to the baseline level at and after 7 d, but, not showing a notable difference between the two groups (P>0.05).GR protein expression in experimental group was similar to GR mRNA.
Conclusions GR expression in response to HSV1 infection appears in a time-depend manner, indicating that GR expression level is closely related to the progress in HSV1-induced facial nerve palsy. Our findings may be of import clinic implication in the rational use of glucocorticoid and attenuation of the phenomenon of hormone resistance in treatment of Bell's facial paralysis.
引文
1. McCormick DP. Herpes simplex virus as a cause of Bell's palsy.1972, Rev Med Virol,2000,10(5):285-289
2. Schirm J, Mulkens PS. Bell's palsy and herpes simplex virus. APMIS,1997, 105(11):815-823
3. Marra CM. Bell's palsy and Hsv-1 infaction. Muscle Nerve,1999, 22(11):1476-1478.
4. Gok U, Alpay HC, Akpolat N, et al, Comparisons of steroid, acyclovir, lipoprostoglandin E1 and steroid+acyclovir treatments in facial paralysis:a rat study. Int J Pediatr Otorhinolaryngol,2005,69(9):1199-204.
5. Atzema C, Goldman RD. Should we use steroids to treat children with Bell's palsy? Can Family Physician,2006,52:313-314.
6. Holland NJ, Weiner GM. Recent developments in Bell's palsy. Br Med J,2004, 329:553-557.
7. Baringer JR. Herpes simplex virus and Bell palsy. Ann Intern Med,1996, 124:63-65.
8. Axelsson S, Lindberg S, Stjernquist-Desstnik A. Outcome of treatment with valacyclovir and prednisone in patients with Bell's palsy. Ann Otol Rhinol Laryngol,2003,112:197-201.
9. Unlu Z, Aslan A, Ozbakkaloglu B, et al. Serologic examinations of hepatitis, cytomegalovirus, and rubella in patients with Bell's palsy. Am J PhysMed Rehabil,2003,82:28-32.
10. Murakami S, Mizobuchi M, Nakashiro Y, et al. Bell palsy and herpes simplex virus:identification of vital DNA in endoneurial fluid and muscle. Ann Intern Med,1996,124:27-30.
11. Ramsey MJ, Dersimonian R, Holtel MR, et al. Corticosteroid treatment for idiopathic facial nerve paralysis:a meta-analysis. Laryngoscope,2000, 110:335-341.
12. Sullivan FM, Swan IR, Donnan PT, er al. Early treatment with prednisolone or acyclovir in Bell's palsy. N Engl J Med,2007,357:1598-1607.
13. Tyler, K. L. Prednisolone-but not antiviral drugs--improves outcome in patients with Bell's palsy. Nat Clin Pract Neuro,2009,15:74-75.
14. Thomander L, Aldskogius H, Vahlne A, et al. Invasion of cranial nerves and brain stem by herpes simplex virus inoculated into the mouse tongue. Ann Otol Rhinol Laryngol,1988,97(5):554-558.
15. Sugita T, Murakami S, Yanagihara N, et al. Facial nerve paralysis induced by herpes simplex virus in mice:an animal model of acute and transient facial paralysis. Ann Otol Rhinol Laryngol,1995,104(7):574-581.
16. Honda N, Hato N, Takahashi H, et al. Pathophysiology of facial nerve paralysis induced by herpes simplex virus type 1 infection. Ann Otol Rhinol Laryngol,2002, 111:616-622.
17. Wakisaka H, Hato N, Honds N, et al. Demyelination associated with HSV-1 induced facial paralysis. Exp Neurol,2002,178(1):68-79.
18.王海波,冯红云,樊兆民,等.Ⅰ型单纯疱疹病毒致小鼠面神经麻痹的实验性研究。中华耳鼻咽喉头颈外科杂志,2006,41：13-16
19.刘稳,高志强,神平,等.单纯疱疹性面神经炎的动物模型.中华耳鼻咽喉头颈外科杂志,2006,41：17-20.
20. Umland SP, Schleimer RP, Johnston SL. Review of the molecular and cellular mechanisms of action of lucocorticoids for use in asthma. Pulm Pharmacol Ther, 2002,15:35-50.
