Lowering serum uric acid to prevent acute kidney injury

Epidemiological, experimental and clinical studies support a role for uric acid in acute kidney injury (AKI). We discuss how the conventional role of uric acid in AKI has now evolved from intratubular crystal deposition to pro-inflammatory, anti-angiogenic and immunological function. Data from recent studies are presented to support the hypothesis that uric acid may have a role in AKI via a crystal-independent process in addition to its traditionally accepted role to induce injury via crystal-dependent pathways.     

Application of liposomes incorporating doxorubicin with sialyl Lewis X to prevent stenosis after rat carotid artery injury

Restenosis remains a serious complication that can occur after angioplasty. This study investigated the efficiency of an active targeting chemotherapy using liposomes, including doxorubicin, whose surface was decorated with sialyl Lewis X (SLX) (Dox-Lipo-SLX) to prevent stenosis after angioplasty. Its delivery was controlled via the affinity between SLX and E-selectin proteins, which are expressed on vessel walls with injury. In vitro experiments confirmed the accumulation of doxorubicin as a consequence of Dox-Lipo-SLX adhering to E-selectin-positive cells. Significant doxorubicin accumulation was observed on injured vessel walls in rats treated with Dox-Lipo-SLX. In contrast, there was little accumulation using free doxorubicin or a liposome containing doxorubicin (Dox-Lipo), but without SLX. Rats were assigned to one of four groups: Dox-Lipo-SLX, Dox-Lipo, free doxorubicin, or no treatment. Dox-Lipo-SLX, Dox-Lipo, and free doxorubicin, including a dose of 0.08mg/kg doxorubicin, were intravenously administered three times in each group after angioplasty. The residual lumen area of rats in the group treated with Dox-Lipo-SLX was significantly larger than those in all other groups. These results demonstrate that an active targeting drug delivery system utilizing Dox-Lipo-SLX effectively prevents stenosis after angioplasty.     

How to prevent phlebotomy-related nerve injury

Phlebotomy-related nerve injury is relatively rare but could be a serious complication of venipuncture; however, widely recognized and effective methods to prevent nerve injury at venipuncture have not been established. By considering the anatomical features of peripheral nerves and veins of the arm, several techniques may be feasible. To prevent median nerve injury, which is the most serious among the nerve injuries in the arm, the following order of vein selection is recommended: (1) radial vein (2) median cubital vein (3) basilic vein (4) forearm veins (5) veins of the back of the hands. However, this order should be changed according to the status of the actual veins of the patient. To avoid the needle from being inserted too deeply, short needles such as butterfly needles may be preferred. Although probing is a very dangerous procedure which must be avoided, re-direction of the needle is an acceptable procedure if it is performed once per venipuncture. In addition to these technical efforts, it is critical to ask each patient before venipuncture whether he or she has experienced nerve injury during previous phlebotomy in order to avoid unnecessary repetitive nerve injuries in the same patient. In order to avoid such situations, we have established a computer-based system to alert phlebotomists to the complications which patients have experienced during venipuncture. These and other methods should be tested in many institutes and data should be systematically collected to investigate whether phlebotomy-related nerve injury can be effectively prevented.     

