克拉霉素和地塞米松在不同类型CRS中作用的初步探讨
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摘要
研究目的:
慢性鼻-鼻窦炎（chronic rhinosinusitis，CRS）是耳鼻咽喉头颈外科常见的炎症反应性疾病。目前,临床多采用大环内酯类及糖皮质激素类药物来控制CRS症状，但其产生抗炎作用的机制以及二者作用的区别目前尚不十分清楚。在本研究中我们对比了克拉霉素及地塞米松刺激前后鼻粘膜组织所产生各种因子的含量变化，来进一步阐明大环内酯类药物及糖皮质激素在慢性鼻-鼻窦炎治疗中的作用及可能的作用机制。
研究方法：
1苏木精-伊红（HE）染色对手术样本石蜡切片进行组织形态观察及总炎性粒细胞和嗜酸性粒细胞计数。
2采用体外鼻黏膜组织块培养方法，分别给予克拉霉素及地塞米松刺激后.收集培养液上清及组织块，real time RT-PCR及ELISA检测相关因子的表达水平。
实验结果：
1根据嗜酸性粒细胞占总炎性细胞百分比，将伴鼻息肉的慢性鼻-鼻窦炎分为嗜酸性粒细胞性伴鼻息肉的慢性鼻-鼻窦炎（eosinophilic CRSwNP, EOS CRSwNP）及非嗜酸性粒细胞性伴鼻息肉的慢性鼻-鼻窦炎（noneosinophilic CRSwNP,NONEOS CRSwNP）
2RANTES、IL-5、IL-13、ECP在嗜酸粒细胞性伴鼻息肉的慢性鼻-鼻窦炎(EosCRSwNP)中明显上调。
3IFN-g、TNF-α、IL-1b在不伴有鼻息肉的慢性鼻-鼻窦炎（CRSsNP）中表达明显上调.
4克拉霉素对慢性鼻-鼻窦炎组织的重要上皮源性DCs调控分子、DCs表型、Th1、Th2、Th17、Treg的细胞因子及趋化因子、先天模式识别受体和组织结构重塑因、的调控作用与地塞米松基本一致。
结论：
Th2类炎性反应在嗜酸粒细胞性伴鼻息肉的慢性鼻-鼻窦炎(Eos CRSwNP)中明显增高，不伴有鼻息肉的慢性鼻-鼻窦炎（CRSsNP）表现出更为突出的Thl反应。克拉霉素与地塞米松在慢性鼻-鼻窦炎治疗中的作用基本一致。
Objective:
Chronic rhinosinusitis (CRS) is a common disease which is characterized by persistentinflammation of the sinonasal mucosa in otorhinolarynology head and neck. Currently, bothmacrolide antibiotics and nasal glucocorticoids have been used for control the symptom ofCRS，but the mechanism of its anti-inflammatory effect and what the difference between theeffect of macrolide and glucocorticoids remains unclear. Our study mainly focused on thedifference efficacy of clarithromycin and dexamethasone on broad panel of cytokines ofsinonasal mucosa prior to and late the stimulus. To further insight into the probablemechanisms behind the beneficial effects of clarithromycin and dexamethasone。
Methods:
1Hematoxylin-eosin（HE） stain was used for histology characteristics of surgicalsamples and count total inflammatory cells and eosinophils.
2Use of nasal mucosal Tissue explant culture measure, administrate clarithromycin or dexamethasone, then culture supernatant and nasal mucosal Tissue were collected aftertreatment. ELISA and real-time RT-PCR analysis were applied to detect the levels of relatedfactors.
Results:
1According to the percentage of eosinophils out of total inflammatory cells，we dividedthe CRSwNP patients’ tissue samples into eosinophilic CRSwNP and non-eosinophilicCRSwNP.
2RANTES、IL-5、IL-13and ECP display higher expression levels only in eosinophilicCRSwNP.
3IFN-g, TNF-α and IL-1b expression levels increased significantly in CRSsNP
4There was basically no difference between the groups undergo clarithromycin anddexamethasone treatment on expression level of chronic rhinosinusitis related innate patternrecognition receptors， tissue remodeling and reconstruction factors, DCs phenotype,critical epithelium-derived DCs regulated molecules and chemokine and cytokines of the Th1,Th2, Th17and Treg cells.
Conclusion:
It should be emphasized that Th2responses enhanced obviously in eosinophilic chronicrhinosinusitis with nasal polyps（Eos CRSwNP）, chronic rhinosinusitis without nasal polyps（CRSsNP） is confirmed to be a predominant Th1skewed inflammation. we found nosignificant difference in therapeutic efficacy between clarithromycin and dexamethasonetreatment。
慢性鼻-鼻窦炎（chronic rhinosinusitis，CRS）是耳鼻咽喉头颈外科常见的炎症反应性疾病。目前,临床多采用大环内酯类及糖皮质激素类药物来控制CRS症状，但其产生抗炎作用的机制以及二者作用的区别目前尚不十分清楚。在本研究中我们对比了克拉霉素及地塞米松刺激前后鼻粘膜组织所产生各种因子的含量变化，来进一步阐明大环内酯类药物及糖皮质激素在慢性鼻-鼻窦炎治疗中的作用及可能的作用机制。
研究方法：
1苏木精-伊红（HE）染色对手术样本石蜡切片进行组织形态观察及总炎性粒细胞和嗜酸性粒细胞计数。
2采用体外鼻黏膜组织块培养方法，分别给予克拉霉素及地塞米松刺激后.收集培养液上清及组织块，real time RT-PCR及ELISA检测相关因子的表达水平。
实验结果：
1根据嗜酸性粒细胞占总炎性细胞百分比，将伴鼻息肉的慢性鼻-鼻窦炎分为嗜酸性粒细胞性伴鼻息肉的慢性鼻-鼻窦炎（eosinophilic CRSwNP, EOS CRSwNP）及非嗜酸性粒细胞性伴鼻息肉的慢性鼻-鼻窦炎（noneosinophilic CRSwNP,NONEOS CRSwNP）
2RANTES、IL-5、IL-13、ECP在嗜酸粒细胞性伴鼻息肉的慢性鼻-鼻窦炎(EosCRSwNP)中明显上调。
3IFN-g、TNF-α、IL-1b在不伴有鼻息肉的慢性鼻-鼻窦炎（CRSsNP）中表达明显上调.
