BML-111, a lipoxin receptor agonist, modulates the immune response and reduces the severity of collagen-induced arthritis

Objective: Lipoxins (LXs) are endogenous antiinflammatory and pro-resolving eicosanoids generated during various inflammatory conditions. Recent research has revealed the novel immunomodulatory function of LXs. The aim of this study is to investigate whether LXs modulate the pathogenesis of collagen-induced arthritis (CIA), a typical chronic immune-mediated inflammatory disease. Methods and results: CIA was induced in DBA/1 mice and BML-111, a lipoxin A ₄ receptor agonist, was administrated. Results indicated that compared with untreated CIA mice, both clinical disease activity scores and histological destruction of joint were significantly reduced in BML-111-treated CIA mice. The dampened joint injury was accompanied by decreased concentrations of serum pro-inflammatory cytokines tumor necrosis factor α and interleukin-6 in BML-111-treated CIA mice. In addition, proliferation of isolated spleen cells, as well as circulating levels of antibody to type II collagen, were reduced significantly in BML-111-treated CIA mice. Conclusion: BML-111 attenuated CIA in part by negatively regulating the immune response, which implicates the potential pharmacological value of LXs in the treatment of chronic immune-mediated inflammatory diseases such as RA. Received 30 July 2007; returned for revision 24 August 2007; received from final revision 14 September 2007; accepted by J. Di Battista 25 October 2007     

系膜增殖性肾炎中花生四烯酸产物对系膜细胞增殖的作用

在抗Ｔｈｙ１．１抗体引起的大鼠系膜增殖性肾炎中，肾小球的增殖性细胞核抗原（ＰＣＮＡ）阳性细胞增多，＾３Ｈ－胸腺嘧啶核苷（＾３Ｈ－ｔｈｙｍｉｄｉｎｅ，＾３Ｈ－ＴｄＲ）掺入法测定的肾小球增殖活性（ＧＰＡ）升高。对肾炎鼠给予５－脂氧合酶抑制剂ＭＫ８８６或血栓素（ＴＸＡ２）合成酶抑制剂Ｆｕｒｅｇｒｅｌａｔｅ或１２－脂氧合酶抑制剂Ｂａｉｃａｌｅｉｎ进行处理，可分别抑制肾小球合成的白三烯（ＬＴ）Ｂ４及１２－羟     

2,3,7,8-Tetrachlorodibenzo-p-dioxin treatment alters eicosanoid levels in several organs of the mouse in an aryl hydrocarbon receptor-dependent fashion

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) adversely affects many mammalian organs and tissues. These effects are mediated by the aryl hydrocarbon receptor (AHR). CYP1A1, CYP1A2 and CYP1B1 are upregulated by the liganded AHR. These (and other) cytochromes P450 can metabolize arachidonic acid into a variety of bioactive eicosanoids. Towards investigating a potential role of eicosanoids in TCDD toxicity, arachidonic acid, two other unsaturated long-chain fatty acids, and up to twenty-five eicosanoids were measured in five organs/tissues of male and female wild-type and Ahr null mice treated or untreated with TCDD. TCDD generally increased the levels of the four dihydroxyeicosatrienoic acids (DHETs) and (where measured) 5,6-epoxyeicosatrienoic acid and 18-, 19- and 20-hydroxyeicosatrienoic acids (HETEs) in the serum, liver, spleen and lungs, but not the heart, of both sexes, and increased the levels in the serum, liver and spleen of several metabolites that are usually considered products of lipoxygenase activity, but which may also be generated by cytochromes P450. TCDD also increased the levels of the esterified forms of these eicosanoids in the liver in parallel with the corresponding free forms. The levels of prostanoids were generally not affected by TCDD. The above changes did not occur in Ahr null mice, and are therefore mediated by the AHR. TCDD increased the mRNA levels of Cyp1a1, Cyp1a2, Cyp1b1 and the Pla2g12a form of phospholipase A₂ to varying degrees in the different organs, and these increases correlated with some but not all the changes in eicosanoids levels in the organs, suggesting that other enzymes may also be involved.     

