脂氧素受体及其介导的促炎症消退信号

炎症的及时消退是防止炎症走向慢性的关键,而脂氧素具有促进炎症消退的独特功效。脂氧素的抗炎促消退效应主要由其特异性受体所介导。脂氧素受体广泛表达于各类炎症相关细胞并受多种炎症刺激的调节,通过PKA、PKC、MAPK等一系列信号途径参与控制炎症的发生发展。     

消退素:内源性促炎症消退新介质

消退素是近期通过脂质组学方法从炎症消退期腹腔渗出液中分离出的由ω-3多不饱和脂肪酸衍生的生物活性分子。新近研究发现消退素具有限制中性粒细胞的过度活化和募集、促进巨噬细胞吞噬凋亡中性粒细胞等功效,并在脓毒症、哮喘等炎症动物模型中展示出良好的抗炎促消退效应。因而,消退素成为继脂氧素之后备受关注的内源性促炎症消退新介质。     

促炎症消退新介质：消退素与保护素

炎症启动（initiation）、发展之后的消退（resolution）是受到体内促消退介质（pro-resolving mediator）调控的主动过程。继发现由花生四烯酸衍生的脂氧素（lipoxin）后,新近又从炎症消退阶段的炎性渗出物中分离出由ω-3多不饱和脂肪酸转化而来的消退素（resolvin）与保护素（protectin）,它们也具有强效的抗炎促消退效应,成为促炎症消退介质的新成员。     

脂氧素——抗组织纤维化的新药物

组织纤维化是器官组织内纤维结缔组织增多而实质细胞减少的一类疾病,组织损伤导致的慢性炎症反应是纤维化形成的根本原因. 脂氧素是体内重要的内源性促炎症消退介质,兼具抗炎和促炎症消退双重作用,对多种炎症细胞和炎症相关基因有显著的负性调节作用,为炎症反应的重要“刹车信号”. 脂氧素可以促进炎症及时消退而防止其蔓延为慢性炎症,因此,它极有可能在抑制纤维化的形成中起到至关重要的作用.近年来,随着对脂氧素研究的不断深入,其抗纤维化作用日益凸显,成为极有价值的抗纤维化潜在药物.     

脂氧素与炎症消退

脂氧素是继前列腺素和白三烯后被证实的又一重要的花生四烯酸代谢产物,新近研究发现脂氧素对多种炎性细胞的功能和多种炎症相关基因的表达有广泛的调节作用,能促进炎症反应的及时消退,被认为是机体内一类重要的内源性脂质抗炎介质,因而在炎症,特别是炎症消退机制的研究中倍受关注。     

脂氧素与炎症的消退

脂氧素(lipoxin,LXs)又被称为脂肪氧合酶相互作用的产物,是在由损伤,感染,炎症等刺激引起的多细胞宿主反应中产生的,是含有三羟四烯结构的类花生酸类物质。LXs是第一个被确定和被克隆的类二十烷酸的并具有生物活性的內源脂质介质,是在体内细胞与细胞的相互作用中形成。目前许多研究发现,LXs能够调节多种炎症相关基因的表达和多种炎症细胞的功能,从而呈现出高效的的促炎症消退的作用。LXs这种独特的抗炎、促消退的功能,使得它成为近年来许多炎症研究的焦点。     

脂氧素的抗炎镇痛与神经保护作用研究进展

脂氧素是一类来源于花生四烯酸具有抗炎和促炎症消退的脂类介质。作为炎症过程中的负性调控因子,被广泛用于治疗各种急慢性炎症、疼痛、脑血管疾病及各种恶性肿瘤。该文将就其在抗炎镇痛和神经保护方面的研究进展作一综述。     