Ozone-induced acute pulmonary injury in inbred mouse strains

To determine if host factors influence the time course and extent of lung injury after acute inhalation of ozone (O3), we evaluated the physiologic and biologic response of nine genetically diverse inbred strains of mice (C57BL/6J, 129/SvIm, BTBR, BALB/cJ, DBA/2J, A/J, FVB/NJ, CAST/Ei, and C3H/HeJ) exposed to O3 (2.0 ppm x 3 h). Whole lung lavage determined that 129/Svlm, BTBR, DBA/2J, and FVB/NJ had a peak increase in polymorphonuclear cells (PMNs) at 6 h, whereas C57BL/6J and CAST/Ei had a peak increase at 24 h after exposure; airway PMNs were minimally elevated in A/J and C3H/HeJ; BALB/cJ had a predominant lymphocytic influx. Interleukin-6 concentration in the lavage fluid was associated with the influx of PMNs, whereas the total protein in the lavage fluid did not always correlate with lavage cellularity. Respiratory responses were monitored using whole body plethysmography and enhanced pause index. C57BL/6J, BALB/cJ, 129/SvIm, and BTBR were highly sensitive to O3 and exhibited significant increases in enhanced pause to methacholine aerosol stimulation at 6 and 24 h after exposure to O3. In contrast, DBA/2J, A/J, FVB/NJ, CAST/Ei, and C3H/HeJ strains had demonstrated increases in sensitivity to MCh at 6 h after exposure, but responses had returned to near baseline by 24 h after exposure to O3. Epithelial cell proliferation as assessed by proliferating cell nuclear antigen staining was evident at 24 h after exposure to O3. C57BL/6J and A/J showed 4% proliferating cell nuclear antigen-positive cells; 129/SvIm, DBA/2J, and FVB/NJ had 1-3%; and BTBR, BALB/cJ, CAST/Ei, and C3H/HeJ had < 1%. Phenotypic measurements in six inbred strains were used for an in silico genome analysis based on the Roche mouse database. Consistent loci on chromosomes 1, 7, and 15 were among those identified to have a significant association with the phenotypes studied. In aggregate, our approach has identified O3-resistant (C3H/HeJ and A/J) and -vulnerable (C57BL/6J and 129/SvIm) strains of mice, and determined novel genomic loci, suggesting a clear genetic basis for the lung response to inhaled O3.     

Inflammatory sequences in acute pulmonary radiation injury.

The histopathologic events in the developing acute pulmonary inflammatory reaction to inhaled particles of Yttrium 90 are detailed. In animals that died or were sacrificed during the first year after inhalation exposure, microscopic findings of acute inflammation predominated and included vascular congestion; stasis, focal hemorrhage; edema; various inflammatory cell infiltrates; cytolysis and desquamation of bronchiolar and alveolar epithelium followed by regeneration; vascular injury and repair; and the eventual development of pulmonary fibrosis. Accumulation of alveolar fibrin deposits was an additional characteristic, though not a constant feature of the early stages of radiation pneumonitis. In addition to the direct effects of radiation on pulmonary cell populations, the histopathologic findings were suggestive of diverse activation of various cellular and humoral mediation systems in their pathogenesis. The potential interrelationships of systems responsible for increased vascular permeability, coagulation and fibrinolysis, chemotaxis, and direct cellular injury were discussed and related to the pathogenesis of the microscopic findings characteristic of early pulmonary radiation injury.     

Ability of restorative and fluoride releasing materials to prevent marginal dentine demineralization

The study aimed to define the in vitro secondary caries inhibiting potential of restorative materials currently used in dental practice. Class V restorations were prepared in extracted human third molars and immersed in a demineralizing solution (lactic acid, pH 4.5) at 37 degrees C for 2 days to simulate secondary caries formation. The bonding and the restorative systems tested in the study were: Scotchbond 1+Z 250 (Group A), Scotchbond 1+F 2000 (Group B), ABF+APX (Group C), ABF+F2000 (Group D). Perimarginal dentine, immediately close to the margin of the restoration, and exposed dentine, at approximately 0.5 mm from the margins of the restoration, after exposure to the acid solution, were investigated; protected dentine, at approximately 4 mm from the margin in a varnish-covered area, was analysed as control. Polarized light microscopy and contact transverse microradiography (TMR) were employed. The output parameters were lesion shape and size (depth in microm) of the exposed dentine, dentine mineral volume%, and integrated mineral loss (Delta Z, in %volmicrom) of the lesions. Compomers (Groups B and D) showed a thinner demineralization of the outer lesions, a less demineralization along the perimarginal dentine (inner lesion) and more caries inhibition zones or CIZs (Delta Z positive values) compared to composites (Groups A and C). In conclusion, Groups B and D materials seemed to partially counteract the marginal demineralization induced by an acid solution and favourably influence the formation of CIZs along the restorations. On the contrary, composites did not show a protective effect, probably due to an insufficient marginal seal and the lack of fluoride release.     

