Pulmonary non-Hodgkin’s lymphoma developed during long-term methotrexate therapy for rheumatoid arthritis

Methotrexate is effective in treating rheumatoid arthritis (RA). Some reports have discussed the possible association between methotrexate and lymphoma. Here, we report a case of pulmonary non-Hodgkin’s lymphoma (NHL) developed after 11?years’ methotrexate therapy for RA. Biopsy of the pulmonary mass demonstrated a diffuse large B-cell lymphoma. After withdrawal of methotrexate without any other intervention for 4?weeks, a significant reduction in the size of the lymphoma was observed. The causative relationship between methotrexate and pulmonary lymphoma is suggested by the persistent remission after stopping methotrexate therapy.     

Genetic analysis of the IL8 gene polymorphism (rs4073) in generalized aggressive periodontitis

ObjectivesInterleukin (IL)-8 is an important chemokine for regulation of the inflammatory response. A single nucleotide polymorphism (SNP) reference sequence (rs) 4073 in the IL8 gene has been shown to regulate IL-8 levels after stimulation with lipopolysaccharide. This study investigates the transmission pattern of the IL8 rs4073 risk allele A and its association with susceptibility to aggressive periodontitis (AgP) in families and in a case–control cohort of unrelated individuals from a Brazilian population.DesignGenotyping was performed by standard polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP) in 13 nuclear families and 184 unrelated subjects. Statistical analysis was performed using the transmission disequilibrium test (TDT) for the family dataset and Chi-square test and multivariate logistic regression modelling for the case–control dataset.ResultsTDT analyses did not detect evidence of over transmission of IL8 rs4073 alleles in affected and unaffected family members (allele T: 52%; allele A: 48%; p = 0.2252). How expected, analyses of cases and unrelated controls showed a significant and inverse association of age with AgP; however, a lack of association between genotypes, ethnic groups and generalized AgP was observed.ConclusionsThe SNP (rs4073) was not associated with AgP in unrelated individuals and there is no evidence of over transmission of the alleles in families with AgP, from Brazilian individuals.     

正压通气对OSAHS患者血清和呼出气冷凝液中内皮素-1及一氧化氮水平的影响

目的探讨自动调节持续气道正压通气(auto-CPAP)治疗对OSAHS患者血管内皮功能紊乱的影响。方法对确诊为OSAHS的实验组进行三个月auto-CPAP治疗,分别测定三个月前后两组血清及EBC中ET-1及NO水平,以及颈动脉内膜中层厚度(IMT)。结果实验组血清和EBC中ET-1水平以及EBC中NO水平均明显下降,IMT较前减少。血清和EBC中ET-1及NO水平与AHI等睡眠监测指标存在相关性。结论 EBC中ET-1及NO水平检测可了解OSAHS患者血管内皮功能紊乱,这种异常可以通过auto-CPAP治疗改善。     

丹参、人参及蛤蚧组方对大鼠肺纤维化凋亡基因作用的研究

目的 研究丹参、人参及蛤蚧组方对博莱霉素致大鼠肺间质纤维化模型凋亡基因的表达,探讨该组方抗肺纤维化的作用机制.方法 SD雄性大鼠50只随机分为对照组、模型组、醋酸泼尼松组、治疗Ⅰ组(低剂量组:丹参83 mg/kg、人参50mg/kg及蛤蚧50mg/kg)及治疗Ⅱ组(高剂量组:丹参166mg/kg、人参50mg/kg及蛤蚧50 mg/kg);于第28天处死大鼠,RT-PCR 法检测大鼠肺组织bax及bcl-2基因mRNA表达水平,用单克隆抗体免疫组化法检测bax及bcl-2蛋白含量.结果 bax基因mRNA及蛋白在模型组、醋酸泼尼松组、治疗Ⅰ组及治疗Ⅱ组的表达明显升高,与对照组相比差异有统计学意义(P＜0.05);同时模型组升高幅度明显,治疗Ⅱ组升高幅度较低,两者相比差异有统计学意义(P ＜0.01);bcl-2基因mRNA及蛋白在醋酸泼尼松组、治疗Ⅰ组及治疗Ⅱ组的表达升高,并治疗Ⅱ组升高更明显,与模型组相比差异有统计学意义(P＜0.05).结论 丹参、人参及蛤蚧组方能通过调节细胞凋亡,下调bax活性,增强Bcl-2的活性,抑制细胞凋亡,减少纤维积聚和纤维化形成.     

还原型谷胱甘肽对哮喘豚鼠气道上皮细胞的保护作用

目的探索还原型谷胱甘肽对哮喘豚鼠气道上皮细胞凋亡的保护作用。方法将40只豚鼠随机分为正常对照组、哮喘组、还原型谷胱甘肽组和地塞米松组,每组10只,应用酶联免疫吸附测定法(ELISA)检测支气管肺泡灌洗液中的干扰素-r(INF-r)水平及肺组织总抗氧化能力(T-AOC),原位末端转移酶标记染色法(TUNEL染色)检测气道上皮细胞凋亡情况,逆转录-聚合酶链反应(RT-PCR)测定肺组织B淋巴细胞/白血病-2信使核糖核酸(Bcl-2 m RNA)的表达。结果与哮喘组相比,还原型谷胱甘肽组支气管肺泡灌洗液中干扰素-r(INF-r)显著升高(P<0.05),与地塞米松组相似(P>0.05),气道上皮细胞凋亡指数(apoptosis index,AI)显著降低(P<0.05),肺组织T-AOC测定及Bcl-2 m RNA的表达均显著升高(P<0.05)。结论还原型谷胱甘肽对哮喘豚鼠气道上皮细胞凋亡具有保护作用。     

Administration of Pigment Epithelium-Derived Factor Inhibits Airway Inflammation and Remodeling in Chronic OVA-Induced Mice via VEGF Suppression

Purpose

Pigment epithelium-derived factor (PEDF) is a recently discovered antiangiogenesis protein. PEDF possesses powerful anti-inflammatory, antioxidative, antiangiogenic, and antifibrosis properties. It has been reported that PEDF can regulate vascular endothelial growth factor (VEGF) expression. This study aimed to evaluate whether recombinant PEDF protein could attenuate allergic airway inflammation and airway remodeling via the negative regulation of VEGF using a murine model of chronic ovalbumin (OVA)-induced asthma and BEAS-2B human bronchial epithelial cells.