4克拉霉素对慢性鼻-鼻窦炎组织的重要上皮源性DCs调控分子、DCs表型、Th1、Th2、Th17、Treg的细胞因子及趋化因子、先天模式识别受体和组织结构重塑因、的调控作用与地塞米松基本一致。
结论：
Th2类炎性反应在嗜酸粒细胞性伴鼻息肉的慢性鼻-鼻窦炎(Eos CRSwNP)中明显增高，不伴有鼻息肉的慢性鼻-鼻窦炎（CRSsNP）表现出更为突出的Thl反应。克拉霉素与地塞米松在慢性鼻-鼻窦炎治疗中的作用基本一致。
Objective:
Chronic rhinosinusitis (CRS) is a common disease which is characterized by persistentinflammation of the sinonasal mucosa in otorhinolarynology head and neck. Currently, bothmacrolide antibiotics and nasal glucocorticoids have been used for control the symptom ofCRS，but the mechanism of its anti-inflammatory effect and what the difference between theeffect of macrolide and glucocorticoids remains unclear. Our study mainly focused on thedifference efficacy of clarithromycin and dexamethasone on broad panel of cytokines ofsinonasal mucosa prior to and late the stimulus. To further insight into the probablemechanisms behind the beneficial effects of clarithromycin and dexamethasone。
Methods:
1Hematoxylin-eosin（HE） stain was used for histology characteristics of surgicalsamples and count total inflammatory cells and eosinophils.
2Use of nasal mucosal Tissue explant culture measure, administrate clarithromycin or dexamethasone, then culture supernatant and nasal mucosal Tissue were collected aftertreatment. ELISA and real-time RT-PCR analysis were applied to detect the levels of relatedfactors.
Results:
1According to the percentage of eosinophils out of total inflammatory cells，we dividedthe CRSwNP patients’ tissue samples into eosinophilic CRSwNP and non-eosinophilicCRSwNP.
2RANTES、IL-5、IL-13and ECP display higher expression levels only in eosinophilicCRSwNP.
3IFN-g, TNF-α and IL-1b expression levels increased significantly in CRSsNP
4There was basically no difference between the groups undergo clarithromycin anddexamethasone treatment on expression level of chronic rhinosinusitis related innate patternrecognition receptors， tissue remodeling and reconstruction factors, DCs phenotype,critical epithelium-derived DCs regulated molecules and chemokine and cytokines of the Th1,Th2, Th17and Treg cells.
Conclusion:
It should be emphasized that Th2responses enhanced obviously in eosinophilic chronicrhinosinusitis with nasal polyps（Eos CRSwNP）, chronic rhinosinusitis without nasal polyps（CRSsNP） is confirmed to be a predominant Th1skewed inflammation. we found nosignificant difference in therapeutic efficacy between clarithromycin and dexamethasonetreatment。
引文
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[1] LOTVALL J, PAWANKAR R, WALLACE DV, et al. We call for iCAALL:International Collaboration in Asthma, Allergy and Immunology[J]. J Allergy ClinImmunol,2012,129(4):904-5.
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[3] ATHMAN R, PHILPOTT D. Innate immunity via Toll-like receptors and Nodproteins[J]. Curr Opin Microbiol,2004,7(1):25-32.
[4] SHIOMORI T, YOSHIDA S, MIYAMOTO H, et al. Relationship of nasal carriage ofStaphylococcus aureus to pathogenesis of perennial allergic rhinitis[J]. J Allergy ClinImmunol,2000,105(3):449-54.
[5] CORREA RG, MILUTINOVIC S, REED JC. Roles of NOD1(NLRC1) and NOD2(NLRC2) in innate immunity and inflammatory diseases[J]. Biosci Rep,2012,32(6):597-608.
[6] KANNEGANTI TD, LAMKANFI M, NUNEZ G. Intracellular NOD-like receptors inhost defense and disease[J]. Immunity,2007,27(4):549-59.
[7] Van LIMBERGEN J, RUSSELL RK, NIMMO ER, et al. Contribution of theNOD1/CARD4insertion/deletion polymorphism+32656to inflammatory boweldisease in Northern Europe[J]. Inflamm Bowel Dis,2007,13(7):882-9.
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[9] GIRARDIN SE, BONECA IG, VIALA J, et al. Nod2is a general sensor ofpeptidoglycan through muramyl dipeptide (MDP) detection[J]. J Biol Chem,2003,278(11):8869-72.
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