Size effects of latex nanomaterials on lung inflammation in mice

Effects of nano-sized materials (nanomaterials) on sensitive population have not been well elucidated. This study examined the effects of pulmonary exposure to (latex) nanomaterials on lung inflammation related to lipopolysaccharide (LPS) or allergen in mice, especially in terms of their size-dependency. In protocol 1, ICR male mice were divided into 8 experimental groups that intratracheally received a single exposure to vehicle, latex nanomaterials (250 μg/animal) with three sizes (25, 50, and 100 nm), LPS (75 μg/animal), or LPS plus latex nanomaterials. In protocol 2, ICR male mice were divided into 8 experimental groups that intratracheally received repeated exposure to vehicle, latex nanomaterials (100 μg/animal), allergen (ovalbumin: OVA; 1 μg/animal), or allergen plus latex nanomaterials. In protocol 1, latex nanomaterials with all sizes exacerbated lung inflammation elicited by LPS, showing an overall trend of amplified lung expressions of proinflammatory cytokines. Furthermore, LPS plus nanomaterials, especially with size less than 50 nm, significantly elevated circulatory levels of fibrinogen, macrophage chemoattractant protein-1, and keratinocyte-derived chemoattractant, and von Willebrand factor as compared with LPS alone. The enhancement tended overall to be greater with the smaller nanomaterials than with the larger ones. In protocol 2, latex nanomaterials with all sizes did not significantly enhance the pathophysiology of allergic asthma, characterized by eosinophilic lung inflammation and Igs production, although latex nanomaterials with less than 50 nm significantly induced/enhanced neutrophilic lung inflammation. These results suggest that latex nanomaterials differentially affect two types of (innate and adaptive immunity-dominant) lung inflammation.     

Health effects of nanomaterials on next generation

In order to discuss the health effects of nanomaterials, we cannot disregard the research on the health effects of airborne particulates. It is said that many of the fine or ultrafine particles in airborne particulates originate from diesel vehicles in metropolitan areas. The results of not only animal experiments but many epidemiologic surveys and volunteer intervention experiments in humans are reported on the health effects of particles. Although the health effects of the particulate matter particle sizes below 10 μm (PM10) were investigated in the initial studies, recently even smaller particles have come to be regarded as questionable and research of the health effects of the minute particulate matter below 2.5 μm (PM2.5) has been done. However, our recent study about maternal exposure to diesel exhaust suggests that health effect study of PM0.1, particles below 0.1 μm (100 nm), namely nanoparticles, is necessary from now on. We are proceeding with the study of the health effects of various types of intentionally produced nanomaterials such as carbon black, carbon nanotube, fullerene and titanium dioxide, examining in particular their influence on next generation. Although there are differences in the sites affected and the seriousness of the damage, basically similar findings to DEPs mentioned above are being discovered in research on nanomaterials. Regardless of dosage and administration method, such as inhalation, endotracheal administration, nasal drip and subcutaneous administration, once nanomaterials enter the bloodstream of a pregnant mother mouse, they move to the offspring and have effects on them. The effects may appear as various symptoms in the process of growth after birth, and can sometimes lead to the onset and aggravation of serious diseases.     

Importance of researches on chronic effects by manufactured nanomaterials

Manufactured nanomaterials are the most important substances for the nanotechnology. The nanomaterials possess different physico-chemical properties from bulk materials. The new properties may lead to biologically beneficial effects and/or adverse effects. However, there are no standardized evaluation methods at present. Some domestic research projects and international OECD programs are ongoing, in order to share the health impact information of nanomaterials or to standardize the evaluation methods. From 2005, our institutes have been conducting the research on the establishment of health risk assessment methodology of manufactured nanomaterials. In the course of the research project, we revealed that the nanomaterials were competent to cause chronic effects, by analyzing the intraperitoneal administration studies and carcinogenic promotion studies. These studies suggested that even aggregated nanomaterials were crumbled into nanosized particles inside the body during the long-term, and the particles were transferred to other organs. Also investigations of the toxicokinetic properties of nanomaterials after exposure are important to predict the chronically targeted tissues. The long lasting particles/fibers in the particular tissues may cause chronic adverse effects. Therefore, focusing on the toxicological characterization of chronic effects was considered to be most appropriate approach for establishing the risk assessment methods of nanomaterials.     