调控肺部炎症消退的内源性介质

炎症反应是宿主重要防御机制之一。慢性炎症或过度炎症反应可导致严重的肺部疾病,如哮喘、急性呼吸窘迫综合征等。新近研究表明炎症消退是一个主动过程,炎症的及时消退是防止炎症过强及走向慢性化的关键环节。因此,调控炎症消退的内源性介质成为新的研究热点。促进炎症消退内源性介质的发现不仅为肺部疾病研究提供新视野,也为全新的促炎症消退治疗策略防治肺部疾病提供理论依据。     

脂氧素A4受体在炎症中的作用

脂氧素A4受体是一种经典的G蛋白偶联受体;其表达在微观上受到转录和翻译水平的调节,在宏观上受到促炎与抗炎介质的调节以及药物、年龄等其它因素的影响。该受体主要表达于白细胞,结合多种激动性配体,调节炎症反应,在炎症中具有重要作用。本综述着重介绍脂氧素A4受体在炎症中所起的作用,并对该受体的称谓进行了简单的整理。     

脂联素在炎症性疾病中的研究进展

脂肪组织不仅是一个被动的能量储存的器官,它还是一个调节机体内分泌、能量代谢及炎症的内分泌器官.脂联素是由Scherer等于1995年在小鼠3T3-L1前脂肪细胞系的分化过程中分离克隆发现的主要由脂肪细胞分泌的一种内源性生物活性蛋白质.目前的研究表明脂联素具有抑制动脉粥样硬化、保护心血管系统、改善胰岛素抵抗、调节脂质代谢及抗炎等多种功能.现就脂联素的结构、基因表达调控以及它在动脉粥样硬化、心脏疾病、脂质代谢等肥胖引起的慢性炎症性疾病和自身免疫性疾病(如类风湿性关节炎,系统性红斑狼疮,克罗恩病)及急性肝炎等急性炎症性疾病中的作用作一综述.系统地介绍脂联素在各种炎症性疾病中发挥效用的机制,更好地认识脂联素的作用机理,为以后介入脂联素作用的调节过程、开发研究新药物等后续研究打下良好的基础.     

Immunoresolvents in asthma and allergic diseases: Review and update

Asthma and allergic diseases are inflammatory conditions developed by excessive reaction of the immune system against normally harmless environmental substances. Although acute inflammation is necessary to eradicate the damaging agents, shifting to chronic inflammation can be potentially detrimental. Essential fatty-acids-derived immunoresolvents, namely, lipoxins, resolvins, protectins, and maresins, are anti-inflammatory compounds that are believed to have protective and beneficial effects in inflammatory disorders, including asthma and allergies. Accordingly, impaired biosynthesis and defective production of immunoresolvents could be involved in the development of chronic inflammation. In this review, recent evidence on the anti-inflam]matory effects of immunoresolvents, their enzymatic biosynthesis routes, as well as their receptors are discussed.     

Cystic fibrosis and lipoxins

Dysregulated neutrophilic inflammation and chronic infection lead to progressive destruction of the airways in cystic fibrosis (CF). Despite considerable recent progress in therapy, the median survival of patients with CF remains around 30 years. The lipoxins are endogenous anti-inflammatory lipid mediators that are important regulators of neutrophilic inflammation. Recent data indicate that there is a pathophysiologically important defect in lipoxin-mediated anti-inflammatory activity in the CF airway, suggesting novel approaches to pathogenesis and therapy in this lethal genetic disease.     

Anti-inflammatory actions of lipoxin A4 and aspirin-triggered lipoxin are SOCS-2 dependent

Control of inflammation is crucial to prevent damage to the host during infection. Lipoxins and aspirin-triggered lipoxins are crucial modulators of proinflammatory responses; however, their intracellular mechanisms have not been completely elucidated. We previously showed that lipoxin A4 (LXA4) controls migration of dendritic cells (DCs) and production of interleukin (IL)-12 in vivo. In the absence of LXA4 biosynthetic pathways, the resulting uncontrolled inflammation during infection is lethal, despite pathogen clearance. Here we show that lipoxins activate two receptors in DCs, AhR and LXAR, and that this activation triggers expression of suppressor of cytokine signaling (SOCS)-2. SOCS-2-deficient DCs are hyper-responsive to microbial stimuli, as well as refractory to the inhibitory actions of LXA4, but not to IL-10. Upon infection with an intracellular pathogen, SOCS-2-deficient mice had uncontrolled production of proinflammatory cytokines, decreased microbial proliferation, aberrant leukocyte infiltration and elevated mortality. We also show that SOCS-2 is a crucial intracellular mediator of the anti-inflammatory actions of aspirin-induced lipoxins in vivo.     

Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators

Active resolution of acute inflammation is a previously unrecognized interface between innate and adaptive immunity. Once thought to be a passive process, the resolution of inflammation is now shown to involve active biochemical programmes that enable inflamed tissues to return to homeostasis. This Review presents new cellular and molecular mechanisms for the resolution of inflammation, revealing key roles for eicosanoids, such as lipoxins, and recently discovered families of endogenous chemical mediators, termed resolvins and protectins. These mediators have anti-inflammatory and pro-resolution properties, thereby protecting organs from collateral damage, stimulating the clearance of inflammatory debris and promoting mucosal antimicrobial defence.     

Biochemical aspects of inflammation

This review considers biochemical aspects of inflammation. The international literature until December 2006 has been analyzed, with the principal attention paid to the most dynamic problems: enzymology of inflammation, its regulation by hormones and signal transducers, and negative feedbacks, which underlie intensive current studies on pathogenesis, diagnostics, and therapy of inflammation. Such achievements as discoveries of defensins, toll-like receptors, interconnections of inflammation and iron metabolism, the roles of oxidative stress and antioxidant defense, lipoxins, inflammatory components of "non-inflammatory" diseases, and action mechanisms of effective drugs are discussed.     

SOCS2-induced proteasome-dependent TRAF6 degradation: a common anti-inflammatory pathway for control of innate immune responses

Pattern recognition receptors and receptors for pro-inflammatory cytokines provide critical signals to drive the development of protective immunity to infection. Therefore, counter-regulatory pathways are required to ensure that overwhelming inflammation harm host tissues. Previously, we showed that lipoxins modulate immune response during infection, restraining inflammation during infectious diseases in an Aryl hydrocarbon receptor (AhR)/suppressors of cytokine signaling (SOCS)2-dependent-manner. Recently, Indoleamine-pyrrole 2,3- dioxygenase (IDO)-derived tryptophan metabolites, including L-kynurenine, were also shown to be involved in several counter-regulatory mechanisms. Herein, we addressed whether the intracellular molecular events induced by lipoxins mediating control of innate immune signaling are part of a common regulatory pathway also shared by L-kynurenine exposure. We demonstrate that Tumor necrosis factor receptor-associated factor (TRAF)6--member of a family of adapter molecules that couple the TNF receptor and interleukin-1 receptor/Toll-like receptor families to intracellular signaling events essential for the development of immune responses--is targeted by both lipoxins and L-kynurenine via an AhR/SOCS2-dependent pathway. Furthermore, we show that LXA?- and L-kynurenine-induced AhR activation, its subsequent nuclear translocation, leading SOCS2 expression and TRAF6 Lys47-linked poly-ubiquitination and proteosome-mediated degradation of the adapter proteins. The in vitro consequences of such molecular interactions included inhibition of TLR- and cytokine receptor-driven signal transduction and cytokine production. Subsequently, in vivo proteosome inhibition led to unresponsiveness to lipoxins, as well as to uncontrolled pro-inflammatory reactions and elevated mortality during toxoplasmosis. In summary, our results establish proteasome degradation of TRAF6 as a key molecular target for the anti-inflammatory pathway triggered by lipoxins and L-kynurenine, critical counter-regulatory mediators in the innate and adaptive immune systems.     

