Quantification of Local De Novo Synthesis Versus Blood Contributions to Quinolinic Acid Concentrations in Brain and Systemic Tissues

Abstract: The source of the neurotoxin quinolinic acid (QUIN) in brain and systemic tissues under normal and pathologic circumstances reflects either de novo synthesis from l -tryptophan and other precursors, or entry of QUIN itself from the blood. To quantify the relative contributions of blood- versus tissue-derived QUIN, [¹³C₇]QUIN was infused subcutaneously via osmotic pumps (0.55 µl/h, 30 mM) in gerbils, and the fraction of QUIN in tissue (Ti; measured in tissue homogenates) derived from blood (BI; measured in serum) was calculated by the formula ([¹³C₇]QUIN_Ti/QUIN_Ti)/([¹³C₇]QUIN_Bl/QUIN_Bl). In controls, blood QUIN contributed 38–49% of QUIN in brain, 70% in CSF, between 40 and 70% in kidney, heart, and skeletal muscle, but <5% in spleen, lung, liver, and intestine. Systemic endotoxin (450 µg/kg) increased blood, brain, CSF, and systemic tissue QUIN levels. Notably, the relative proportion of QUIN derived from blood in brain, spleen, lung, and intestine was unchanged by endotoxin, but increased in kidney, heart, and skeletal muscle. In contrast, cerebral ischemic injury (10 min of bilateral carotid artery occlusion) increased regional brain QUIN concentrations at 4 days post ischemia, with a proportional increase in the amount of QUIN derived from de novo synthesis by brain tissue. In the blood and systemic tissues of postischemic gerbils, there were no changes in systemic tissue or blood QUIN levels, or changes in the relative proportions of blood- versus systemic tissue-derived QUIN. These results establish that the brain normally synthesizes QUIN, that the blood is a significant source of QUIN in controls and during acute systemic immune activation, and that the rate of QUIN formation by brain tissue increases in conditions of brain and systemic immune activation.     

Synthesis of a dimeric monosaccharide lipid A mimic and its synergistic effect on the immunostimulatory activity of lipopolysaccharide

Bacterial endotoxin lipopolysaccharide (LPS) is a potent immune stimulant, with the recognition of LPS and its active principal lipid A mediated by the Toll-like receptor 4 (TLR4)/MD-2 receptor complex. Due to the broad downstream implications of TLR4-mediated signalling, TLR4 ligands show great potential for immunotherapeutic manipulations. In this paper a dimeric monosaccharide lipid A mimic (3) has been designed as a potential TLR4 ligand. The chemical synthesis and the preliminary biological studies are described. Compound 3 shows a significant synergistic effect on LPS-induced ICAM-1 expression in human monocytic THP-1 cells.     

Intestinal and cardiac inflammatory response shows enhanced endotoxin receptor (CD14) expression in magnesium deficiency

Substance P is elevated in plasma and in other tissues during Mg-deficiency, and was found localised to neuronal C-fibres of cardiac and intestinal tissues, where it could promote neurogenic inflammation. Plasma prostaglandin E₂ (PGE₂), indicative of systemic inflammation, rose significantly (≥4 fold, p<0.01) after 1 week and remained elevated through week 2 and 3 in rat on the Mg-deficient (MgD) diet. Concomitantly, total blood glutathione decreased by 50%. Immunohistochemical staining for endotoxin (lipopolysaccaride, LPS) receptor, CD14 was prominent in macrophage-type cells in intestinal tissue; more importantly, cardiac tissue revealed both CD11b (monocyte/macrophage surface protein) and CD14 positive cells after 3 weeks in rats on MgD diet. Western blot analysis indicated a significant increase in the endotoxin receptor protein level in the 3 week MgD hearts. Since CD14 is known to be up-regulated in cells exposed to LPS, these observations suggest that prolonged Mg-deficiency results in increased intestinal permeability to bacterial products that induce the endotoxin receptor in cells localized to myocardial and intestinal tissues. These CD14 positive cells may amplify the cardiomyopathic inflammatory process by stimulating TNF-α and other pro-inflammatory cytokines. (Mol Cell Biochem 278: 53–57, 2005)     

Systemic immune parameters after prior radiation therapy in patients receiving immune checkpoint inhibitors