21. Kingery WS, Castellote JM, Maze M. Methylprednisolone prevents the development of autotomy and neuropathic edema in rats, but has no effect on nociceptive thresholds. Pain,1999,80:555-566.
22. Koenig HL, Schumacher M, Ferzaz B, et al. Progesterone synthesis and myelin formation by Schwann cells. Science,1995,268:1500-1503.
23. Chan JR, Phillips 2nd LJ, GlaserM. Glucocorticoids and progestins signal the initiation and enhance the rate of myelin formation. Proc Natl Acad Sci USA, 1998,95:10459-10464.
24. De Kloet ER, Vreugdenhil E, Oitzl MS, et al. Brain corticosteroid receptor balance in health and disease. Endocr Rev,1998,19:269-301.
25. De Kloet ER, Van Acker SA, Sibug RM, et al. Brain mineralocorticoid receptors and centrally regulated functions. Kidney Int,2000,57:1329-1336.
26. Abraham I, Harkany T, Horvath K, Luiten P. Action of glucocorticoids on survival of nerve cells:promoting neuroregeneration or neuroprotection? J Neuroendocrinol,2001,13:749-760.
27.沈波,陶乐,朱志安。颅脑外伤后神经细胞糖皮质激素受体表达变化与激素抵抗。中华急诊医学杂志,2005,14：297-299.
28. Yan P, Xu J, Li Q, et al. Glucocorticoid receptor expression in the spinal cord after traumatic injury in adult rats. J Neurosci,1999,19(21):9355-9363.
29. Engstrom M, Berg T, Stjemquist-Desatnik A, et al. Prednisolone and valaciclovir in Bell's palsy:a randomised double-blind, placebo controlled,multicentre trial[J]. Lancet Neurology,2008,7(11):993-1000.
30. May M, Wette R, HardinW B, et al. The use of steroids in Bell's palsy:a prospective controlled study[J]. Laryngoscope 1976,86(8):1111-1122.
31. Abraham I, Harkany T, Horvath K, Luiten P. Action of glucocorticoids on survival of nerve cells:promoting neuroregeneration or neuroprotection? J Neuroendocrinol,2001,13:749-760.
32. Kumar R, Thompson EB. Gene regulation by the glucocorticoid receptor: structure function relationship. J Steroid Biochem Mol Biol.2005,94(5):383-394.
33. Beck IM, Vanden Berghe W, Vermeulen L, et al. Crosstalk in inflammation:the interplay of glucocorticoid receptor-based mechanisms and kinases and phosphatases. Endocr Rev.2009,30(7):830-882.
34. Rosenfeld MG, Lunyak VV, Glass CK Sensors and signals:a coactivator/ corepressor/ epigenetic code for integrating signal dependent programes of transcriptional response. Genes Dev,2006,20(11):1405-1428.
35. Pratt WB, Toft DO. Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery, Exp Biol Med. (Maywood) 2003 228(2):111-133.
36. Wang Z, Chen W, Kono E, et al. Garabedian MJ. Modulation of glucocorticoid receptor phosphorylation and transcriptional activity by a C-terminal-associated protein phosphatase. Mol Endocrinol.2007,21(3):625-634.
37. De Bosscher K. Selective Glucocorticoid Receptor modulators. J Steroid Biochem Mol Biol.2010,120(2-3):96-104.
38. Meijsing SH, Pufall MA, So AY, et al. DNA binding site sequence directs glucocorticoid receptor structure and activity. Science.2009,324(5925):407-410.
39. John S, Sabo PJ, Johnson TA, et al. Interaction of the glucocorticoid receptor with the chromatin landscape. Mol Cell.2008,29(5):611-624.
40. De Bosscher K, Haegeman G. Mol Endocrinol. Minireview:latest perspectives on antiinflammatory actions of glucocorticoids.2009,23(3):281-291.
41. Bougarne N, Paumelle R, Caron S, et al. PPARalpha blocks glucocorticoid receptor alpha-mediated transactivation but cooperates with the activated glucocorticoid receptor alpha for transrepression on NF-kappaB. Proc Natl Acad Sci USA.2009,106(18):7397-7402.
42. Ogawa S, Lozach J, Benner C, et al.Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell.2005,122(5):707-721.
43. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N Engl J Med.2005,353(16):1711-1723.