1,8-桉油精对卵白蛋白致哮喘豚鼠的气道高反应性和炎症的抑制作用

目的探讨1,8-桉油精(1,8-cineol)对哮喘豚鼠肺功能的改善作用及其机制。方法豚鼠第0天和第7天ip给予0.5ml含卵白蛋白(OVA)20μg的氢氧化铝凝胶致敏,28d后OVA攻击制备哮喘模型。观察豚鼠OVA攻击后1h,1,8-桉油精10,30和100mg.kg-1对豚鼠吸入OVA后1,2,3,4,10,20和30min时气道阻力(Raw)和肺顺应性(Cdyn)变化及支气管肺泡灌洗液(BALF)中白细胞数和细胞分类的影响,并测量豚鼠肺组织中嗜酸细胞阳离子蛋白(ECP)、白细胞介素4(IL-4)、IL-8和肿瘤坏死因子α(TNF-α)的含量。观察豚鼠OVA攻击后17h再吸入乙酰甲胆碱(MCh)后,1,8-桉油精10,30和100mg.kg-1对Raw和Cdyn及BALF中白细胞数和细胞分类的影响,并测量豚鼠肺组织中ECP,IL-4,IL-8和TNF-α的含量。结果与正常对照组比较,豚鼠OVA攻击后1h,在4min时模型组Raw达到高峰;与模型组比较,1,8-桉油精30和100mg.kg-1明显抑制Raw增加(P<0.05);在3min时模型组Cdyn达到高峰,与模型组比较,1,8-桉油精10,30和100mg.kg-1均能明显抑制Cdyn降低(P<0.05);模型组豚鼠肺组织ECP,IL-4和TNF-α含量明显高于正常对照组(P<0.05);1,8-桉油精100mg.kg-1组ECP,IL-4和TNF-α含量均明显低于模型组(P<0.05),模型组与正常对照组豚鼠肺组织IL-8含量无明显差异。与模型组比较,1,8-桉油精100mg.kg-1能明显减少BALF中白细胞数和嗜酸性粒细胞比例(P<0.05)。致敏豚鼠OVA攻击17h后,模型组豚鼠Raw与正常对照组比较显著升高(P<0.05),模型组豚鼠Cdyn与正常对照组比较有显著性差异(P<0.01),1,8-桉油精100mg.kg-1对MCh引起的Raw的增加有明显的抑制作用,1,8-桉油精10,30和100mg.kg-1对MCh引起的Cdyn降低有明显的改善作用;与模型组相比,1,8-桉油精100mg.kg-1能明显减少BALF中白细胞数和中性粒细胞比例,降低肺组织ECP,IL-8和TNF-α含量(P<0.01);模型组与正常对照组豚鼠肺组织IL-4含量无明显差异;1,8-桉油精30mg.kg-1也能降低哮喘豚鼠肺组织中ECP和TNF-α含量(P<0.01)。结论在哮喘急性发作时,1,8-桉油精通过减少嗜酸性粒细胞,下调嗜酸性粒细胞的活性,从而抑制了哮喘的急性发作。在哮喘迟发相阶段,1,8-桉油精可通过下调IL-8水平,降低TNF-α活性,从而抑制或改善由IL-8水平升高导致的中性粒细胞聚集于支气管肺泡而直接引起的哮喘加重和持续状态。     

Anti-inflammatory effects of exogenous uridine in an animal model of lung inflammation