IntroductionPreclinical studies have demonstrated the ability of radiation therapy (RT) to augment immune response and tumor control by immune checkpoint inhibitors (ICI). However, numerous clinical trials combining RT and ICI have yielded relatively disappointing results. To improve understanding of optimal use of these therapies, we assessed systemic immune effects of prior RT in patients receiving ICI.Methods and MaterialsPre- and post-ICI blood samples were collected from patients enrolled in a prospective immunotherapy biospecimen protocol. Mutiplex panels of 40 cytokines and 120 autoantibodies (Ab) were analyzed. We identified differences in these parameters according to receipt, timing, and type of prior RT. We calculated P values using the Pearson product-moment correlation coefficient and false discovery rate (FDR) using the Benjamini-Hochberg Procedure.ResultsAmong 277 total patients, 69 (25%) received RT in the 6 months prior to ICI initiation. Among RT-treated patients, 23 (33%) received stereotactic RT, and 33 (48%) received curative intent RT. There was no significant difference in demographics or type of immunotherapy between patients according to prior RT exposure. Baseline complement C8 Ab and MIP-1d/CCL15 were significantly higher among patients with prior RT. For MIP-1d/CCL15, only prior stereotactic RT was associated with significant differences.ConclusionsPrior RT is associated with few changes in systemic immune parameters in patients receiving ICI. The underlying mechanisms and optimal approach to harnessing the potential synergy of RT and ICI require further prospective clinical investigation.     

Time course and mechanistic analysis of human umbilical cord perivascular cell mitigation of lipopolysaccharide-induced systemic and neurological inflammation

Background aimsBecause of their potent immunomodulatory and anti-inflammatory properties, mesenchymal stromal cells are a major focus in the field of stem cell therapy. However, the precise mechanisms underlying this are not entirely understood. Human umbilical cord perivascular cells (HUCPVCs) are a promising cell therapy candidate. This study was designed to evaluate the time course and mechanisms by which HUCPVCs mitigate lipopolysaccharide (LPS)-induced systemic and neurological inflammation in immunocompetent mice. To explore the underlying mechanisms, the authors investigated the biodistribution and fate of HUCPVCs.MethodsMale C57BL/6 mice were randomly allocated to four groups: control, LPS, HUCPVCs or LPS + HUCPVCs. Quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and cytokine arrays were used to assess changes in pro-inflammatory mediators systemically and in the brain. Depressive-like behavioral changes were evaluated via a forced swim test. Quantum dot (qDot) labeling and immunohistochemistry were used to assess the biodistribution and fate of HUCPVCs and interactions with recipient innate immune cells.ResultsA single intravenously delivered dose of HUCPVCs significantly reduced the systemic inflammation induced by LPS within the first 24 h after administration. HUCPVC treatment abrogated the upregulated expression of pro-inflammatory genes in the hippocampus and cortex and attenuated depressive-like behavior induced by LPS treatment. Biodistribution analysis revealed that HUCPVC-derived qDots rapidly accumulated in the lungs and demonstrated limited in vivo persistence. Furthermore, qDot signals were associated with major recipient innate immune cells and promoted a shift in macrophages toward a regulatory phenotype in the lungs.ConclusionsOverall, this study demonstrates that HUCPVCs can successfully reduce systemic and neurological inflammation induced by LPS within the first 24 h after administration. Biodistribution and fate analyses suggest a critical role for the innate immune system in the HUCPVC-based immunomodulation mechanism.     

不同肠内营养支持方案对2型糖尿病并发急性脑卒中患者肠黏膜屏障功能和Th17/Treg免疫应答平衡的影响

摘要 目的：对比不同肠内营养支持方案对2型糖尿病（T2DM）并发急性脑卒中患者肠黏膜屏障功能和Th17/Treg免疫应答平衡的影响。方法：选取我院2019年3月~2021年2月期间收治的93例T2DM并发急性脑卒中患者,按照信封抽签法将患者分为对照组（46例）和研究组（47例）,对照组接受传统肠内营养支持方案,研究组接受个体化肠内营养支持方案,观察两组血糖水平、营养指标、肠黏膜屏障功能和Th17/Treg免疫应答平衡变化。结果：研究组治疗 1~7 d 后的血糖水平均低于对照组（P<0.05）。治疗7 d后,研究组血清前白蛋白、白蛋白、血红蛋白水平高于对照组（P<0.05）。治疗7 d后,研究组血浆内毒素（ET）、二胺氧化酶（DAO）低于对照组（P<0.05）。治疗7 d后,研究组Th17、Th17/Treg低于对照组;Treg高于对照组（P<0.05）。结论：个体化肠内营养支持方案有利于降低T2DM并发急性脑卒中患者的血糖水平,促进肠粘膜屏障功能的恢复,进而改善机体营养状态及免疫状态。     

