The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution

Studies into the mechanisms in resolution of self-limited inflammation and acute reperfusion injury have uncovered a new genus of pro-resolving lipid mediators coined specialized pro-resolving mediators (SPM) including lipoxins, resolvins, protectins and maresins that are each temporally produced by resolving-exudates with distinct actions for return to homeostasis. SPM evoke potent anti-inflammatory and novel pro-resolving mechanisms as well as enhance microbial clearance. While born in inflammation-resolution, SPM are conserved structures with functions discovered in microbial defense, pain, organ protection and tissue regeneration, wound healing, cancer, reproduction, and neurobiology-cognition. This review covers these SPM mechanisms and other new omega-3 PUFA pathways that open their path for functions in resolution physiology.     

Specialized pro-resolving mediators as modulators of immune responses

Specialized pro-resolving mediators (SPMs) are endogenous small molecules produced mainly from dietary omega-3 polyunsaturated fatty acids by both structural cells and cells of the active and innate immune systems. Specialized pro-resolving mediators have been shown to both limit acute inflammation and promote resolution and return to homeostasis following infection or injury. There is growing evidence that chronic immune disorders are characterized by deficiencies in resolution and SPMs have significant potential as novel therapeutics to prevent and treat chronic inflammation and immune system disorders. This review focuses on important breakthroughs in understanding how SPMs are produced by, and act on, cells of the adaptive immune system, specifically macrophages, B cells and T cells. We also highlight recent evidence demonstrating the potential of SPMs as novel therapeutic agents in topics including immunization, autoimmune disease and transplantation.     

特异性促炎症消退介质在炎症调控中的研究进展

特异性促炎症消退介质(specialized pro-resolving mediators,SPM)是一种由必需脂肪酸衍生而来的酶类物质,在组织炎症消退过程中发挥抑制炎症反应,促进炎症消退的作用。了解SPM在恢复感染组织中的机制及作用,有利于为SPM应用于宿主定向治疗提供理论依据。为此,本文将对促炎症介质对炎症的内源性调节作用进行综述。     

Endogenous galectin-1 and acute inflammation: emerging notion of a galectin-9 pro-resolving effect

The role of endogenous galectin-1 (Gal-1) in acute inflammation has been poorly investigated. We therefore performed the carrageenan-induced paw edema model in wild-type and Gal-1(-/-) mice. On subplantar injection of carrageenan, Gal-1(-/-) mice displayed a similar first phase of edema (≤24 hours) to wild-type mice; however, a much less pronounced second phase (48 to 96 hours) was evident in this genotype. This reduced inflammation was associated with lower paw expression of inflammatory genes and cell infiltrates. Analysis of galectin protein and mRNA expression revealed high expression of Gal-1 in wild-type paws during resolution (≥48 hours), with some expression of galectin-9 (Gal-9). Administration of stable Gal-1 to wild-type mice completely ablated the first phase of edema but was ineffective when administered therapeutically at the 24-hour time point. Conversely, Gal-9 administration did not alter the first phase of edema but significantly reduced the second phase when administered therapeutically. This suggests anti-inflammatory actions for both proteins in this model albeit at different phases of the inflammatory response. Collectively, these data indicate that the absence of endogenous Gal-1 results in an abrogated response during the second phase of the edema reaction.     

IL-6 and APPs: anti-inflammatory and immunosuppressive mediators

Acute inflammation is accompanied by changes in the concentrations of acute phase proteins (APPs), While much is known about the cytokines involved in the initiation of inflammation, less is known about the mediators involved in its resolution. Recent data suggest that interleukin 6 (IL-6) and IL-6-regulated APPs are anti-inflammatory and immuno-suppressive, and may negatively regulate the acute phase response.     