Design, synthesis and bioactions of novel stable mimetics of lipoxins and aspirin-triggered lipoxins

The lipoxins (LX) are a class of potent endogenous oxygenated products that are enzymatically generated from arachidonic acid and have novel anti-inflammatory properties and promote resolution. Elucidation of the biochemical pathways involved in the metabolic inactivation of LX and the discovery of the aspirin-triggered lipoxins (ATL) provided the basis for the design and synthesis of stable analogs of LX and ATL. This special issue review describes the efforts that led to the design and synthesis of stable LX/ATL mimetics, which permitted the detailed elucidation of their novel biological roles, leading to the development of new anti-inflammatory agents that mimic their actions. These synthetic molecules provided the means to uncover the physiologic roles of both the LX and the ATL biosynthetic pathways which led to several unexpected discoveries. Among these findings is the involvement of polyisoprenyl phosphates (PIPP) in intracellular signaling mediated by presqualene diphosphate (PSDP), and the recognition of the novel roles of these lipid mediators in regulating cell trafficking during inflammation as well as in promoting resolution of inflammatory processes. These efforts also provided the basis for examining the potential therapeutic role of LX/ATL stable mimetics and led to the development of new analogs with improved pharmacokinetics that opened the way to potentially new approaches to treating human diseases.     

Liver: the formation and actions of aspirin-triggered lipoxins

Eicosanoids play a key role in the initiation, progression and resolution of the inflammatory response. Although most current anti-inflammatory strategies are focused on the pharmacological inhibition of pro-inflammatory eicosanoids, such as prostaglandins and leukotrienes, mounting evidence indicates the existence of potent endogenous eicosanoids able to control inflammation and orchestrate its resolution. The first eicosanoids recognized as anti-inflammatory compounds generated by our own organism were the lipoxins (LXs). More recently, a new series of carbon-15 epimers of LXs, with anti-inflammatory properties similar to those of native LXs, was identified during aspirin treatment. Since their formation is specific to this venerable non-steroidal anti-inflammatory drug, the term aspirin-triggered LXs (ATLs) was coined for these compounds. This chapter deals with the biosynthesis of LXs and ATLs in the liver, the largest solid organ/gland in the body, and discusses the most relevant actions of these lipid mediators in the context of liver inflammation and injury.     

Regulation of inflammation in cancer by eicosanoids

Inflammation in the tumor microenvironment is now recognized as one of the hallmarks of cancer. Endogenously produced lipid autacoids, locally acting small molecule lipid mediators, play a central role in inflammation and tissue homeostasis, and have recently been implicated in cancer. A well-studied group of autacoid mediators that are the products of arachidonic acid metabolism include: the prostaglandins, leukotrienes, lipoxins and cytochrome P450 (CYP) derived bioactive products. These lipid mediators are collectively referred to as eicosanoids and are generated by distinct enzymatic systems initiated by cyclooxygenases (COX 1 and 2), lipoxygenases (5-LOX, 12-LOX, 15-LOXa, 15-LOXb), and cytochrome P450s, respectively. These pathways are the target of approved drugs for the treatment of inflammation, pain, asthma, allergies, and cardiovascular disorders. Beyond their potent anti-inflammatory and anti-cancer effects, non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 specific inhibitors have been evaluated in both preclinical tumor models and clinical trials. Eicosanoid biosynthesis and actions can also be directly influenced by nutrients in the diet, as evidenced by the emerging role of omega-3 fatty acids in cancer prevention and treatment. Most research dedicated to using eicosanoids to inhibit tumor-associated inflammation has focused on the COX and LOX pathways. Novel experimental approaches that demonstrate the anti-tumor effects of inhibiting cancer-associated inflammation currently include: eicosanoid receptor antagonism, overexpression of eicosanoid metabolizing enzymes, and the use of endogenous anti-inflammatory lipid mediators. Here we review the actions of eicosanoids on inflammation in the context of tumorigenesis. Eicosanoids may represent a missing link between inflammation and cancer and thus could serve as therapeutic target(s) for inhibiting tumor growth.