Estimation of lymphocyte subsets and cytokine levels in workers occupationally exposed to cadmium

IntroductionOccupational exposure to Cadmium (Cd) may have serious health effect on workers. However, little is known about its effect on immune system. Moreover, previous studies have been inconclusive in stating the effect of Cd on immune system. The aim of our study was to estimate immune parameters in workers occupationally exposed to Cd.Material and methods110 individuals occupationally exposed to Cd and 97 apparently healthy non-exposed individuals were recruited for this study. Blood Cadmium levels were determined by AAS. Lymphocyte subset were analyzed using flow cytometry and the cytokine levels were determined by ELISA.ResultsExposed group have significantly higher levels of B-Cd. % of CD8 cells were higher in exposed while % of CD4 cells showed a decreasing trend in the exposed group. Among the CD3CD4 T cell subsets Th1 (%) and Tregs (%) cells were lower while Th17 (%) were higher in exposed group. Increased levels of IL-4 (Th2), IL-6 (Th2) and TNF- α (Th1) and decreased levels of IL-2 (Th1) and IL-10 (Tregs) were observed in Cd exposed workers which is indicative of a predominant pro-inflammatory response in Cd exposed workers. IL-17 (Th17) levels did not show any significant difference between the two groups. Increased Th17/Tregs ratio in the exposed group is also suggestive of an increased pro-inflammatory immune response in exposed group.ConclusionTo conclude, even low level of exposure to Cd in occupational settings is associated with alterations in Th17 cells, which may further predispose an individual to other systemic abnormalities.     

A time-course comparative clinical and immune response evaluation study between the human pathogenic Orientia tsutsugamushi strains: Karp and Gilliam in a rhesus macaque (Macaca mulatta) model

BackgroundScrub typhus is a vector-borne febrile illness caused by Orientia tsutsugamushi transmitted by the bite of Trombiculid mites. O. tsutsugamushi has a high genetic diversity and is increasingly recognized to have a wider global distribution than previously assumed.Methodology/principle findingsWe evaluated the clinical outcomes and host immune responses of the two most relevant human pathogenic strains of O. tsutsugamushi; Karp (n = 4) and Gilliam (n = 4) in a time-course study over 80 days post infection (dpi) in a standardized scrub typhus non-human primate rhesus macaque model. We observed distinct features in clinical progression and immune response between the two strains; Gilliam-infected macaques developed more pronounced systemic infection characterized by an earlier onset of bacteremia, lymph node enlargement, eschar lesions and higher inflammatory markers during the acute phase of infection, when compared to the Karp strain. C-reactive protein (CRP) plasma levels, interferon gamma (IFN-γ, interleukin-1 receptor antagonist (IL-1ra), IL-15 serum concentrations, CRP/IL10- and IFN-γ/IL-10 ratios correlated positively with bacterial load in blood, implying activation of the innate immune response and preferential development of a T helper-type 1 immune response. The O. tsutsugamushi-specific immune memory responses in cells isolated from skin and lymph nodes at 80 dpi were more markedly elevated in the Gilliam-infected macaques than in the Karp-infected group. The comparative cytokine response dynamics of both strains revealed significant up-regulation of IFN-γ, tumor necrosis factor (TNF), IL-15, IL-6, IL-18, regulatory IL-1ra, IL-10, IL-8 and granulocyte-colony-stimulating factor (G-CSF). These data suggest that the clinical outcomes and host immune responses to scrub typhus could be associated with counter balancing effects of pro- and anti-inflammatory cytokine-mediated responses.Currently, no data on characterized time-course comparisons of O. tsutsugamushi strains regarding measures of disease severity and immune response is available. Our study provides evidence for the strain-specificity of host responses in scrub typhus, which supports our understanding of processes at the initial inoculation site (eschar), systemic disease progression, protective and/or pathogenic host immune mechanisms and cellular immune memory function.Conclusions/significanceThis study characterised an improved intradermal rhesus macaque challenge model for scrub typhus, whereby the Gilliam strain infection associated with higher disease severity in the rhesus macaque model than the previous Karp strain infection. Difficulties associated with inoculum quantitation for obligate-intracellular bacteria were overcome by using functional inoculum titrations in outbred mice. The Gilliam-based rhesus macaque model provides improved endpoint measurements and contributes towards the identification of correlates of protection for future vaccine development.     

