脂氧素A_4通过调节炎症因子保护对乙酰氨基酚所致肝损伤

目的：了解脂氧素A4对对乙酰氨基酚致急性肝损伤的影响并探讨其机制。方法：取40只雄性新西兰大白兔随机分为对照组、PCM组、LXA4组、NAC组和LXA4＋NAC组,每组8只。造模后给予不同处理,测定血清AST、ALT;免疫组化染色检测肝组织TNF-α、IL-10和NF-κB p65表达。结果：脂氧素A4明显减轻肝组织损伤和肝细胞凋亡,降低血清AST、ALT,减少TNF-α和NF-κB的表达,提高IL-10的表达。结论：脂氧素A4能通过调节炎症因子减轻对乙酰氨基酚导致的急性肝损伤。     

CFTR: more than just a chloride channel

This review examines the cystic fibrosis transmembrane conductance regulator (CFTR) protein. After summarizing the ion channels regulated by CFTR, the review focuses on the functions of CFTR that do not relate directly to a disease mechanism based on a channelopathy. The key concept is that newly synthesized CFTR has to enter lipid vesicles which bud from the endoplasmic reticulum. This is abnormally low in DeltaF508 CFTR. Normal wild type vesicular CFTR enters a recycling pool of lipid vesicles which transiently dock with the apical membrane only for CFTR to be retrieved shortly after into a sub-apical recycling compartment. This retrieval is abnormally fast in DeltaF508 CFTR. The review discusses the relationship between this process and the difficult topic of fat metabolism and then explores the possible links between abnormal fatty acid turnover and inflammatory cascades that are abnormal in cystic fibrosis. Finally the review concentrates on the emerging functions of a protein kinase (AMP-activated kinase) which is bound near the C terminus of the CFTR protein whose functions could intergrate some of the abnormalities in lipid metabolism that result from mislocalization of CFTR in clinical disease.     

Shifting the paradigm from inhibitors of inflammation to resolvers of inflammation in periodontitis

An initial shift in our understanding of the basis of periodontal disease occurred early in the 2000s. The host response, rather than the bacterial burden, was the principal determinant of the disease. Microbial dysbiosis that occurs in periodontal disease results from a hyperinflammatory state in the host. A second shift in periodontal disease is taking place. This time in the realm of treatment strategies. Rather than targeting antimicrobials or inhibitors of individual inflammatory mediators, preclinical studies support using resolution pharmacology to convert the pro-inflammatory condition into a non-inflammatory one, thereby resolving both the local and systemic inflammation associated with periodontal disease. Here, I describe the bases for these shifts in paradigms.     

Lipoxin A4 levels in asthma: relation with disease severity and aspirin sensitivity

BACKGROUND: Lipoxin (LX) A4, an endogenous anti-inflammatory eicosanoid, has been found to be low in patients with severe asthma. However, few studies also suggested more diminished LX A4 levels in aspirin-exacerbated respiratory disease (AERD) when compared with aspirin-tolerant asthma (ATA). It is, therefore, currently not clear whether the asthma severity or the presence of AERD has a primary role in the disturbed LX metabolism. OBJECTIVE: To detect LX A4 and 15-epi-LX A4 levels in asthma patients with and without AERD of comparable severity. METHODS: The study groups consisted of 22 subjects with AERD, 22 subjects with ATA and 10 volunteers without asthma and aspirin sensitivity. Whole-blood samples were stimulated with calcium ionophore, A23187 (5 x 10(-5) m) and A23187 (5 x 10(-5) m)+aspirin (10(-4) m). LX A4 and 15-epi-LX A4 levels were analysed by the enzyme immune assay method. RESULTS: Severe asthma patients in both AERD [0.5 (0.8)] ng/mL and ATA [0.5 (0.45) ng/mL] groups showed diminished generation for LX A4 to stimulation with A23187 in comparison with other severity degrees in their groups (P=0.02 and 0.046, respectively). LX A4 generation in both severe groups was comparable with each other (P>0.05). Although severe cases with AERD showed a diminished capacity to generate 15-epi-LX A4, this did not reach statistical significance. CONCLUSION: This study indicated that diminished LX A4 generation was unique to severe asthma phenotype regardless of comorbid aspirin sensitivity. Clinical Implications Lower LX A4 levels in severe asthma would suggest a possibility for LX analogues as future treatment options in these patients.     