乌司他丁保护百草枯中毒大鼠肺免受损伤的作用

目的:探讨乌司他丁保护百草枯中毒大鼠肺免受损伤的作用及其机制。方法:Wistar大鼠108只,随机分为对照组、百草枯组和乌司他丁组。百草枯组和乌司他丁组给予百草枯灌胃染毒,对照组给予无菌生理盐水灌胃,乌司他丁组同时给予乌司他丁治疗。1、3、7、14、21、28 d测血清中的MDA、SOD、IL-6、IL-10和TNF-α水平,以及肺组织中的p38 MAPK、MMP-2和TIMP-1表达水平。结果:1、3、7 d百草枯组和乌司他丁组的SOD均较对照组下降(P0.01),乌司他丁组SOD明显高于百草枯组(P0.05)。1、3、7 d百草枯组和乌司他丁组的MDA、IL-6、IL-10及TNF-α均较对照组增高(P0.01),乌司他丁组各指标明显低于百草枯组(P0.05)。1、3、7、14、21、28d百草枯组和乌司他丁组肺组织中的p38 MAPK及TIMP-1均较对照组增高(P0.01),乌司他丁组各指标明显低于百草枯组(P0.05)。1、3、7、14、21 d百草枯组和乌司他丁组肺组织中的MMP-2均较对照组增高(P0.01),乌司他丁组MMP-2明显低于百草枯组(P0.05)。结论:乌司他丁通过抑制p38 MAPK信号通路及抗炎、抗氧化作用保护百草枯中毒大鼠肺免受损伤的作用。     

Present-day aspects (diagnosis, clinical course and treatment) of acute progressive pulmonary tuberculosis

A total of 103 patients with acute progressive pulmonary tuberculosis whose age ranged from 18 to 60 years were examined. Caseous pneumonic, infiltrative-caseous, disseminated, and rapidly progressive fibrocavernous tuberculosis was found in 45.6, 17.5, 16.5, and 20.4% of cases, respectively. The clinical picture was characterized by its acute onset with significant intoxication syndrome. Moreover, all the patients had respiratory and immunological failure, varying disseminated intravascular coagulation syndrome, non-specific bronchopulmonary infection; some presented with pulmonary hemorrhage, spontaneous pneumothorax and pleural empyema. The sputum smear test was positive in all the patients. If there was no evidence for drug resistance, patients had a 4-month regimen using isoniazid, rifampicin, pyrazinamide, ethembutol, and kanamycin. In the subsequent 10-12 months, isoniazid, rifampicin, and ethambutol were given. The patients with multidrug resistant tuberculosis were administered protionamide, ofloxacin, amikacin, supplemented by pyrazinamide and ethambutol. The combined chemotherapy could stop bacterial isolation in more than 80% of patients, make the process stable, and prepare them for planned surgical treatment. When complications occurred and the disease was in steady progress, salvage operations were made, which was the only possible way of preventing the progression of disease at times and of saving life in the patient.     

Automated bed to aid pulmonary drainage and prevent decubitus ulcers

A bed that automatically and periodically rotates a patient from side to side, and tilts the patient's head-to-toe axis about the horizontal plane, has been constructed to aid pulmonary drainage and prevent decubitus ulcers in a sleeping patient. The bed, which has been satisfactorily in use by the patient for one year, includes adjustable and separate frequencies of activation, ranges of movement, and alarm circuits for both motions. The complete system is relatively inexpensive, constructed from easily obtainable components, and should be easy for other institutions to duplicate.     