胃癌根治术后腹腔热灌注化疗对患者血清CEA、CA19-9水平及免疫功能的影响

目的:探讨胃癌根治术后腹腔灌注化疗对患者血清CEA(血清癌胚抗原,carcinoembryonic antigen)、CA19-9(糖链抗原19-9,carbohydrate antigen19-9)水平及免疫功能的影响。方法:回顾性2015年2月至2017年4月我院收治的胃癌患者临床资料,依据接受治疗方案不同分为全身静脉化疗组(对照组)和全身静脉化疗联合腹腔热灌注化疗组(观察组),每组各41例。检测和比较两组患者化疗前(治疗前)与化疗1个月后(治疗后)血清肿瘤标志物CEA、CA19-9与免疫功能指标水平的变化,治疗后毒副作用发生情况及治疗前后生活质量的改善情况。结果:治疗前,两组间血清CEA、CA19-9、CD3~+、CD4~+、CD8~+、CD4+/CD8~+水平比较差异均无统计学意义(P0.05);观察组治疗后血清CEA、CA19-9及CD8~+水平显著低于对照组,CD3~+、CD4~+、CD4~+/CD8~+水平显著高于对照组,差异有统计学意义(P0.05);两组骨髓抑制、恶心呕吐、腹痛腹泻及肠梗发生率比较差异均不显著无统计学意义(P=0.478,0.668,0.315,0.552);观察组生活质量改善总有效率为85.37%,显著高于对照组(70.73%,P=0.017)。结论:与单纯全身化疗相比,胃癌根治术后腹腔灌注化疗可更有效降低患者血清CEA、CA19-9水平,改善患者免疫功能,提高其生活质量,且安全性较高。     

Pneumoproteins and markers of inflammation and platelet activation in the blood of grain dust exposed workers

Abstract

Purpose: To investigate if blood biomarkers could indicate early signs of lung damage or cardiovascular risk due to exposure to grain dust.

Materials and methods: Pneumoproteins and markers of inflammation and platelet activation were analysed in blood samples of 102 grain elevator and compound feed mill workers. Differences between exposed (n?=?67) and controls (n?=?35), and associations with exposure measurements and respiratory health were investigated by multiple linear regression analyses.

Results: Concentrations of CC-16 and IL-6 were higher in exposed workers compared with controls (p?<?0.001 for both), whereas fibrinogen was lower (p?=?0.005). Concentrations of CRP, TNF-α, sCD40L and sP-selectin were similar in both groups. Serum CC-16 was significantly higher in workers with farm childhood, regardless of exposure. The impact of farm childhood on CC-16 interacted with smoking. None of the biomarkers were associated with exposure measurements or any of the tested respiratory health parameters.

Conclusion: Dust exposure induced inflammatory and anti-inflammatory reactions, but did not induce systemic inflammation and had no effect on platelet activation. No cause–effect relationship could be established in spite of relatively high exposure levels, particularly to endotoxin. Whether increased serum CC-16 is an early sign of lung damage or a reversible defense reaction remains unclear.     

Effects of endotoxin (lipopolysaccharides) on experimental aspergillosis in leukemic mice

In an attempt to evaluate effects of bacterial endotoxin on systemic fungal infection, experimental systemic Aspergillus infection was induced in leukemic mice (AKR strain) with (Group B) or without (Group A) preceding intraperitoneal administration of Pseudomonas aeruginosa derived lipopolysaccharides. All mice in group A died within 4 days after intravenous inoculation of Aspergillus fumigatus spores and developed extensive and disseminated fungal lesions without inflammatory reactions. In contrast, 5 of 10 mice in group B were alive at day 4 and 1 mouse in group B was alive when the experiment was terminated on the 14th day. These mice showed less extensive fungal lesions with definite, albeit minimal, inflammatory reactions which were composed of macrophages and neutrophils. In addition, serum iron levels and iron saturation rates were significantly lower in mice in group B than in group A. These results indicate that P. aeruginosa endotoxin has a deterring effect on systemic Aspergillus infection in leukemic mice.     