重症胰腺炎二十碳烯酸的异常代谢与大黄素,施他宁的作用

目的：探讨重症胰腺炎（AHNP）胰组织出血、坏死与二十碳烯酸类的异常代谢关系。方法：以牛黄胆酸钠诱发大鼠AHNP模型，测定前列腺素E2（PGE2）、6-酮-前列腺素F1a（6－keto－PGE1a）、血栓烷B2（TXB2）等变化，并以大黄素、施他宁药物干预，以了解AHNP时二十碳烯酸类的异常代谢和上述药物的作用。结果：重症胰腺炎时血浆TXB2显著增高．发病6小时达假手术组的4．5倍，而6－keto－PGF1a或PGE2的测定值则呈降低趋势．应用大黄素或施他宁后，TXB2测定值显著降低，施他宁组TXB2测定值较之于大黄素组降低更为显著；6－keto－PGE1a和PGE2则呈上升趋势．给药两组12小时生存率高于非治疗组；给药两组胰腺细胞坏死等病理损害减轻．结论：大黄素和施他宁对AHNP时TXB2等异常代谢有明显调整作用，与此相关的改善微循环和细胞保护机制可能是两药治疗AHNP的重要药理基础；联合应用大黄素与施他宁可能会有协同作用．     

重症胰腺炎二十碳烯酸类的异常代谢与大黄素、生长抑素的作用

重症胰腺炎(AHNP)胰组织出血、坏死被认为与二十碳烯酸类的异常代谢有关。在牛磺胆酸钠诱发大鼠AHNP模型,测定前列腺素E_1(PGE_2)、6-酮-前列腺素F_2(6-keto-PGF_2),血栓烷B_2(TXB_2)等变化,并以大黄素、生长抑素进行药物干预,以了解AHNP时二十碳烯酸类的异常代谢和上述药物的作用,结果显示,重症胰腺炎时血浆TXB_2显著增高,发病6小时达假手术组的4.5倍,而6-keto-PGF或PGE的测定值则呈降低趋势。应用大黄素或生长抑素后,TXB_2测定值显著降低,生长抑素组TXB_2测定值较之于大黄素组降低更为显著:6-keto-PGF_1和PGE_2则呈上升趋势。给药两组12小时生存率显著高于非治疗组:病理组织学评分及电镜超微结构观察示给药两组腺细胞坏死等病理损害减轻。作者认为,大黄素和生长抑素对AHNP时TXB_2等异常代谢有明显调整作用,与此相关的改善微循环和细胞保护机制可能是两药治疗AHNP的重要药理基础:联合应用大黄素与生长抑素可能会有协同作用。     

New insights into the resolution of inflammation

The goal of treating chronic inflammatory diseases must be to inhibit persistent inflammation and restore tissue function. To achieve this we need to improve our understanding of the pathways that drive inflammation as well as those that bring about its resolution. In particular, resolution of inflammation is driven by a complex set of mediators that regulate cellular events required to clear inflammatory cells from sites of injury or infection and restore homeostasis. Indeed, it may be argued that dysfunctional resolution may underpin the aetiology of some chronic inflammatory disease and that a novel goal in treating such diseases is to develop drugs based on the mode of endogenous pro-resolution factors in order to drive on-going inflammation down a pro-resolution pathway. And while we are improving our understanding of the resolution of acute and chronic inflammation, much remains to be discovered. Here we will discuss the key endogenous checkpoints necessary for mounting an effective yet limited inflammatory response and the crucial biochemical pathways necessary to prevent its persistence and trigger its resolution. In doing so, we will provide an update on what is known about resolution of acute inflammation, in particular its link with adaptive immunity.     

Effects of cyclo-oxygenase inhibition on ozone-induced respiratory inflammation and lung function changes