Nucleosides like adenosine, uridine and their nucleotide derivatives (e.g. ATP and UTP) play important roles in many cellular functions, sometimes by acting as signalling molecules through binding to specific P2 nucleotide receptors. P2 receptors are subdivided into P2X and P2Y subfamilies, the latter of which are G-protein coupled receptors. P2Y receptors and nucleoside transporters have been detected in human and rat lungs, where they mediate effects of interest in airway diseases. The aim of this study was to investigate whether uridine has any anti-inflammatory properties in an asthma-like animal model of lung inflammation. The Sephadex-induced lung inflammation model in Sprague-Dawley rats was chosen mainly due to its localised inflammatory response and uridine's limited oral bioavailability. The dextran beads, with or without the addition of uridine, were instilled intratracheally into the lungs, which were excised and examined after 24 h. Sephadex alone led to massive oedema and infiltration of macrophages, neutrophils and eosinophils. Microgranulomas with giant cell formations were clearly visible around the partially degraded beads. Uridine reduced both the oedema and the infiltration of leukocytes significantly, measured as lung wet weight and leukocyte counts in bronchoalveolar lavage fluid, respectively. Uridine appeared to affect the tumour necrosis factor (TNF) levels, although this could not be statistically confirmed due to large variations within the Sephadex control group. We conclude that uridine has anti-inflammatory effects, and that the exact mechanism(s) of action requires further study.     

纳米材料对胎盘屏障功能毒性作用的研究进展

纳米材料因其粒径小和比表面积大等独特理化性质而被广泛应用于物理、化学、生物和医学等各个领域,其对人体及环境可能造成的潜在危害也愈发受到人们的重视,其中纳米材料孕期暴露对后代发育的影响更是备受关注。近年来,数种常见纳米氧化物、碳纳米材料、量子点及金属纳米材料对胎盘屏障毒性作用的相关研究发现,多数纳米材料能够穿过胎盘屏障并破坏胎盘正常结构,甚至影响子代的生长发育及性成熟,其毒性程度常与纳米材料尺寸、包被材料、剂量和暴露方式相关。纳米材料的胎盘屏障毒性作用机制研究也取得进展,期望能有更为科学完善的体系以对纳米材料毒性进行全面评价。     

Health effects and time course of particulate matter on the cardiopulmonary system in rats with lung inflammation

Recent epidemiological studies associate health effects and particulate matter in ambient air. Exacerbation of the particle-induced inflammation can be a mechanism responsible for increased hospitalization and death due to cardiopulmonary events in high-risk groups of the population. Systems regulating blood pressure that depend on lung integrity can be involved in progression of cardiovascular diseases. This study focused on the expression levels of various genes involved in cardiovascular and pulmonary diseases to assess their role in the onset of cardiovascular problems due to ambient particulate matter and compared these with the corresponding products. Rats with ozone-induced (1600 microg/m(3); 8 h) pulmonary inflammation were exposed to 0.5 mg, 1.5 mg, or 5 mg of particulate matter (PM) from Ottawa Canada (EHC-93) by intratracheal instillation. mRNA levels of various genes and their products were measured 2, 4, and 7 d after instillation. At 2 d after exposures to PM, tumor necrosis factor (TNF)-alpha levels in bronchoalveolar lavage fluid (BALF) were elevated approximately 4 times for the highest EHC-93 dose. MIP-2 protein levels in BALF were elevated approximately three times during the entire time period studied, whereas IL-6 levels were not affected compared to control groups. The MIP-2 mRNA levels revealed a similar pattern of induction. A twofold increase in endothelin (ET)-1 levels at d 2 and a 20% decrease in angiotensin-converting enzyme (ACE) activity at d 7 were measured in plasma. A 60% decrease of ACE and ET-1 mRNA levels suggested a possible endothelial damage in the lung blood vessels. Inducible nitric oxide synthase (iNOS) mRNA was found to be increased 3.5 times 2 d after instillation of the particles. Therefore, the endothelial damage could have been caused by large amounts of the free radical NO. Also, plasma levels of fibrinogen were elevated (20%), which could presumably increase blood viscosity, leading to decreased tissue blood flow. These changes in hematological and hemodynamic parameters observed in our study are in line with heart failure in high-risk groups of the population after high air pollution episodes.     