Phosphatase and tensin homolog (PTEN) in antigen-presenting cells controls Th17-mediated autoimmune arthritis

IntroductionAutoreactive T cells are a central element in many systemic autoimmune diseases. The generation of these pathogenic T cells is instructed by antigen-presenting cells (APCs). However, signaling pathways in APCs that drive autoimmune diseases, such as rheumatoid arthritis, are not understood.MethodsWe measured phenotypic maturation, cytokine production and induction of T cell proliferation of APCs derived from wt mice and mice with a myeloid-specific deletion of PTEN (myeloid PTEN^-/-) in vitro and in vivo. We induced collagen-induced arthritis (CIA) and K/BxN serum transfer arthritis in wt and myeloid-specific PTEN^-/- mice. We measured the cellular composition of lymph nodes by flow cytometry and cytokines in serum and after ex vivo stimulation of T cells.ResultsWe show that myeloid-specific PTEN^-/- mice are almost protected from CIA. Myeloid-specific deletion of PTEN leads to a significant reduction of cytokine expression pivotal for the induction of systemic autoimmunity such as interleukin (IL)-23 and IL-6, leading to a significant reduction of a Th17 type of immune response characterized by reduced production of IL-17 and IL-22. In contrast, myeloid-specific PTEN deficiency did not affect K/BxN serum transfer arthritis, which is independent of the adaptive immune system and solely depends on innate effector functions.ConclusionsThese data demonstrate that the presence of PTEN in myeloid cells is required for the development of CIA. Deletion of PTEN in myeloid cells inhibits the development of autoimmune arthritis by preventing the generation of a pathogenic Th17 type of immune response.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0742-y) contains supplementary material, which is available to authorized users.     

糖皮质激素联合吗替麦考酚酯分散片对系统性红斑狼疮患者的疗效及对免疫功能的影响

目的:研究糖皮质激素联合吗替麦考酚酯分散片治疗系统性红斑狼疮患者的临床疗效及对免疫功能的影响。方法:选取2014年9月至2015年8月本院收治的84例系统性红斑狼疮患者,根据投硬币法分为观察组和对照组,42例每组。对照组使用单纯的糖皮质激素,观察组在此基础上使用吗替麦考酚酯分散片。比较两组患者临床疗效,治疗前后免疫球蛋白A(IgA)、免疫球蛋白(IgG)、免疫球蛋白(IgM)、C反应蛋白(CRP)、血沉(ESR)的变化及不良反应的发生情况。结果:治疗后,观察组临床总有效率显著高于对照组(P0.05)。治疗前,两组患免疫球蛋白A(IgA)、免疫球蛋白(IgG)、免疫球蛋白(IgM)、C反应蛋白(CRP)、血沉(ESR)水平比较差异均无统计学意义(P0.05);治疗后,两组患者IgA、IgG、IgM、CRP、ESR水平均较治疗前显著降低(P0.05),与对照相比,观察组的IgA、IgG、IgM、CRP、ESR明显降低(P0.05)。两组组的不良反应率比较差异无统计学意义(P0.05)。结论:糖皮质激素联合吗替麦考酚酯分散片能有效改善系统性红斑狼疮患者的免疫功能,临床疗效良好,安全性高。     