金属氧化物材料对小鼠急性肺损伤作用的研究

 摘要：目的 以C57 BL/6小鼠为模型对氧化铜、氧化铁、氧化钛、氧化硅等金属氧化物纳米材料的呼吸系统毒性进行比较和评估。方法 给C57 BL/6小鼠气管注射金属氧化物纳米材料,对给药后小鼠的死亡率、肺湿干比以及小鼠肺泡灌洗液中细胞因子的水平进行检测。结果 注射较高剂量氧化铜纳米材料的小鼠在24 h 内全部死亡,而相同剂量下注射其他金属氧化物未导致小鼠死亡;注射氧化铜纳米的小鼠肺湿干比显著高于对照组,且小鼠肺泡灌洗液中白细胞介素6的水平显著上升,而其他金属氧化物并未导致小鼠肺湿干比或白细胞介素6的水平的显著升高。结论 氧化铜纳米材料对C57 BL/6小鼠具有很强的致死性,并且引起小鼠肺水肿,导致小鼠急性肺损伤。而其他几种金属氧化物纳米材料的毒性较低,对小鼠的急性肺损伤作用较小。炎症因子IL-6水平在注射氧化铜纳米后显著增加,可能在氧化铜诱导的急性肺损伤中起到重要作用。     

Influence of endotoxin-induced acute lung injury on pulmonary innate and adaptive immunity

OBJECTIVE: The aim of our study was to analyze pulmonary innate and adaptive immune responses during endotoxemia-induced acute lung injury (ALI). EXPERIMENTAL DESIGN: Female BALB/c mice were challenged by endotoxin given intraperitoneally and followed for 24 h by unrestrained plethysmographic analysis. After this period, the mice were sacrificed by CO2 anesthesia and lung histopathology, pulmonary and serum levels of pro-inflammatory cytokines, numbers of lymphocyte subsets in blood and lung, and lung-derived macrophages (Mphi) were analyzed. MAIN RESULTS: Animals with endotoxemia demonstrated significant depression of tidal volumes indicating respiratory failure compared to control mice. Lung histopathology of endotoxin-exposed animals revealed alveolar leakage characterizing ALI. Pulmonary levels of interleukin (IL)-1beta, IL-6 and interferon (IFN)-gamma in animals with endotoxemia were significantly elevated, whereas serum levels of IL-6 only were increased. IFN-gamma was strongly expressed by lung-derived Mphi with high CD11b expression, and this subset significantly increased in the lungs after endotoxin challenge. Additionally, the numbers of lung-resident CD4+ and total T-lymphocytes were significantly reduced after challenge. CONCLUSION: These data suggest that endotoxemia-induced ALI is associated with exaggerated and sustained pulmonary innate immune responses partly mediated by activated Mphi, whereas adaptive immunity in the lungs is compromised.     

Effect of acute lung injury on structure and function of pulmonary surfactant films

The structural and functional alterations in pulmonary surfactant that occur during acute lung injury were studied using rat lung surfactant large aggregates (LA) isolated from normal nonventilated lungs (N), and from standard ventilated (V) and injuriously ventilated (IV) excised lungs. N lungs inflated significantly better than IV lungs, with V lungs intermediate. Although IV LA phosphatidylcholine levels were unchanged, cholesterol and protein were elevated. V LA exhibited PC/cholesterol and PC/protein ratios intermediate between N and IV. In contrast to total cholesterol and protein levels, these ratios were not significantly different from IV LA. N and V LA, but not IV LA, adsorbed rapidly and were able to generate surface pressures (pi) near 70 mN/m during surface area reduction at 37 degrees C on a captive bubble tensiometer. Langmuir-Wilhelmy surface balance studies at 23 degrees C showed N LA films consistently attained pi approaching 70 mN/m during ten compression-expansion cycles. IV films were less effective and failed to achieve high pi consistently after the sixth cycle. V films were intermediate. Epifluorescence studies revealed compression of adsorbed N LA films formed well-defined liquid-condensed (LC) domains, but fewer, smaller domains were observed with IV films and, to a lesser extent, V films. Atomic force microscopy on Langmuir-Blodgett N films transferred at pi = 30 mN/m showed high, well-defined LC domains. IV films showed thinner, intermediate height, possibly fluid domains, which contain large numbers of small higher domains with heights corresponding to LC domains. V films were intermediate. We conclude that acute lung injury induced by hyperventilation, and to a lesser extent standard ventilation, of excised lungs alters surfactant surface activity and the ability of natural surfactant to form surface structures at the air-water interface.     