44. Gallagher P, Reid KS, Ferrier IN. Neuropsychological functioning in health and mood disorder:Modulation by glucocorticoids and their receptors. Psychoneuroendocrinology.2009,34:S 196-207.
45. Wang S, Lim G, Zeng Q, et al. Expression of central glucocorticoid receptors after peripheral nerve injury contributes to neuropathic pain behaviors in rats. J Neurosci, 2004,24(39):8595-8605.
46. Itoh M, Adachi M, Yasui H, et al. Nuclear export of glucocorticoid receptor is enhanced y c-Jun N-terminal kinase-mediated phosphorylation. Mol Endocrinol. 2002 Oct;16(10):2382-2392.
47. Neeck G, Renkawitz R, Eggert M. Molecular aspects of glucocorticoid hormone action in rheumatoid arthritis. Cytokines Cell Mol Ther.2002 Dec;7(2):61-69.
48. Wang S, Lim G, Zeng Q, et al. Central glucocorticoid receptors modulate the expression and function of spinal NMD A receptors after peripheral nerve injury. J Neurosci.2005 Jan 12;25(2):488-495.
1. GINA 2006 Workshop Report:Global strategy for asthma management and prevention. WHO/NHLBI workshop report:National Institutes of Health, National Heart, Lung and Blood Institute, Publication Number 95-3659; Updated 2004.
2. Bousquet J, van Cauwenberge P, and members of the ARIA Science Committee: Pharmacologic and anti-IgE treatment of allergic rhinitis. ARIA Update (in collaboration with GA2LEN) Allergy 61,1086-1096 (2006)
3. Fokkens W, Lund V, Mullol J, on behalf of the European Position Paper on Rhinosinusitis and Nasal Polyps group. European Position Paper on Rhinosinusitis and Nasal Polyps 2007. Rhinology Suppl 20,1-136 (2007)
4. Stahn C, Lowenberg M, Hommes DW, Buttgereit F:Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists. Mol Cell Endocrinol 275,71-78(2007)
5. Kino T:Tissue glucocorticoid sensitivity:Beyond stochastic regulation on the diverse actions of glucocorticoids. Horm Metab Res 39,420-424 (2007)
6. Lu NZ, Cidlowski JA:Translational regulatory mechanisms generate N-terminal glucocorticoid receptor isoforms with unique transcriptional target genes. Mol Cell 18,331-342(2005).
7. Lu NZ, Cidlowski JA:Glucocorticoid receptor isoforms generate transcription specificity. Trends Cell Biol 16,301-307 (2006)
8. Pujols L, Mullol J, Picado C:Alpha and beta glucocorticoid receptors:relevance in airway diseases. Curr Allergy Asthma Rep 7,93-99 (2007)
9. Duma D, Jewell CM, Cidlowski JA:Multiple glucocorticoid receptor isoforms and mechanisms of post-translational modification. J Steroid Biochem Mol Biol 102, 11-21 (2006)
10. Heitzer MD, Wolf IM, Sanchez ER, Witchel SF, DeFranco DB:Glucocorticoid receptor physiology. Rev Endocr Metab Disord 8,321-330 (2007)
11. Lewis-Tuffin LJ, Jewell CM, Bienstock RJ, Collins JB, Cidlowski JA:Human glucocorticoid receptor beta binds RU-486 and is transcriptionally active. Mol Cell Biol 27,2266-2282 (2007).
12. Neeck G, Renkawitz R, Eqqert M. Molecular aspects of glucocorticoid homone action in rheumatoid arthritis. Cytokines Cell Mol Ther,2002,7:61-69.
13. Haqendorf A, Koper JW, de Jong FH, et al. Expression of the human glucocorticoid receptor splice variants alpha, beta, and P in peripheral blood mononuclear leukocytes in healthy controls and in patients with hyper-and hypocortisolism. J Clin Endocrinol Metah,2005,90:6237-6243.
14. Cristiana S. Post-transcriptional and nongenomic effects of glucocorticoids. Proceed Am Society,2004,1:255-263.
15. Bartholome B, Spies CM, Caber T, et al. Membrane glucocorticoid receptor are expressed in normal human peripheral blood mononuclear cells and up-reglulated after in vitro stimulation and in patients with rheumatoid arthritis. FASEB J,2004,18:70-80.