Akt1/p27kip1途径介导脂氧素A4抑制TNF-α所致的系膜细胞增殖

目的：研究脂氧素A4(LXA4)是否抑制肿瘤坏死因子-α(TNF-α)所致的肾小球系膜细胞增殖，并探讨LXA4作用的信号转导机制。方法：用不同浓度的脂氧素A4预外理培养的大鼠肾小球系膜细胞，再加入TNF-α(10ng／m1)共同孵育；或单用TNF-α刺激肾小球系膜细胞。用四甲基偶氮唑蓝(MTT)法检测细胞增殖；用RT-PCR法检测细胞周期素E与mRNA表达；用Westemblot检测308位苏氨酸(Thr308)磷酸化的蛋白激酶Aktl及细胞周期负调控蛋白P27^kipl表达量。结果：LXA4呈剂量依赖性地抑制TNF-α诱导的系膜细胞增殖。在系膜细胞增殖同时TNF-α引起的细胞周期素E的蛋白表达也被LXA4下调。LXA4减少TNF-α诱导的肾小球系膜细胞中308位苏氨酸磷酸化的Akt1蛋白。LXA4呈剂量依赖性地阻止TNF-α所致的P27^kipl表达下调。结论：LXA4能够抑制TNF-α所致的大鼠系膜细胞的增殖，其机制依赖于Akt1／P27^kipl信号转导途径。     

Serum Levels of Lipoxin A4 do not Predict the Development of Subsequent Asthma among Young Children with Acute Bronchiolitis

Background. Acute bronchiolitis frequently causes wheezing in infants and young children, although its relationship to asthma remains unclear. We hypothesized that serum lipoxin A₄ levels may be used as an early predictive biomarker of subsequent asthma in young children with acute bronchiolitis. Methods. We recruited 69 children who were divided into 3 groups: 47 children younger than 24 months with acute bronchiolitis as an experimental group (Group 1); 11 children aged 2–24 months with viral acute gastroenteritis as a non-allergic control group (Group 2); and 11 children older than 24 months with physician-diagnosed asthma exacerbations as an asthma control group (Group 3). We determined white blood cell counts, eosinophil counts, and serum levels of C-reactive protein, interleukin-4, interleukin-5, prostaglandin E₂, tumor necrosis factor-alpha, and lipoxin A₄. Results. The mean serum levels of lipoxin A₄ in the groups with acute bronchiolitis (1), acute gastroenteritis (2), and asthma (3) were 0.0430.028, 0.0540.015, and 0.0510.031 ng/ml, respectively. When compared by t-tests, there were no significant differences between Groups 1 and 2, or Groups 1 and 3 (p0.05), despite a significant difference between Groups 2 and 3 (p=0.0392). In a final regression model, serum lipoxin A₄ levels were positively correlated with age, female gender, white blood cell counts, and interleukin-5 levels in all patients, while asthma patients had lower serum lipoxin A₄ levels compared to the other two groups. Conclusion. Serum levels of lipoxin A₄ cannot be used as an early predictive diagnostic marker for asthma in young children with acute bronchiolitis.     

脂氧素A_4对大鼠局部永久性脑缺血的保护作用

目的探讨脂氧素A4(lipoxinA4,LXA4)对大鼠局部永久性脑缺血损伤的保护作用。方法健康成年SD♂大鼠,体重200～250g,随机分为4组:假手术组(Sham),缺血模型组(Model),LXA410ng治疗组,LXA4100ng治疗组。用改良线栓法制备大鼠右侧大脑中动脉永久性缺血模型。Sham组插入栓线仅约10mm。大鼠于放线栓成功后10min内给予右侧侧脑室内注射等容量的LXA4(5μl)或生理盐水(5μl)。缺血24h后,评价神经功能缺损情况;2,3,5-氯化三苯四唑(TTC)染色观察脑梗死范围;分光光度计法测定缺血侧脑皮质丙二醛(MDA)含量和髓过氧化物酶(MPO)活性;ELISA法检测缺血侧皮质肿瘤坏死因子α(TNF-α)和白介素1β(IL-1β)的含量;HE染色观察脑组织病理学改变。结果LXA410ng、100ng能明显改善神经功能损伤症状,减少大鼠局部永久性缺血后脑梗死体积百分比,降低脑组织MPO活性以及MDA、TNF-α和IL-1β的含量,减轻脑组织病理学损伤,且LXA4100ng组在改善大鼠神经功能及抑制皮质TNF-α的表达上明显优于10ng组。结论LXA4对大鼠局部永久性脑缺血损伤有一定保护作用。