Mitochondrial injury of pulmonary alveolar epithelial cells in acute paraquat intoxication

The primary ultrastructural changes in pulmonary alveolar epithelial cells are described in paraquat-injected rats. Within 6-12 hr a single intravenous injection of 40 mg/kg paraquat dichloride caused selective mitochondrial swelling and loss of intramitochondrial granules within 24 hr in alveolar Type II cells. As the mitochondrial injury advanced, microvilli disappeared from apical plasma membrane followed by a cell destruction and detachment from basement membrane. This was accompanied by secondary damage to Type II cells and interstitial cells. These results indicate that paraquat may affect primarily the Type II cells and the first lesion produced occurs in mitochondria.     

Time course of respiratory mechanics and pulmonary structural remodelling in acute lung injury

The aim of this study was to evaluate the time course of in vivo and in vitro respiratory mechanics and examine whether these parameters could reflect the temporal changes in lung parenchyma remodelling in paraquat (PQ)-induced lung injury. Measurements were done 1, 3 and 8 weeks after the intraperitoneal (i.p.) injection of saline (control) or paraquat (7mgkg(-1)) in rats. Airway and tissue resistances increased from control in PQ1 and PQ3 and returned to control values in PQ8, in accordance with the magnitude of bronchoconstriction. Viscoelastic/inhomogeneous pressure, tissue elastance, the number of polymorphonuclear cells, and collagen fibre content in lung parenchyma increased in PQ1 and remained elevated in PQ3 and PQ8. Static elastance increased in PQ1, returned to control values after 3 weeks, and was correlated with the volume fraction of collapsed alveoli. In conclusion, there is a restoration of normal alveolar-capillary lung units with a gradual improvement in airway and tissue resistances and static elastance. However, the on-going fibrotic process kept elevated tissue elastance and viscoelastic/inhomogeneous pressure.     

LPS性肺损伤大鼠一氧化氮合酶表达和肺细胞凋亡变化

目的: 观察内毒素性肺损伤过程中肺细胞凋亡和一氧化氮合酶（NOS）mRNA表达的时程性变化及关系,探讨LPS性肺损伤（ALI）的发病机制。方法: 健康雄性SD大鼠48只,随机分成2组:①对照组：静注等量生理盐水；②模型组(LPS组)：静注LPS复制ALI模型,分别于给药1、3、6、9及12h后采集样品；逆转录聚合酶链反应（RT-PCR）法测定肺组织中NOSmRNA表达变化；电镜、流式细胞术检测肺细胞凋亡率；免疫组化法测定Bcl-2和Bax；光镜、电镜观察肺组织病理变化。结果: 与对照组比较，LPS组iNOSmRNA表达随时间延长而增强，给予LPS 3 h后有显著差异(P<0.05)，eNOSmRNA随时间延长而降低，给LPS 3 h时有显著差异(P<0.05)，nNOSmRNA在观察时间内没有变化；光镜和电镜下可见在观察时间内1 h起肺损伤随时间延长加重；流式细胞术显示LPS组凋亡细胞随时间延长增多，9 h达高峰，12 h有所降低；免疫组化结果显示，LPS组随时间延长Bcl-2减少，主要表现在肺上皮细胞，Bax增多；对照组无明显变化。结论: 不同一氧化氮合酶在ALI中表达强度不同；抗凋亡蛋白Bcl-2和促凋亡蛋白Bax是ALI时调节细胞凋亡的途径之一；一氧化氮合酶可能通过调节Bcl-2和Bax平衡而影响凋亡。     