16. Gametchu B, Chen F, Sackey F, et al. Plasma membrane-resident glucocorticoid receptors in rodent lymphoma and human leukemia models. Steroids,1999, 64:107-119.
17. Antonini SR, Latronico AC, Eliss LL, et al. Glucocorticoid receptor gene polymorphisms in ACTH-secteting pituitary tumours. Clin Endorcrinol.2002, 579:657-662.
18. Lane SJ, Lee TH. Mechanisms of corticosteroid resisitance in asthmatic patients. In Arch Allery Immunol,1997,113:193-195.
19. Barnes PJ. Molecular mechanisms and cellular effects of glucocorticosteroids. Immumol Allergy Clin North Am,2005,25:451-468.
20. Celec P. Nuclear factor kappa B-molecular biomedicine:the next generation. Biomedicine Pharmacotherapy,2005,58:365-371.
21. De Bosscher K, Vanden Berghe W, Vermeulen L. Glucocorticoids repress NF-kappaB-driven genes by disturbing the interaction of p65 with the basal transcription machinery, irrespective of coactivator levels in the cell. Proc Natl Acad Sci USA,2000,97:3919-3924.
22. Karolien De Bosscher, Wim Vanden Berghe, Guy Haegeman. The interplay between the Glucocorticoid Receptor and Nuclear Factor-k B or Activator Protien-l:Molecular Mechanisms for Gene Repression. Endocrine Reviews, 2003,24:488-522.
23. Hugo Leis, Angustias Page, Angel Ramfrez. Glucocorticoid receptor counteracts tumorigenic activity of akt in skin through interference with the phosphatidylinositol 3-kinase signaling pathway. Molecular Endocrinology,2004, 18:303-331.
24. Bruan A, Nicolas M, Munoz A. Glucocorticoid receptor-JNK interaction mediates inhibition of the JNK pathway by glucocorticoids. EMBO J,2003, 22:6035-6044.
25. Valia A, Darina H, Sheila F. Rapid effects of dexamethasone on intracellular pH and Na/H exchanger activity in human bronchial epithelial cells. Journal Biological Chemistry,2005,280:35807-35814.
26. Florian PL, Zhihong H, Jean CP. Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids. J Clinical Investigation,2002, 110:1729-1738.
27. Borski RJ. Nongenomic membrane action of glucocorticoids in vertebrates. Trends Endocrinol Metab,2000,11:427-436.
28. Buttgerrit F, Scheffold A. Rapid glucocorticoid effects on immune cells. Steroids, 2002,67(6):529-534.
2. Schirm J, Mulkens PS. Bell's palsy and herpes simplex virus. APMIS,1997, 105(11):815-823
3. Marra CM. Bell's palsy and Hsv-1 infaction. Muscle Nerve,1999, 22(11):1476-1478.
4. Gok U, Alpay HC, Akpolat N, et al, Comparisons of steroid, acyclovir, lipoprostoglandin E1 and steroid+acyclovir treatments in facial paralysis:a rat study. Int J Pediatr Otorhinolaryngol,2005,69(9):1199-204.
5. Atzema C, Goldman RD. Should we use steroids to treat children with Bell's palsy? Can Family Physician,2006,52:313-314.
6. Holland NJ, Weiner GM. Recent developments in Bell's palsy. Br Med J,2004, 329:553-557.
7. Baringer JR. Herpes simplex virus and Bell palsy. Ann Intern Med,1996, 124:63-65.
8. Axelsson S, Lindberg S, Stjernquist-Desstnik A. Outcome of treatment with valacyclovir and prednisone in patients with Bell's palsy. Ann Otol Rhinol Laryngol,2003,112:197-201.
9. Unlu Z, Aslan A, Ozbakkaloglu B, et al. Serologic examinations of hepatitis, cytomegalovirus, and rubella in patients with Bell's palsy. Am J PhysMed Rehabil,2003,82:28-32.
10. Murakami S, Mizobuchi M, Nakashiro Y, et al. Bell palsy and herpes simplex virus:identification of vital DNA in endoneurial fluid and muscle. Ann Intern Med,1996,124:27-30.
11. Ramsey MJ, Dersimonian R, Holtel MR, et al. Corticosteroid treatment for idiopathic facial nerve paralysis:a meta-analysis. Laryngoscope,2000, 110:335-341.