Size effect of intratracheally instilled particles on pulmonary inflammation and vascular thrombosis

Particulate air pollution is associated with cardiorespiratory effects and ultrafine particles (UFPs, diameter < 100 nm) are believed to play an important role. We studied the acute (1 h) effect of intratracheally instilled unmodified (60 nm), negatively charged carboxylate-modified (60 nm), or positively charged amine-modified (60 or 400 nm) polystyrene particles on bronchoalveolar lavage (BAL) indices and on peripheral thrombosis in hamster. The latter was assessed by measuring the extent of photochemically induced thrombosis in a femoral vein via transillumination. Unmodified and negative UFPs did not modify thrombosis and BAL indices. Positive UFPs increased thrombosis at 500 microg per animal (+ 341 +/- 96%) and at 50 microg per animal (+ 533 +/- 122%), but not at 5 microg per animal. Neutrophils, lactate dehydrogenase, and histamine were increased in BAL at all these doses but protein concentration was increased only at 500 microg per animal. Positive 400-nm particles (500 microg per animal) did not affect thrombosis, although they led to a neutrophil influx and an increase in BAL proteins and histamine. Using the Platelet Function Analyser (PFA-100), the platelets of hamsters were activated by the in vitro addition of positive UFPs and 400-nm particles to blood. We conclude that intratracheally administered positive ultrafine and 400-nm particles induce pulmonary inflammation within 1 h. Positive UFPs, but not the 400-nm particles enhance thrombosis. Hence, particle-induced lung inflammation and thrombogenesis can be partially uncoupled.     

Indirect monitoring of lung inflammation

The assessment of airway inflammation by non-invasive methods could provide a signal to start anti-inflammatory treatment before the onset of symptoms and the impairment of lung function. It could also be useful in the follow-up of patients with lung disease, and for guiding drug treatment. Measuring inflammatory markers in exhaled breath condensate is potentially the easiest way to quantify lung inflammation. The clinical applicability of this method could facilitate the practice of respiratory medicine.     

Protective effects of ethyl acetate extracts of Rimulus Cinnamon on systemic inflammation and lung injury in endotoxin-poisoned mice

Rimulus cinnamon is the dried twig of Cinnamomum cassia Presl. It is widely used in China for the treatment of inflammatory processes, amenorrhea, and other diseases. We aimed to study the protective effects of ethyl acetate extracts of R. cinnamon (EAE) on systemic inflammation and lung injury in endotoxin-poisoned mice. EAE was administered 5 d prior to lipopolysaccharide (LPS) challenge with 15?mg/kg LPS. The administration of EAE increased the levels of interferon-γ (IFN-γ) and decreased the levels of interleukin-18 (IL-18) and tumor necrosis factor-α (TNF-α) in the serum. Additionally, EAE relieved the pathological changes in the tissues of the lungs and spleen, and significantly reduced the number of neutrophils in the lung tissues. In addition, treatment with EAE decreased the mRNA expression of the NLR family, pyrin domain-containing protein 3 (NLRP3), caspase-1, and interleukin-1β (IL-1β) in the lungs, as well as the expression of NLRP3, caspase-1 (p20), and pro-IL-1β proteins. These results demonstrated the promising anti-inflammatory effects of EAE in endotoxin-poisoned mice. Furthermore, EAE could alleviate the lung injury of endotoxin-poisoned mice by antagonizing the activation of the NLRP3 inflammasome.     

Inhibitory effects of kaempferol-3-O-rhamnoside on ovalbumin-induced lung inflammation in a mouse model of allergic asthma