Vaccines to prevent severe acute respiratory syndrome coronavirus-induced disease

An important effort has been performed after the emergence of severe acute respiratory syndrome (SARS) epidemic in 2003 to diagnose and prevent virus spreading. Several types of vaccines have been developed including inactivated viruses, subunit vaccines, virus-like particles (VLPs), DNA vaccines, heterologous expression systems, and vaccines derived from SARS-CoV genome by reverse genetics. This review describes several aspects essential to develop SARS-CoV vaccines, such as the correlates of protection, virus serotypes, vaccination side effects, and bio-safeguards that can be engineered into recombinant vaccine approaches based on the SARS-CoV genome. The production of effective and safe vaccines to prevent SARS has led to the development of promising vaccine candidates, in contrast to the design of vaccines for other coronaviruses, that in general has been less successful. After preclinical trials in animal models, efficacy and safety evaluation of the most promising vaccine candidates described has to be performed in humans.     

Regional pulmonary inflammation in an endotoxemic ovine acute lung injury model

The regional distribution of inflammation during acute lung injury (ALI) is not well known. In an ovine ALI model we studied regional alveolar inflammation, surfactant composition, and CT-derived regional specific volume change (sVol) and specific compliance (sC). 18 ventilated adult sheep received IV lipopolysaccharide (LPS) until severe ALI was achieved. Blood and bronchoalveolar lavage (BAL) samples from apical and basal lung regions were obtained at baseline and injury time points, for analysis of cytokines (IL-6, IL-1β), BAL protein and surfactant composition. Whole lung CT images were obtained in 4 additional sheep. BAL protein and IL-1β were significantly higher in injured apical vs. basal regions. No significant regional surfactant composition changes were observed. Baseline sVol and sC were lower in apex vs. base; ALI enhanced this cranio-caudal difference, reaching statistical significance only for sC. This study suggests that apical lung regions show greater inflammation than basal ones during IV LPS-induced ALI which may relate to differences in regional mechanical events.     

Lack of endothelial nitric-oxide synthase leads to progressive focal renal injury

Because endothelial nitric-oxide synthase (eNOS) is generally considered protective against renal injury, we examined eNOS knockout mice for kidney pathology. In 80% of the adults examined, the renal surface was marked by distinct indented scars containing crowded small glomeruli but lacking attached tubules. Although vasculature was intact in the scars, Bowman's space was dilated and glomerular tufts were degenerated. The atubular glomeruli were embedded in a dense interstitial matrix composed of cells positive for fibroblast (FSP-1) or macrophage (F4/80) markers, degenerated proximal tubules and collecting ducts, and diffuse fibrotic deposits. Surrounding regions of kidney contained mostly normal-appearing tubules, but enlarged or sclerotic glomeruli were also present. In neonatal animals, apoptosis and necrosis were concentrated in tubules within focal parenchymal zones, with narrowing of the glomerulotubular "neck." In summary, targeted deletion of eNOS in mice leads to progressive focal renal abnormalities, including glomerular hypoplasia, and tubular cell death, leading to separation of glomeruli from tubules and tubular disruption. These abnormalities begin developing during the normal up-regulation of eNOS in the maturing kidney and are similar to those of a variety of chronic renal disorders. Endogenous renal eNOS production therefore seems critical for the maintenance of nephron maturation and integrity.     

The antioxidant hydroxypyridine-6 as an agent to prevent postresuscitation heart damage]

It was demonstrated in experiments on an intact organism and on an isolated isovolemically contracting rat heart that acute fatal blood loss and subsequent resuscitation cause depression of the contractile function due to extreme activation of lipid peroxidation processes and disturbed heart energy metabolism. Preliminary administration of the water soluble antioxidant oxypyridine-6 significantly reduces the heart functional metabolic disorders in the early postresuscitation period and reduces the postresuscitation mortality almost by half during the first 60 minutes after restoration to life.