12. Sullivan FM, Swan IR, Donnan PT, er al. Early treatment with prednisolone or acyclovir in Bell's palsy. N Engl J Med,2007,357:1598-1607.
13. Tyler, K. L. Prednisolone-but not antiviral drugs--improves outcome in patients with Bell's palsy. Nat Clin Pract Neuro,2009,15:74-75.
14. Thomander L, Aldskogius H, Vahlne A, et al. Invasion of cranial nerves and brain stem by herpes simplex virus inoculated into the mouse tongue. Ann Otol Rhinol Laryngol,1988,97(5):554-558.
15. Sugita T, Murakami S, Yanagihara N, et al. Facial nerve paralysis induced by herpes simplex virus in mice:an animal model of acute and transient facial paralysis. Ann Otol Rhinol Laryngol,1995,104(7):574-581.
16. Honda N, Hato N, Takahashi H, et al. Pathophysiology of facial nerve paralysis induced by herpes simplex virus type 1 infection. Ann Otol Rhinol Laryngol,2002, 111:616-622.
17. Wakisaka H, Hato N, Honds N, et al. Demyelination associated with HSV-1 induced facial paralysis. Exp Neurol,2002,178(1):68-79.
18.王海波,冯红云,樊兆民,等.Ⅰ型单纯疱疹病毒致小鼠面神经麻痹的实验性研究。中华耳鼻咽喉头颈外科杂志,2006,41：13-16
19.刘稳,高志强,神平,等.单纯疱疹性面神经炎的动物模型.中华耳鼻咽喉头颈外科杂志,2006,41：17-20.
20. Umland SP, Schleimer RP, Johnston SL. Review of the molecular and cellular mechanisms of action of lucocorticoids for use in asthma. Pulm Pharmacol Ther, 2002,15:35-50.
21. Kingery WS, Castellote JM, Maze M. Methylprednisolone prevents the development of autotomy and neuropathic edema in rats, but has no effect on nociceptive thresholds. Pain,1999,80:555-566.
22. Koenig HL, Schumacher M, Ferzaz B, et al. Progesterone synthesis and myelin formation by Schwann cells. Science,1995,268:1500-1503.
23. Chan JR, Phillips 2nd LJ, GlaserM. Glucocorticoids and progestins signal the initiation and enhance the rate of myelin formation. Proc Natl Acad Sci USA, 1998,95:10459-10464.
24. De Kloet ER, Vreugdenhil E, Oitzl MS, et al. Brain corticosteroid receptor balance in health and disease. Endocr Rev,1998,19:269-301.
25. De Kloet ER, Van Acker SA, Sibug RM, et al. Brain mineralocorticoid receptors and centrally regulated functions. Kidney Int,2000,57:1329-1336.
26. Abraham I, Harkany T, Horvath K, Luiten P. Action of glucocorticoids on survival of nerve cells:promoting neuroregeneration or neuroprotection? J Neuroendocrinol,2001,13:749-760.
27.沈波,陶乐,朱志安。颅脑外伤后神经细胞糖皮质激素受体表达变化与激素抵抗。中华急诊医学杂志,2005,14：297-299.
28. Yan P, Xu J, Li Q, et al. Glucocorticoid receptor expression in the spinal cord after traumatic injury in adult rats. J Neurosci,1999,19(21):9355-9363.
29. Engstrom M, Berg T, Stjemquist-Desatnik A, et al. Prednisolone and valaciclovir in Bell's palsy:a randomised double-blind, placebo controlled,multicentre trial[J]. Lancet Neurology,2008,7(11):993-1000.
30. May M, Wette R, HardinW B, et al. The use of steroids in Bell's palsy:a prospective controlled study[J]. Laryngoscope 1976,86(8):1111-1122.
31. Abraham I, Harkany T, Horvath K, Luiten P. Action of glucocorticoids on survival of nerve cells:promoting neuroregeneration or neuroprotection? J Neuroendocrinol,2001,13:749-760.
32. Kumar R, Thompson EB. Gene regulation by the glucocorticoid receptor: structure function relationship. J Steroid Biochem Mol Biol.2005,94(5):383-394.
33. Beck IM, Vanden Berghe W, Vermeulen L, et al. Crosstalk in inflammation:the interplay of glucocorticoid receptor-based mechanisms and kinases and phosphatases. Endocr Rev.2009,30(7):830-882.