The modification of natural flavonoid by glycosylation alters their physicochemical and pharmacokinetic properties, such as increased water solubility and stability, reduced toxicity, and sometimes enhanced or even new pharmacological activities. Kaempferol (KF), a plant flavonoid, and its glycosylated derivative, kaempferol-3-O-rhamnoside (K-3-rh), were evaluated and compared for their anti-inflammatory, anti-oxidant, and anti-asthmatic effects in an asthma model mouse. The results showed that K-3-rh fully maintained its anti-inflammatory and anti-asthmatic effects compared with KF in an asthma model mouse. Both KF and K-3-rh significantly reduced the elevated inflammatory cell numbers in the bronchoalveolar lavage fluid (BALF). KF and K-3-rh also significantly inhibited the increase in Th2 cytokines (IL-4, IL-5, and IL-13) and TNF-α protein levels through inhibition of the phosphorylation Akt and effectively suppressed eosinophilia in a mouse model of allergic asthma. The total immunoglobulin (Ig) E levels in the serum and BALF were also blocked by KF and K-3-rh to similar extents. K-3-rh exerts similar or even slightly higher inhibitory effects on Th2 cytokines and IgE production compared with KF, whereas K-3-rh was less effective at DPPH radical scavenging and the inhibition of ROS generation in inflammatory cells compared with KF. These results suggested that the K-3-rh, as well as KF, may also be a promising candidate for the development of health beneficial foods or therapeutic agents that can prevent or treat allergic asthma.     

Reduced allergic lung inflammation in rats following formaldehyde exposure: Long-term effects on multiple effector systems

Clinical and experimental evidences show that formaldehyde (FA) exposure has an irritant effect on the upper airways. As being an indoor and outdoor pollutant, FA is known to be a causal factor of occupational asthma. This study aimed to investigate the repercussion of FA exposure on the course of a lung allergic process triggered by an antigen unrelated to FA. For this purpose, male Wistar rats were subjected to FA inhalation for 3 consecutive days (1%, 90-min daily), subsequently sensitized with ovalbumin (OVA)-alum via the intraperitoneal route, and 2 weeks later challenged with aerosolized OVA. The OVA challenge in rats after FA inhalation (FA/OVA group) evoked a low-intensity lung inflammation as indicated by the reduced enumerated number of inflammatory cells in bronchoalveolar lavage as compared to FA-untreated allergic rats (OVA/OVA group). Treatment with FA also reduced the number of bone marrow cells and blood leukocytes in sensitized animals challenged with OVA, which suggests that the effects of FA had not been only localized to the airways. As indicated by passive cutaneous anaphylactic reaction, FA treatment did not impair the anti-OVA IgE synthesis, but reduced the magnitude of OVA challenge-induced mast cell degranulation. Moreover, FA treatment was associated to a diminished lung expression of PECAM-1 (platelet-endothelial cell adhesion molecule 1) in lung endothelial cells after OVA challenge and an exacerbated release of nitrites by BAL-cultured cells. Keeping in mind that rats subjected solely to either FA or OVA challenge were able to significantly increase the cell influx into lung, our study shows that FA inhalation triggers long-lasting effects that affect multiple mediator systems associated to OVA-induced allergic lung such as the reduction of mast cells activation, PECAM-1 expression and exacerbation of NO generation, thereby contributing to the decrease of cell recruitment after the OVA challenge. In conclusion, repeated expositions to air-borne FA may impair the lung cell recruitment after an allergic stimulus, thereby leading to a non-responsive condition against inflammatory stimuli likely those where mast cells are involved.     

Endothelial cell activation,oxidative stress and inflammation induced by a panel of metal-based nanomaterials

Abstract

The importance of composition, size, crystal structure, charge and coating of metal-based nanomaterials (NMs) were evaluated in human umbilical vein endothelial cells (HUVECs) and/or THP-1 monocytic cells. Biomarkers of oxidative stress and inflammation were assessed because they are important in the development of cardiovascular diseases. The NMs used were five TiO₂ NMs with different charge, size and crystal structure, coated and uncoated ZnO NMs and Ag which were tested in a wide concentration range. There were major differences between the types of NMs; exposure to ZnO and Ag resulted in cytotoxicity and increased gene expression levels of HMOX1 and IL8. The intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1(VCAM-1) expression were highest in TiO₂ NM-exposed cells. There was increased adhesion of THP-1 monocytic cells onto HUVECs with Ag exposure. None of the NMs increased the intracellular ROS production. There were no major effects of the coating of ZnO NMs. The TiO₂ NMs data on ICAM-1 and VCAM-1 expression suggested that the anatase form was more potent than the rutile form. In addition, the larger TiO₂ NM was more potent than the smaller for gene expression and ICAM-1 and VCAM-1 expression. The toxicological profile of cardiovascular disease-relevant biomarkers depended on composition, size and crystal structure of TiO₂ NMs, whereas the charge on TiO₂ NMs and the coating of ZnO NMs were not associated with differences in toxicological profile.     