Nitro-fatty acids: novel anti-inflammatory lipid mediators

Nitro-fatty acids are formed and detected in human plasma, cell membranes, andtissue, modulating metabolic as well as inflammatory signaling pathways. Here wediscuss the mechanisms of nitro-fatty acid formation as well as their keychemical and biochemical properties. The electrophilic properties of nitro-fattyacids to activate anti-inflammatory signaling pathways are discussed in detail.A critical issue is the influence of nitroarachidonic acid on prostaglandinendoperoxide H synthases, redirecting arachidonic acid metabolism and signaling.We also analyze in vivo data supporting nitro-fatty acids aspromising pharmacological tools to prevent inflammatory diseases.     

肾上腺素对小鼠巨噬细胞中促炎／抗炎介质比值的影响

目的：研究肾上腺素对脂多糖（LPS）诱导的小鼠单核巨噬细胞株RAW264.7中促炎介质［肿瘤坏死因子（TNF-α）、一氧化氮（NO）、环加氧酶-2（COX-2）］和抗炎介质［血红素氧化酶-1（HO-1）、白介素10（IL-10）］表达及NF-κB活化的影响。 方法： 以10 μg/L的LPS刺激体外培养的RAW264.7细胞作为炎症模型，加入不同浓度的肾上腺素（1、5、10、50 μmol/L）孵育24 h后，收集培养上清并提取细胞总蛋白，酶联免疫法测定上清中TNF-α、IL-10浓度，Griess法检测上清NO含量(以NO2-/NO3-表示)，免疫印迹法检测细胞总蛋白中COX-2、HO-1、IκB-α的含量。 结果： 10 μg/L的LPS明显诱导TNF-α、NO(NO2-/NO3-)、COX-2、IL-10及HO-1的产生；LPS+肾上腺素组与LPS单独作用组相比促炎介质TNF-α、NO(NO2-/NO3-)、COX-2的表达量显著下降，而抗炎介质IL-10、HO-1的表达却明显增强；肾上腺素与LPS共同作用组中IκB-α的含量与单独LPS作用组相比无明显差异。 结论： 肾上腺素下调LPS诱导的巨噬细胞中促炎介质的表达同时促进抗炎介质的表达，这种效应并不通过影响NF-κB的活化来实现。     

Eicosanoids: lipid mediators of inflammation in transplantation

Eicosanoids are a family of lipid mediators derived from the metabolism of arachidonic acid. Eicosanoids, such as prostanoids and leukotrienes, have a wide range of biological actions including potent effects on inflammation and immunity. It has been almost 20 years since the first reports emerged suggesting a role for eicosanoids in transplantation. Since then, a number of functions have been ascribed to these mediators, ranging from immunomodulation to regulation of allograft hemodynamics. In this review, we will highlight the effects of eicosanoids in transplantation, focusing particularly on evidence provided by gene targeting studies. In the future, pharmacological manipulation of eicosanoids and their receptors may provide a novel approach for controlling inflammation and promoting allograft acceptance.     

Specialised lipid mediators and their targets

Inflammation is a complex process governed by the interaction of multiple cell types of the innate immune system and secreted mediators. Such mediators may act in a paracrine or autocrine fashion on target effector cells. An appropriate inflammatory response is characterised by dynamically regulated initiation, propagation and eventual resolution and restoration of tissue homeostasis. Dysregulation of any of these processes may underlie chronic inflammatory conditions such as atherosclerosis, diabetes and arthritis. Our growing understanding of the active processes underlying the resolution of inflammation suggest novel therapeutic paradigms. Here we review specialised lipid mediators and their targets which regulate such innate processes.     

调节自主神经系统:心血管疾病抗炎治疗的新领域

<正>目前普遍认为高血压、动脉粥样硬化、血脂异常、糖尿病等疾病的发生、发展和转归与炎症免疫反应有着密切联系。同时,心血管疾病中也伴有自主神经病变,表现为交感神经和迷走神经支配紊乱或结构损伤,其主要的病理特征是迷走神经张力减低而交感神经张力亢进。因此,改善自主神经紊乱同时减轻机体低度炎症反应将成为防治心血管疾病的重要方向。近60年的研究表明神经系统可接受免疫系统信号,并可传出神经冲动调节免疫系统活动。     