34. Rosenfeld MG, Lunyak VV, Glass CK Sensors and signals:a coactivator/ corepressor/ epigenetic code for integrating signal dependent programes of transcriptional response. Genes Dev,2006,20(11):1405-1428.
35. Pratt WB, Toft DO. Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery, Exp Biol Med. (Maywood) 2003 228(2):111-133.
36. Wang Z, Chen W, Kono E, et al. Garabedian MJ. Modulation of glucocorticoid receptor phosphorylation and transcriptional activity by a C-terminal-associated protein phosphatase. Mol Endocrinol.2007,21(3):625-634.
37. De Bosscher K. Selective Glucocorticoid Receptor modulators. J Steroid Biochem Mol Biol.2010,120(2-3):96-104.
38. Meijsing SH, Pufall MA, So AY, et al. DNA binding site sequence directs glucocorticoid receptor structure and activity. Science.2009,324(5925):407-410.
39. John S, Sabo PJ, Johnson TA, et al. Interaction of the glucocorticoid receptor with the chromatin landscape. Mol Cell.2008,29(5):611-624.
40. De Bosscher K, Haegeman G. Mol Endocrinol. Minireview:latest perspectives on antiinflammatory actions of glucocorticoids.2009,23(3):281-291.
41. Bougarne N, Paumelle R, Caron S, et al. PPARalpha blocks glucocorticoid receptor alpha-mediated transactivation but cooperates with the activated glucocorticoid receptor alpha for transrepression on NF-kappaB. Proc Natl Acad Sci USA.2009,106(18):7397-7402.
42. Ogawa S, Lozach J, Benner C, et al.Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell.2005,122(5):707-721.
43. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N Engl J Med.2005,353(16):1711-1723.
44. Gallagher P, Reid KS, Ferrier IN. Neuropsychological functioning in health and mood disorder:Modulation by glucocorticoids and their receptors. Psychoneuroendocrinology.2009,34:S 196-207.
45. Wang S, Lim G, Zeng Q, et al. Expression of central glucocorticoid receptors after peripheral nerve injury contributes to neuropathic pain behaviors in rats. J Neurosci, 2004,24(39):8595-8605.
46. Itoh M, Adachi M, Yasui H, et al. Nuclear export of glucocorticoid receptor is enhanced y c-Jun N-terminal kinase-mediated phosphorylation. Mol Endocrinol. 2002 Oct;16(10):2382-2392.
47. Neeck G, Renkawitz R, Eggert M. Molecular aspects of glucocorticoid hormone action in rheumatoid arthritis. Cytokines Cell Mol Ther.2002 Dec;7(2):61-69.
48. Wang S, Lim G, Zeng Q, et al. Central glucocorticoid receptors modulate the expression and function of spinal NMD A receptors after peripheral nerve injury. J Neurosci.2005 Jan 12;25(2):488-495.
1. GINA 2006 Workshop Report:Global strategy for asthma management and prevention. WHO/NHLBI workshop report:National Institutes of Health, National Heart, Lung and Blood Institute, Publication Number 95-3659; Updated 2004.
2. Bousquet J, van Cauwenberge P, and members of the ARIA Science Committee: Pharmacologic and anti-IgE treatment of allergic rhinitis. ARIA Update (in collaboration with GA2LEN) Allergy 61,1086-1096 (2006)
3. Fokkens W, Lund V, Mullol J, on behalf of the European Position Paper on Rhinosinusitis and Nasal Polyps group. European Position Paper on Rhinosinusitis and Nasal Polyps 2007. Rhinology Suppl 20,1-136 (2007)
4. Stahn C, Lowenberg M, Hommes DW, Buttgereit F:Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists. Mol Cell Endocrinol 275,71-78(2007)
5. Kino T:Tissue glucocorticoid sensitivity:Beyond stochastic regulation on the diverse actions of glucocorticoids. Horm Metab Res 39,420-424 (2007)
6. Lu NZ, Cidlowski JA:Translational regulatory mechanisms generate N-terminal glucocorticoid receptor isoforms with unique transcriptional target genes. Mol Cell 18,331-342(2005).