盆炎洁颗粒抗炎作用的研究

目的观察盆炎洁颗粒的抗炎作用。方法采用小鼠耳肿胀、大鼠角叉菜胶性关节炎及塑料环致大鼠子宫炎症模型。结果连续3d灌胃盆炎洁颗粒7．5g生药/kg、22．5g生药/kg可明显抑制二甲苯性小鼠耳肿胀；灌胃4．5g生药/kg、13．5g生药/kg对大鼠关节炎及子宫炎模型均有明显抑制作用，其抗炎强度与阳性药妇炎康片相似。结论盆炎洁颗粒具有良好的抗炎作用。     

Biological responses to nanomaterials: understanding nano-bio effects on cell behaviors

Abstract

The unique properties of nanomaterials in drug delivery and tissue engineering have captured a great deal of attention as experimental tools in bioimaging, diagnostic, and therapeutic processes. A plenty of research have provided a strong evidence that nanostructures not only passively interact with cells but also actively engage and mediate cell functions and molecular processes. Undoubtedly, it is crucially important to better understand biological responses to engineered nanomaterials, especially in view of their potential for biomedical applications. In this review, we shall highlight recent advances in exploring nano-bio effects in diverse systems of nanoparticles, nanotopographies, and mixed composite scaffolds. We will also discuss their manipulating functions on cellular behaviors and important biological processes of adhesion, morphology, proliferation, migration, differentiation, and even hidden mechanisms including molecular signaling pathways. At last, the perspectives will be addressed for further directions of nanomaterial designs with the purpose of better drug delivery and cell therapies.     

Differential effects of formaldehyde exposure on the cell influx and vascular permeability in a rat model of allergic lung inflammation

Exposure to air pollutants such as formaldehyde (FA) leads to inflammation, oxidative stress and immune-modulation in the airways and is associated with airway inflammatory disorders such as asthma. The purpose of our study was to investigate the effects of exposure to FA on the allergic lung inflammation. The hypothesized link between reactive oxygen species and the effects of FA was also studied. To do so, male Wistar rats were exposed to FA inhalation (1%, 90 min daily) for 3 days, and subsequently sensitized with ovalbumin (OVA)-alum by subcutaneous route. One week later the rats received another OVA-alum injection by the same route (booster). Two weeks later the rats were challenged with aerosolized OVA. The OVA challenge of rats upon FA exposure induced an elevated release of LTB₄, TXB₂, IL-1β, IL-6 and VEGF in lung cells, increased phagocytosis and lung vascular permeability, whereas the cell recruitment into lung was reduced. FA inhalation induced the oxidative burst and the nitration of proteins in the lung. Vitamins C, E and apocynin reduced the levels of LTB₄ in BAL-cultured cells of the FA and FA/OVA groups, but increased the cell influx into the lung of the FA/OVA rats. In OVA-challenged rats, the exposure to FA was associated to a reduced lung endothelial cells expression of intercellular cell adhesion molecule 1 (ICAM-1). In conclusion, our findings suggest that FA down regulate the cellular migration into the lungs after an allergic challenge and increase the ability of resident lung cells likely macrophages to generate inflammatory mediators, explaining the increased lung vascular permeability. Our data are indicative that the actions of FA involve mechanisms related to endothelium–leukocyte interactions and oxidative stress, as far as the deleterious effects of this air pollutant on airways are concerned.     