全胸腔镜下肺叶切除联合系统淋巴清扫对肺癌患者血清疼痛相关因子和免疫功能的影响及预后的影响因素分析

摘要 目的：探讨全胸腔镜下肺叶切除（VATS）联合系统淋巴清扫对肺癌患者血清疼痛相关因子和免疫功能的影响,并分析预后的影响因素。方法：选择我院于2014年3月~2016年3月期间收治的肺癌患者116例,采用随机数字表法分为对照组和研究组,各58例。对照组患者给予传统开胸肺叶切除联合系统淋巴清扫治疗,研究组给予VATS联合系统淋巴清扫治疗,对比两组手术相关指标、血清疼痛相关因子和免疫功能,随访记录研究组患者5年生存率,分析预后的影响因素。结果：与对照组相比,研究组手术时间更长,术中出血量更少,术后住院时间、切口长度、引流时间更短（P<0.05）。两组术后1 d去甲肾上腺素（NE）、前列腺素E2（PGE2）、P物质（SP）、皮质醇（Cor）水平均较术前升高,但研究组低于对照组（P<0.05）。两组术后1 d CD3⁺、CD4⁺、CD4⁺/CD8⁺均较术前降低,但研究组高于对照组,CD8+较术前升高,但研究组低于对照组（P<0.05）。单因素分析结果可知：研究组患者的预后与组织分化、吸烟史、病灶直径、临床分期、清扫淋巴结个数有关（P<0.05）。多因素Logistic回归分析结果可知：临床分期、清扫淋巴结个数是研究组患者预后的影响因素（P<0.05）。结论：ATS联合系统淋巴清扫可减轻肺癌患者术后疼痛及免疫抑制,虽然手术时间更长,但可以改善其他围术期指标。此外,临床分期、清扫淋巴结个数是患者预后的影响因素,应引起临床重视。     

Effect of different treatments on macrophage differentiation in chronic obstructive pulmonary disease and repeated pulmonary infection

ObjectiveTo observe the differentiation of macrophages in lung tissue and alveolar lavage fluid of mice with severe pulmonary infection and the changes after intervention with ceftriaxone and ulinastatin, and to explore the pathogenesis of severe pulmonary infection under immunosuppressive state and the intervention effect of two drugs.Methods40 male Balb/c mice are randomly divided into normal group, model group, ulinastatin group, and ceftriaxone group with 10 mice in each group. Mice models of acute lung injury with immunodeficiency are established by methylprednisolone and endotoxin, and then treated with ulinastatin and ceftriaxone. Respiratory frequencies of mice in each group are measured at 3 h and 6 h after drug use through trachea, and then the mice are anaesthetized with uratan and killed 6 h after drug use. The number of alveolar macrophages and neutrophils in alveolar lavage fluid is collected and detected, and the pathological changes are observed. The positive expression of CD163 in lung tissue is detected by IHC (immunohistochemistry), and real-time quantitative PCR (Polymerase Chain Reaction) is used to detect the expression of Ml and M2 markers in bronchoalveolar lavage fluid (BALF).ResultCompared with the normal group, the mice in the model group breathed shallowly and quickly, occasionally nodded breathing, respiratory distress, and respiratory rate increased. Compared with the model group, the mice in the ulinastatin group and ceftriaxone group breathed slowly, occasionally have shortness of breath, smooth breathing, and slow breathing rate, and the mice in ulinastatin group breathe more smoothly. The number of macrophages and neutrophils in BALF of model group is higher than that of normal group. The number of macrophages and neutrophils in ulinastatin group and ceftriaxone group is lower than that of model group and the difference is statistically significant, and the number of macrophages and neutrophils in ulinastatin group is relatively less than that in model group.ConclusionIn the early stage of severe pulmonary infection under immunosuppressive state, the organism is in the CARS (Compensatory Anti-inflammatory Response Syndrome) stage; M1 macrophages had immune paralysis and M2 macrophages are abnormally activated. Compared with ceftriaxone, ulinastatin can alleviate lung injury more effectively and protect the lung of mice with acute lung injury. The protective mechanism of ulinastatin on lung of mice infected with immunocompromised endotoxin may be through inhibiting M1 macrophages and regulating non-specific immune function.     

HIV-1 RNA Dysregulates the Natural TLR Response to Subclinical Endotoxemia in Kenyan Female Sex-Workers

Background

Subclinical endotoxemia has been reported in HIV-1 infected persons and may drive systemic immune activation and pathogenesis. Proinflammatory responsiveness to endotoxin (LPS) is mediated by Toll-like receptor 4 (TLR4). We therefore examined the association between plasma LPS levels, HIV RNA, and TLR4 expression and cytokine responses in the blood of HIV infected and uninfected participants in a cohort of female sex-workers in Kenya.