Consultation for the prevention of atherosclerotic diseases

We have conducted a population-based, long-term trial with the purpose of investigating risk factors for atherosclerotic diseases in a Japanese population, from 1996 (Niigata Study). Through the trial, we have learned what is going on at the initial phase of atherosclerotic diseases. This experience plays an important role in contributing to clinical decision-making. We are engaging ourselves in improving not only diagnoses but also therapies and research relating to atherosclerotic diseases. We are specialized in performing laboratory tests for lipid analysis such as the two-dimensional nondenaturing electrophoresis of lipoproteins, which is exclusively conducted in our laboratory. Three children with the oculocerebrorenal syndrome of Lowe, for example, were confirmed by these lipid analyses and also by gene analyses performed by us. Our potential goal is a regenerative or cellular therapy for patients with vascular insufficiency. We are now conducting basic research for angiogenesis.     

生物治疗 肿瘤治疗的新希望

生物治疗（Biotherapy）通常是指通过调动机体的防御机制或借助生物制剂的作用，以调节机体的生物学反应，从而抑制或阻止肿瘤生长的治疗方法。20世纪80年代，美国学者Oldham提出了生物反应调节（BRM）理论，以后生物治疗成为继手术、放疗、化疗之后的第四大肿瘤治疗模式。并因其安全、有效、毒副作用低等特点，被认为是本世纪肿瘤综合治疗模式中最活跃、最有前途的手段。     

Perspective: Resident physician wellness: a new hope

Residency training is a challenging period in a physician's career owing to a multitude of stressors perhaps not previously encountered. In some cases, these stressors may culminate in a state of burnout. In response, much has been written about the issues of personal wellness during residency training. Recently, duty hours reform has been the major focus of addressing resident wellness; however, this intervention has established little benefit and has created unintended negative consequences. Alternatively, an emerging solution may be the implementation of resident wellness programs into residency training. Such programs are defined by a combination of active and passive initiatives targeting the various domains of physical, mental, social, and intellectual wellness. In contrast to duty hours reform, resident wellness programs are generally free from controversy and have been shown to improve resident wellness and enhance empathy.This article highlights the salient causes of burnout as it applies to present-day resident physicians and the patient care they provide. Moreover, in the wake of the controversy surrounding duty hours reform, a novel approach to resident wellness involving structured resident wellness programs is discussed. Specifically included are the fundamental components of a wellness program, the advantages held over duty hours reform, methods to evaluate program efficacy, and the current evidence to support these initiatives. Formal wellness curricula, including an evaluative process, should be an integral component of physician training. These programs represent a new hope in the solution to the long-debated issue of burnout and wellness during residency training.     

Prevention of mitochondrial diseases: a hope through assisted reproductive technologies

Mitochondrial diseases are a heterogenic and poorly studied group of diseases, considered serious in most cases and currently without treatment. Although assisted reproduction proposed strategies to prevent them, such as pre-implantation genetic diagnosis, these techniques are not sufficiently successful. However, the recent publication of two assistedreproduction techniques – meiotic spindle transfer in nonhuman primates and pronuclear transfer in humans – generate a clear ray of hope for the prevention of these diseases. This review analyzes the characteristics and meaning of these new findings and their future clinical implications.     

Leukotrienes and atherosclerosis: new roles for old mediators

Lipid mediators generated from arachidonic acid through the action of 5-lipoxygenase have been known for over two decades and are implicated in a wide variety of inflammatory disorders. G-protein-coupled receptors mediate the effects of different leukotrienes in distinct cell types. Novel cellular and molecular targets were recently discovered for these mediators, with important consequences for the function of both adaptive and innate immune systems. These studies have outlined crucial new roles for leukotrienes in the recruitment of T lymphocytes and in the development of atherosclerotic lesions, suggesting novel mechanisms for their actions. Through the development of appropriate animal models, leukotrienes are becoming renewed targets for treatment of many inflammatory diseases including atherosclerosis.