Perspectives on pulmonary inflammation and lung cancer risk in cigarette smokers

Cigarette mainstream smoke (MSS) inhaled by smokers is a complex aerosol composed of minute liquid droplets suspended within a mixture of combustion gases (CO, CO2, NOx, etc.) and semivolatile compounds. The minute liquid droplets represent the particulate or "tar" phase, while the combustion gases and semivolatiles comprise the vapor phase. For historical and technical reasons, the vast majority of studies on the carcinogenicity of MSS have focused on the particulate phase. The particulate phase is mutagenic and cytotoxic in vitro, proinflammatory, and promotes tumor formation in animal models. In addition to cytotoxic compounds found in the particulate phase, the vapor phase of MSS contains a number of cytotoxic constituents including reactive aldehydes and carbonyls capable of damaging cells and inducing pulmonary inflammation. A large body of evidence suggests that smoking-induced pulmonary inflammation may play an important role in increasing lung cancer risk in smokers. Use of aspirin and nonsteroidal anti-inflammatory drugs is associated with reduced cancer development in animal models and lower lung cancer rates in smokers. A number of benign nonpulmonary and pulmonary diseases characterized by chronic inflammation increase the risk of cancer at the affected site in the absence of chemical exposure. Animal models displaying tumorigenic responses following exposure to either whole smoke or smoke fractions show elevated rates of cellular proliferation. A relationship between pulmonary inflammation and lung cancer is mechanistically plausible because inflammatory cells secrete activated oxygen species, inflammatory mediators, and proteolytic enzymes that can both damage DNA and lead to increases in reparative cell proliferation rates.     

Effects of intrauterine infection or inflammation on fetal lung development

Intrauterine infection or inflammation is common in cases of preterm birth. Preterm infants are at risk of acute respiratory distress as a result of lung immaturity; evidence of exposure to infection and/or inflammation before birth is associated with a reduced risk of neonatal respiratory distress syndrome (RDS). Experimentally induced intrauterine inflammation or infection in sheep causes a precocious increase in pulmonary surfactant in the preterm lungs that improves preterm lung function, consistent with the reduced risk of RDS in human infants exposed to infection and/or inflammation before birth. The effects of intrauterine inflammation on fetal lung development appear to result from direct action of proinflammatory stimuli within the lungs rather than by systemic signals, such as the classical glucocorticoid-mediated lung maturation pathway. However, paracrine and/or autocrine production and/or metabolism of glucocorticoids in fetal lung tissue may occur as a result of inflammation-induced changes in the expression of 11β-hydroxysteroid dehydrogenase (types 1 and 2). Likely candidates that mediate inflammation-induced surfactant production by the preterm lung include prostaglandin E(2) and/or other arachidonic acid metabolites. Intrauterine inflammation induces the expression of enzymes responsible for prostaglandin production in fetal lung tissue. Inhibition of prostaglandin production prevents, at least in part, the effects of inflammation on fetal lungs. Our experiments are identifying mechanisms of surfactant production by the preterm lungs that may be exploited as novel therapies for preventing respiratory distress in preterm infants. Elucidation of the effects of inflammation on the fetal lungs and other organs will allow more refined approaches to the care of preterm infants exposed to inflammation in utero.     

白藜芦醇对脂多糖诱导的小鼠重症肺炎的保护作用

目的:探讨白藜芦醇对实验性小鼠重症肺炎的保护作用及机制.方法:建立脂多糖吸入所致的小鼠实验性急性重症肺炎模型,然后给予白藜芦醇腹腔注射给药,观察小鼠肺组织病理、肺组织湿/干质量比、支气管肺泡灌洗液中细胞分类计数变化,并检测肺组织中TNF-α、IL-1β、IL-6等炎症因子的表达差异.结果:实验性急性重症肺炎模型小鼠在接受白藜芦醇3～4 d后症状开始减轻,肺部炎症缓解.白藜芦醇治疗后,小鼠肺泡灌洗液中单核巨噬细胞、淋巴细胞、中性粒细胞及白细胞中性粒细胞计数和百分比均小于模型组,肺组织中TNF-α、IL-1β、IL-6的表达均显著低于模型组.结论:白藜芦醇有一定的抗炎作用,可以缓解小鼠重症肺炎症状,其机制可能是降低炎性肺组织中TNF-α、IL-1β、IL-6等的含量,从而减轻炎症反应.