Methodology/Principal Findings

Ex vivo plasma and peripheral blood mononuclear cells (PBMC) were assessed for LPS and TLR mRNA, respectively. The effects of HIV single stranded RNA, a TLR8 ligand, on TLR4 and LPS signaling were further assessed in short term PBMC culture. Both HIV uninfected and infected subjects frequently had low detectable LPS levels in their plasmas. Significantly increased LPS levels were associated with chronic HIV-1 infection, both treated and untreated, but not with other acute or semi-chronic conditions reported. In HIV-uninfected subjects, TLR4 mRNA expression levels correlated inversely with plasma LPS levels, suggesting chronic endotoxin ‘tolerance’ in vivo. A similar effect of reduced TLR4 mRNA was seen in short term PBMC culture after stimulation with LPS. Interestingly, the apparent in vivo tolerance effect was diminished in subjects with HIV infection. Additionally, pre-stimulation of PBMC with LPS lead to proinflammatory (TNF-α) tolerance to subsequent LPS stimulation; however, pre-treatment of PBMC with HIV single-stranded RNA40, could enhance TLR4-mediated LPS responsiveness in vitro.

Conclusions/Significance

Thus, dysregulation of endotoxin tolerance by HIV-1 RNA may exacerbate HIV chronic immune activation and pathogenesis.     

D-二聚体测定在慢性阻塞性肺疾病的疗效评价及预后意义的研究进展

慢性阻塞性肺疾病(简称慢阻肺)是一种呼吸科常见病,其并发症多,病死率高。在慢阻肺急加重期,细胞因子、炎症介质及内毒素首先损伤血管内皮,引发全身凝血功能障碍和负氮平衡。作为体内高凝状态和纤溶亢进的分子标志物之一,D-二聚体是交联纤维蛋白在纤溶酶作用下产生的一种特异性降解产物,其反映继发性纤溶活性意义。多项研究表明,D-二聚体水平对慢阻肺的治疗效果的评价及预后有重要意义。本文将通过总结D-二聚体的结构及与吸烟、年龄、血气分析及肺功能等方面的关系来阐述D-二聚体与慢阻肺相关性,并总结D-二聚体相关的慢阻肺的治疗方法及其对慢阻肺预后方面的相关意义。     

不同肠内营养液对老年重度AECOPD机械通气患者肠道屏障功能、免疫功能和炎症因子的影响

摘要 目的：探讨不同肠内营养液对老年重度慢性阻塞性肺疾病急性加重期（AECOPD）机械通气患者营养状况、肠道屏障功能、免疫功能和炎症因子的影响。方法：纳入2019年10月-2021年10月在我院住院治疗的老年重度AECOPD患者90例作为研究对象,采用密封信封法随机分为含膳食纤维肠内营养组（FEN组）及不含膳食纤维肠内营养组（NFEN组）各45例。两组患者均接受重度AECOPD规范治疗,并接受机械通气治疗。FEN组给予能全力进行营养支持治疗,NFEN组给予能全素进行营养支持治疗,两组患者均接受持续30 d的肠内营养。比较两组患者治疗前和治疗30 d后营养状况指标血清白蛋白（ALB）、前白蛋白（PA）、血红蛋白（Hb）,肠道屏障功能指标D-乳酸（DLA）、细菌内毒素（BE）、二胺氧化酶（DAO）,T淋巴细胞亚群（CD4⁺、CD8⁺、CD4⁺/CD8⁺）、体液免疫功能指标免疫球蛋白（Ig）G、IgM、IgA,炎症因子降钙素原（PCT）和白介素-6（IL-6）水平的变化,以及两组患者ICU住院天数、机械通气时间和并发症的差异。结果：治疗30 d后,FEN组ALB、PA和Hb水平均显著高于NFEN组（P<0.05）;FEN组DLA、BE和DAO水平均显著低于NFEN组（P<0.05）;FEN组CD4⁺、CD4⁺/CD8⁺以及IgG、IgA水平均显著高于NFEN组（P<0.05）;FEN组PCT、IL-6水平均显著低于NFEN组（P<0.05）。FEN组患者ICU住院天数、机械通气时间及并发症均显著少于NFEN组,差异有统计学意义（P<0.05）。结论：含膳食纤维肠内营养有利于改善老年重度AECOPD机械通气患者营养状况,修复肠道黏膜屏障功能,提高免疫功能,减轻炎症反应,从而改善预后,含膳食纤维的肠内营养支持治疗效果更佳。