Resolvin E1 Ameliorates Pulpitis by Suppressing Dental Pulp Fibroblast Activation in a Chemerin Receptor 23-dependent Manner

IntroductionTimely resolution of pulp inflammation is a prerequisite for the healing of inflamed dental pulp. Stromal cells, particularly fibroblasts, play a critical role in the inflammation resolution process. Resolvin E1 (RvE1) is a lipid-derived endogenous proresolution molecule that mediates this resolution process. In the present study, we investigated the effects of RvE1 on dental fibroblasts during the pathogenesis of pulpitis.MethodsThe pulp tissues in maxillary incisors of male Sprague-Dawley rats (N = 50) were exposed to the oral environment for 0, 9, 24, and 48 hours, after which they were treated with RvE1 or its vehicle. The inflammatory changes after 24 hours were assessed using hematoxylin-eosin staining, immunohistochemistry, enzyme-linked immunosorbent assay, and quantitative polymerase chain reaction. Chemerin receptor 23 (ChemR23) expression in rat pulp tissues and human dental fibroblasts was detected by immunofluorescence, Western blot analysis, and quantitative polymerase chain reaction. Finally, small interfering RNA-based knockdown studies were performed to evaluate the effects of RvE1 inhibition on proinflammatory genes and nuclear factor kappa B signaling of human dental pulp fibroblasts.ResultsEarly treatment (within 24 hours after pulp exposure) with RvE1 promoted a decline in the number of inflammatory cells and gene expression of proinflammatory cytokines. Moreover, it reduced ChemR23 expression in the fibroblastlike cells of inflamed pulp tissues. In vitro, ChemR23 was widely expressed in human dental fibroblasts. RvE1 significantly suppressed cytokine production by fibroblasts, with down-regulation of the nuclear translocation of nuclear factor kappa B p65 in these cells. Knockdown of ChemR23 almost abolished the anti-inflammatory effect of RvE1.ConclusionsRvE1 can suppress the activation of dental pulp fibroblasts in a ChemR23-dependent manner and inhibit inflammation in the relevant early stages of pulpitis.     

消退素D1抗三叉神经痛的研究

目的 探讨消退素D1的抗三叉神经痛作用。方法 健康SD大鼠按体质量随机分为模型组、消退素D1（30、90、270 μg/kg）组和苯妥英钠阳性对照组,采用脑内注射青霉素G钾致大鼠三叉神经痛模型,考察消退素D1抗三叉神经痛作用。健康SD大鼠按体质量随机分为假手术组、模型组、消退素D1（30、90、270 μg/kg）组和苯妥英钠阳性对照组,采用慢性压迫性损伤眶下神经致大鼠三叉神经痛模型,考察消退素D1抗三叉神经痛作用。结果 消退素D1（30、90、270 μg/kg）能够显著延长大鼠出现疼痛反应（发生尖叫、甩头和后肢抓挠面部）的潜伏期,减少大鼠60 min内的疼痛反应时间;能够显著升高慢性压迫性损伤大鼠眶下神经致三叉神经痛模型大鼠的疼痛反应阈值。结论 消退素D1具有抗三叉神经痛作用。     

Metabolism and biological production of resolvins derived from docosapentaenoic acid (DPAn-6)

17S-HDPAn-6 (17S-hydroxydocosa-4Z,7Z,10Z,13Z,15E-pentaenoic acid) and 10S,17S-HDPAn-6 (10S,17S-dihydroxydocosa-4Z,7Z,11E,13Z,15E-pentaenoic acid) are potent anti-inflammatory resolvins derived from DPAn-6 (docosapentaenoic acid n-6) and are analogous in structure and action to DHA (docosahexaenoic acid)-derived resolvins. These resolvins have proven to be potential drug candidates, albeit with therapeutic profiles that need optimization. The main objectives of this study were to evaluate key features of DPAn-6 derived resolvins that are important for therapeutic efficacy, demonstrate that these DPAn-6 resolvins could be produced naturally, and could therefore have physiological significance. Here we demonstrate biological production, examine pharmacokinetic profiles and identify key routes of metabolic inactivation of DPAn-6 derived resolvins. We compare their metabolic stability to a known resolvin, 17S-HDHA (17S-hydroxydocosa-4Z,7Z,10Z,13Z,15E,19Z-hexaenoic acid) and show that order of their stabilities is 10S,17S-HDPAn-6 > 17S-HDPAn-6 > 17S-HDHA. We show that both these compounds are not strong inhibitors of cytochrome-P450 enzymes. We evaluate activity of compounds in the delayed-type hypersensitivity model, results of which show that compounds need optimization for enhanced duration and magnitude of action. Analysis of the metabolic stability and identification of metabolites of these compounds could play an important role in the design of better analogs with longer durations of action and hence better efficacy.     