Methods

In an in vivo experiment, mice sensitized with OVA were chronically airway challenged with aerosolized 1% OVA solution for 8 weeks. Treated mice were given injections of recombinant PEDF protein (50 or 100 µg/kg body weight) via the tail vein. In an in vitro experiment, we investigated the effects of recombinant PEDF protein on VEGF release levels in BEAS-2B cells stimulated with IL-1β.

Results

Recombinant PEDF protein significantly inhibited eosinophilic airway inflammation, airway hyperresponsiveness, and airway remodeling, including goblet cell hyperplasia, subepithelial collagen deposition, and airway smooth muscle hypertrophy. In addition, recombinant PEDF protein suppressed the enhanced expression of VEGF protein in lung tissue and bronchoalveolar lavage fluid (BALF) in OVA-challenged chronically allergic mice. In the in vitro experiment, VEGF expression was increased after IL-1β stimulation. Pretreatment with 50 and 100 ng/mL of recombinant PEDF protein significantly attenuated the increase in VEGF release levels in a concentration-dependent manner in BEAS-2B cells stimulated by IL-1β.

Conclusions

These results suggest that recombinant PEDF protein may abolish the development of characteristic features of chronic allergic asthma via VEGF suppression, providing a potential treatment option for chronic airway inflammation diseases such as asthma.     

Mechanisms for T cell tolerance induced with granulocyte colony-stimulating factor

Granulocyte colony-stimulating factor (G-CSF) has been widely accepted as a mediator of T cell tolerance. The immune modulatory effect of G-CSF on T cells is believed to be mediated exclusively through other effector cells, such as monocytes, tolerogenic dendritic cells (DC), and myeloid-derived suppressor cells. Recent advances confirmed the direct effects of G-CSF in inducing immune tolerance of T cells through the G-CSF-G-CSF receptor pathway and related molecular mechanisms. This review aims to summarize the findings associated with the direct and indirect mechanisms for T cell tolerance induced with G-CSF. The role of G-CSF in preventing graft-versus-host disease (GVHD) and in treating autoimmune diseases (ADs) is also discussed. It is conceivable that G-CSF and immune cell compositions, such as tolerogenic DC and CD4⁺CD25⁺Foxp3⁺ T cells, modulated by G-CSF could become an integral part of the immunomodulatory therapies against GVHD and ADs in the future.     

Statins may ameliorate pulmonary hypertension via RhoA/Rho-kinase signaling pathway

Statins are the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors that function as potent inhibitors of cholesterol biosynthesis and have been used for many years for the treatment of hypercholesterolemia. However, accumulating experimental and clinical studies have revealed that the health benefits associated with statins treatment, particularly those conferred on the cardiovascular system, were the cholesterol-independent. Because statins inhibit an early step in the cholesterol biosynthetic pathway, they also inhibit the synthesis of isoprenoids such as farnesylpyrophosphate and geranylgeranylpyrophosphate, which are important postranslational lipid attachments for intracellular signaling molecules such as the Rho GTPases. The isoprenylation of Rho is a prerequisite for Rho activation, facilitating its interaction with the plasma membrane, undergoing GDP-GTP exchange and be activated. Inhibition of RhoA geranylgeranylation by statins decreases membrane GTP-bound active RhoA and subsequent Rho-kinase activity. Activated RhoA via its downstream effector Rho-kinase is involved in a wide range of cellular functions, such as cell migration, proliferation and apoptosis. Recently, rising evidences suggested that RhoA/Rho-kinase pathway was essentially involved in various models of pulmonary hypertension and statins effectively ameliorated pulmonary hypertension. Based on this findings, we hypothesis that statins attenuate pulmonary hypertension via RhoA/Rho-kinase signaling pathway in vivo.     

Killed but metabolically active Pseudomonas aeruginosa-based vaccine induces protective humoral- and cell-mediated immunity against Pseudomonas aeruginosa pulmonary infections

Pseudomonas aeruginosa (Pa) is a significant cause of morbidity and mortality, especially in cystic fibrosis patients. Its eradication is difficult due to a wide phenotypic adaptability and an increase of its resistance to antibiotics. After the failure of several recombinant vaccines which mainly triggered humoral response, live-attenuated vaccines received attention thanks to their ability to elicit a broad immunity with both humoral- and cell-mediated responses, essential to fight this pathogen. In this study, we developed an innovative and safer live-attenuated Pa vaccine based on a Killed But Metabolically Active (KBMA) attenuation method. KBMA Pa has been further rationally designed to overexpress beneficial effectors like the type 3 secretion system apparatus. We demonstrated that KBMA Pa elicits a high and broad humoral response in mice against several antigens of particular interest such as OprF and PcrV proteins. Moreover, we assessed cytokines in the serum of immunized mice and showed that KBMA Pa elicits Th1, Th2 and especially Th17 pathways of cell-mediated immune responses. Th17 pathway involvement was also confirmed after specific stimulation of helper T cells in immunized mice. Finally, we showed that this vaccine is safe and has a protective effect in a murine acute pulmonary infectious challenge. In conclusion, KBMA Pa is a new platform with high potential for the development of a vaccine against Pa.