7. Lu NZ, Cidlowski JA:Glucocorticoid receptor isoforms generate transcription specificity. Trends Cell Biol 16,301-307 (2006)
8. Pujols L, Mullol J, Picado C:Alpha and beta glucocorticoid receptors:relevance in airway diseases. Curr Allergy Asthma Rep 7,93-99 (2007)
9. Duma D, Jewell CM, Cidlowski JA:Multiple glucocorticoid receptor isoforms and mechanisms of post-translational modification. J Steroid Biochem Mol Biol 102, 11-21 (2006)
10. Heitzer MD, Wolf IM, Sanchez ER, Witchel SF, DeFranco DB:Glucocorticoid receptor physiology. Rev Endocr Metab Disord 8,321-330 (2007)
11. Lewis-Tuffin LJ, Jewell CM, Bienstock RJ, Collins JB, Cidlowski JA:Human glucocorticoid receptor beta binds RU-486 and is transcriptionally active. Mol Cell Biol 27,2266-2282 (2007).
12. Neeck G, Renkawitz R, Eqqert M. Molecular aspects of glucocorticoid homone action in rheumatoid arthritis. Cytokines Cell Mol Ther,2002,7:61-69.
13. Haqendorf A, Koper JW, de Jong FH, et al. Expression of the human glucocorticoid receptor splice variants alpha, beta, and P in peripheral blood mononuclear leukocytes in healthy controls and in patients with hyper-and hypocortisolism. J Clin Endocrinol Metah,2005,90:6237-6243.
14. Cristiana S. Post-transcriptional and nongenomic effects of glucocorticoids. Proceed Am Society,2004,1:255-263.
15. Bartholome B, Spies CM, Caber T, et al. Membrane glucocorticoid receptor are expressed in normal human peripheral blood mononuclear cells and up-reglulated after in vitro stimulation and in patients with rheumatoid arthritis. FASEB J,2004,18:70-80.
16. Gametchu B, Chen F, Sackey F, et al. Plasma membrane-resident glucocorticoid receptors in rodent lymphoma and human leukemia models. Steroids,1999, 64:107-119.
17. Antonini SR, Latronico AC, Eliss LL, et al. Glucocorticoid receptor gene polymorphisms in ACTH-secteting pituitary tumours. Clin Endorcrinol.2002, 579:657-662.
18. Lane SJ, Lee TH. Mechanisms of corticosteroid resisitance in asthmatic patients. In Arch Allery Immunol,1997,113:193-195.
19. Barnes PJ. Molecular mechanisms and cellular effects of glucocorticosteroids. Immumol Allergy Clin North Am,2005,25:451-468.
20. Celec P. Nuclear factor kappa B-molecular biomedicine:the next generation. Biomedicine Pharmacotherapy,2005,58:365-371.
21. De Bosscher K, Vanden Berghe W, Vermeulen L. Glucocorticoids repress NF-kappaB-driven genes by disturbing the interaction of p65 with the basal transcription machinery, irrespective of coactivator levels in the cell. Proc Natl Acad Sci USA,2000,97:3919-3924.
22. Karolien De Bosscher, Wim Vanden Berghe, Guy Haegeman. The interplay between the Glucocorticoid Receptor and Nuclear Factor-k B or Activator Protien-l:Molecular Mechanisms for Gene Repression. Endocrine Reviews, 2003,24:488-522.
23. Hugo Leis, Angustias Page, Angel Ramfrez. Glucocorticoid receptor counteracts tumorigenic activity of akt in skin through interference with the phosphatidylinositol 3-kinase signaling pathway. Molecular Endocrinology,2004, 18:303-331.
24. Bruan A, Nicolas M, Munoz A. Glucocorticoid receptor-JNK interaction mediates inhibition of the JNK pathway by glucocorticoids. EMBO J,2003, 22:6035-6044.
25. Valia A, Darina H, Sheila F. Rapid effects of dexamethasone on intracellular pH and Na/H exchanger activity in human bronchial epithelial cells. Journal Biological Chemistry,2005,280:35807-35814.
26. Florian PL, Zhihong H, Jean CP. Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids. J Clinical Investigation,2002, 110:1729-1738.
27. Borski RJ. Nongenomic membrane action of glucocorticoids in vertebrates. Trends Endocrinol Metab,2000,11:427-436.
28. Buttgerrit F, Scheffold A. Rapid glucocorticoid effects on immune cells. Steroids, 2002,67(6):529-534.