特异性促炎症消退介质在牙周炎中作用的研究进展

牙周炎是由牙菌斑生物膜引起的牙周支持组织的慢性炎症性疾病。特异性促炎症消退介质(SPM)是由多不饱和脂肪酸经酶促反应衍生而来的脂质介质,可积极调控炎症的消退,改变微生物组成,缓解疼痛并促进组织再生,有望在牙周炎防治中发挥辅助作用。本文就SPM的分类及作用机制进行综述,并总结了其在牙周组织炎症过程中作用的最新研究进展,以期为牙周炎发生发展机制的研究提供参考,为牙周炎的防治提供新的思路。     

Resolvins AT-D1 and E1 differentially impact functional outcome,post-traumatic sleep,and microglial activation following diffuse brain injury in the mouse

Traumatic brain injury (TBI) is induced by mechanical forces which initiate a cascade of secondary injury processes, including inflammation. Therapies which resolve the inflammatory response may promote neural repair without exacerbating the primary injury. Specific derivatives of omega-3 fatty acids loosely grouped as specialized pro-resolving lipid mediators (SPMs) and termed resolvins promote the active resolution of inflammation. In the current study, we investigate the effect of two resolvin molecules, RvE1 and AT-RvD1, on post-traumatic sleep and functional outcome following diffuse TBI through modulation of the inflammatory response.Adult, male C57BL/6 mice were injured using a midline fluid percussion injury (mFPI) model (6–10 min righting reflex time for brain-injured mice). Experimental groups included mFPI administered RvE1 (100 ng daily), AT-RvD1 (100 ng daily), or vehicle (sterile saline) and counterbalanced with uninjured sham mice. Resolvins or saline were administered daily for seven consecutive days beginning 3 days prior to TBI to evaluate proof-of-principle to improve outcome. Immediately following diffuse TBI, post-traumatic sleep was recorded for 24 h post-injury. For days 1–7 post-injury, motor outcome was assessed by rotarod. Cognitive function was measured at 6 days post-injury using novel object recognition (NOR). At 7 days post-injury, microglial activation was quantified using immunohistochemistry for Iba-1.In the diffuse brain-injured mouse, AT-RvD1 treatment, but not RvE1, mitigated motor and cognitive deficits. RvE1 treatment significantly increased post-traumatic sleep in brain-injured mice compared to all other groups. RvE1 treated mice displayed a higher proportion of ramified microglia and lower proportion of activated rod microglia in the cortex compared to saline or AT-RvD1 treated brain-injured mice. Thus, RvE1 treatment modulated post-traumatic sleep and the inflammatory response to TBI, albeit independently of improvement in motor and cognitive outcome as seen in AT-RvD1-treated mice. This suggests AT-RvD1 may impart functional benefit through mechanisms other than resolution of inflammation alone.     

Xuebijing Injection (血必净注射液) and Resolvin D1 Synergize Regulate Leukocyte Adhesion and Improve Survival Rate in Mice with Sepsis-Induced Lung Injury