Inhalation of O₃ causes airways neutrophilic inflammation accompanied by other changes including increased levels of cyclo-oxygenase products of arachidonic acid in bronchoalveolar lavage fluid (BALF). Ozone (O₃) exposure also causes decreased forced vital capacity (FVC) and forced expiratory volume after 1 s (FEV₁), associated with cough and substernal pain on inspiration, and small increases in specific airway resistance (SRAW). The spirometric decrements are substantially blunted by pretreatment with indomethacin. Since the O₃-induced decrement in FVC is due to involuntary inhibition of inspiration, a role for stimulation of nociceptive respiratory tract afferents has been suggested and cyclo-oxygenase products have been hypothesized to mediate this stimulation. However, the relation (if any) between the O₃-induced neutrophilic airways inflammation and decreased inspiratory capacity remains unclear. We studied the effects of pharmacologic inhibition of O₃-induced spirometric changes on the inflammatory changes. Each of ten healthy men was exposed twice (5-week interval) to 0.4 ppm O₃ for 2 h, including 1 h of intermittent exercise (ventilation 60l · min^–1). One-and-a-half hours prior to and midway during each exposure the subject ingested 800 mg and 200 mg, respectively, of the non-steroidal anti-inflammatory drug ibuprofen (IBU), or placebo [PLA (sucrose)], in randomized, double-blind fashion. Spirometry and body plethysmography were performed prior to drug administration, and before and after O₃ exposure. Immediately following postexposure testing, fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) was performed. Neither IBU nor PLA administration changed pre-exposure lung function. O₃ exposure (with PLA) caused a significant 17% mean decrement in FE₁ (P < 0.01) and a 56% increase in mean SRAW. Following IBU pretreatment, O₃ exposure induced a significantly lesser mean decrement in FEV₁ (7%) but still a 50% increase in mean SRAW. IBU pretreatment significantly decreased post-O₃ BAL levels of prostaglandin E₂ (PGE₂) by 60.4% (P < 0.05) and thromboxane B₂ (TxB₂) by 25.5% (P < 0.05). Of the proteins, only interleukin-6 was significantly reduced (45%, P < 0.05) by IBU as compared to PLA pretreatment. As expected, O₃ exposure produced neutrophilia in BALF. There was, however, no effect of IBU on this finding. None of the major cell types in the BALF differed significantly between pretreatments. We found no association between post-exposure changes of BALF components and pulmonary function decrements. We conclude that IBU causes significant inhibition of O₃-induced increases in respiratory tract PGE₂ and TxB₂ levels concomitant with a blunting of the spirometric response. This is consistent with the hypothesis that the products of AA metabolism mediate inhibition of inspiration. However, IBU did not alter the modest SRAW response to O₃. The neutrophilic component of the inflammatory response to O₃ was not significantly affected by IBU and does not appear to be directly related to the spirometric response.     

Actions of sulphasalazine and analogues on mucosal eicosanoid formation and metabolism in patients with ulcerative colitis

Sulphasalazine is the most widely prescribed drug for ulcerative colitis. Following oral administration sulphasalazine practically unabsorbed reaches the colon where it is split by colonie bacteria to 5-aminosalicylic acid and sulphapyridine. Although there is no doubt that 5-aminosalicylic acid is the active ingredient of sulphasalazine in ulcerative colitis, indications of disease-modifying effects of the intact molecule exist in rheumatoid arthritis. A substantial amount of evidence has accumulated that sulphasalazine and its analogues exert their therapeutic benefit in patients with ulcerative colitis through modulation of the formation and metabolism of eicosanoids, in particular leukotrienes, but they may also reduce inflammation by acting as inhibitors of platelet activating factor, interleukins, intestinal mast cell- and basophil cell-stimulated histamine release, in addition to being effective scavengers of the active oxygen species, suppressors of buturate metabolism, and modulators of polymorphonuclear leukocyte and lymphocyte functions. Although the mode of action of sulphasalazine and its analogues in ulcerative colitis is still incompletely understood, basic and clinical research into these multiactive compounds have paved the road for new drug development. Until then, sulphasalazine remains an effective means for the oral delivery to the colonie mucosa of the anti-inflammatory actions provided by mesalazine.     

Role of platelets and the arachidonic acid pathway in the regulation of neutrophil oxidase activity

The intercellular mechanisms involved in platelet-mediated regulation of neutrophil function remain incompletely understood. This study investigated the role of the arachidonic acid pathway in the modulation of chemoattractant-induced production of oxygen metabolites, measured as luminol-amplified chemiluminescence (CL). We demonstrate that platelets dose-dependently inhibit the CL response in neutrophils stimulated with N-formyl-methionyl-leucyl-phenylalanine (fMLP). Incubation with eicosatetrayonic acid (ETYA), a combined cyclooxygenase and lipooxygenase inhibitor, dramatically decreased the fMLP-induced CL response in neutrophils, an effect that was further enhanced in the presence of platelets. The separate effects of eicosatriyonic acid (ETI ) and indomethacin, specific inhibitors of lipoxygenase and cyclooxygenase, respectively, were significantly lower compared to the action of ETYA. On the contrary, impediment of arachidonic acid release with the phospholipase A 2 inhibitor arachidonyl trifluoromethyl ketone (ATK ) markedly increased the production of oxygen radicals triggered by fMLP. The addition of exogenous arachidonic acid clearly decreased the fMLP-induced CL response in neutrophils, which further strengthens a downregulating effect of arachidonic acid on oxidase activity. This inhibitory action of arachidonic acid, however, was reversed upon co-incubation with platelets. In conclusion, this study suggests that an accumulation of arachidonic acid, following chemotactic peptide stimulation, turns off neutrophil oxidase activity. Furthermore, platelets may support the synthesis of reactive arachidonic acid metabolites, which modulate oxygen radical production in neutrophils.