Objective: To investigate the effect of combined application of Xuebijing Injection(血必净注射液, XBJ) and resolvin D1(RvD1) on survival rate and the underlying mechanisms in mice with sepsisinduced lung injury. Methods: The cecal ligation and puncture(CLP) method was used to develop a mouse sepsis model. Specific pathogen free male C57 BL/6 mice were randomly divided into 5 groups(n=20 each): sham, CLP, CLP+XBJ, CLP+RvD1 and CLP+XBJ+RvD1. After surgery, mice in the CLP+XBJ, CLP+RvD1 and CLP+XBJ+RvD1 groups were given XBJ(25 μL/g body weight), RvD1(10 ng/g body weight), and their combination(the same dose of XBJ and RvD1), respectively. In each group, 12 mice were used to observe 1-week survival rate, while the rest were executed at 12 h. Whole blood was collected for flow cytometric analysis of leukocyte adhesion molecules CD18, lung tissues were harvested for observing pathological changes, and testing the activity of myeloperoxidase(MPO) and the expression of intercellular cell adhesion molecule 1(ICAM-1). Results: Compared with the CLP group, the histopathological damage of the lung tissues was mitigated, MPO activity was decreased in the CLP+XBJ and CLP+RvD1 groups(P0.05). In addition, the 1-week survival rate was improved, proportion of CD18-expressing cells in whole blood and ICAM-1 protein expression in lung tissue were decreased in the CLP+XBJ+RvD1 group(P0.05 or P0.01). Conclusion: XBJ together with RvD1 could effectively inhibit leukocyte adhesion, reduce lung injury, and improve the survival rate of mice with sepsis.     

新型抗炎介质消退素与肾脏疾病

消退素是最近发现具有较强抗炎作用的长链多不饱和脂肪酸衍生物家族,可分为E类及阿司匹林触发型等.消退素能在肾组织中天然合成,外源性注射消退素D1可保护缺血再灌注诱发的肾损伤.消退素E1能有效对抗肾脏纤维化,抑制梗阻性肾病中肌成纤维细胞的增生.有研究提示消退素对肾移植排斥反应、内毒素相关肾损伤等具有一定治疗作用.本文就消退素在肾脏疾病领域的研究现状作一综述.     

Lipid mediator interplay: resolvin D1 attenuates inflammation evoked by glutathione-conjugated lipid peroxidation products

Non-enzymatic oxidation of cellular lipids, one of the characteristic features of inflammation, leads to formation of highly reactive and toxic α,β-unsaturated aldehydes, such as 4-hydroxy-trans-2-nonenal (HNE). Conjugation of HNE with reduced glutathione (GS-HNE) is widely believed to represent a form of detoxification. The study by Spite et al. in the current issue of the British Journal of Pharmacology shows that glutathiolation of HNE confers potent pro-inflammatory properties on this α,β-unsaturated aldehyde. They find that GS-HNE directly activates human neutrophil granulocytes in vitro and evokes peritonitis in mice. Pre-treatment with resolvin D1, which is derived from ω-3 fatty acids, markedly attenuated the peritoneal leukocyte accumulation and production of prostaglandins and leukotrienes induced by GS-HNE. Their findings have profound implications for the analysis of inflammation in describing the generation of a novel class of pro-inflammatory mediators, through glutathione-dependent metabolism of lipid-peroxidation products, and emphasize the therapeutic potential of resolvin D1 in inflammatory diseases.This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009     

Resolvins and protectins: mediating solutions to inflammation

Resolution of inflammation has historically been viewed as a passive process, occurring as a result of the withdrawal of pro-inflammatory signals, including lipid mediators such as leukotrienes and prostaglandins. Thus, most anti-inflammatory drugs have traditionally targeted primarily mediator pathways that are engaged at the onset of inflammation. Only recently has it been established that inflammation resolution is an active process with a distinct set of chemical mediators. Several clinical and epidemiological studies have identified beneficial effects of polyunsaturated fatty acids (PUFAs) for a variety of inflammatory diseases, yet without mechanistic explanations for these beneficial effects. Resolvins and protectins are recently identified molecules that are generated from ω-3 PUFA precursors and can orchestrate the timely resolution of inflammation in model systems. Dysregulation of pro-resolving mediators is associated with diseases of prolonged inflammation, so designing pharmacological mimetics of naturally occurring pro-resolving mediators offers exciting new targets for drug design. This review describes the discovery and synthesis of these novel lipid mediators, their receptors and mechanisms of action, and summarizes the studies to date that have uncovered roles for resolvins and protectins in disease states.This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009