Endothelial pathomechanisms in acute lung injury

Acute lung injury (ALI) and its most severe extreme the acute respiratory distress syndrome (ARDS) refer to increased-permeability pulmonary edema caused by a variety of pulmonary or systemic insults. ALI and in particular ARDS, are usually accompanied by refractory hypoxemia and the need for mechanical ventilation. In most cases, an exaggerated inflammatory and pro-thrombotic reaction to an initial stimulus, such as systemic infection, elicits disruption of the alveolo-capillary membrane and vascular fluid leak. The pulmonary endothelium is a major metabolic organ promoting adequate pulmonary and systemic vascular homeostasis, and a main target of circulating cells and humoral mediators under injury; pulmonary endothelium is therefore critically involved in the pathogenesis of ALI. In this review we will discuss mechanisms of pulmonary endothelial dysfunction and edema generation in the lung with special emphasis on the interplay between the endothelium, the immune and hemostatic systems, and highlight how these principles apply in the context of defined disorders and specific insults implicated in ALI pathogenesis.     

Measurement of various respiratory dynamics parameters following acute inhalational exposure to soman vapor in conscious rats

Abstract

Respiratory dynamics were investigated in head-out plethysmography chambers following inhalational exposure to soman in untreated, non-anesthetized rats. A multipass saturator cell was used to generate 520, 560 and 600?mg?×?min/m³ of soman vapor in a customized inhalational exposure system. Various respiratory dynamic parameters were collected from male Sprague-Dawley rats (300--350?g) during (20?min) and 24?h (10?min) after inhalational exposure. Signs of CWNA-induced cholinergic crisis were observed in all soman-exposed animals. Percentage body weight loss and lung edema were observed in all soman-exposed animals, with significant increases in both at 24?h following exposure to 600?mg?×?min/m³. Exposure to soman resulted in increases in respiratory frequency (RF) in animals exposed to 560 and 600?mg?×?min/m³ with significant increases following exposure to 560?mg?×?min/m³ at 24?h. No significant alterations in inspiratory time (IT) or expiratory time (ET) were observed in soman-exposed animals 24?h post-exposure. Prominent increases in tidal volume (TV) and minute volume (MV) were observed at 24?h post-exposure in animals exposed to 600?mg?×?min/m³. Peak inspiratory (PIF) and expiratory flow (PEF) followed similar patterns and increased 24?h post-exposure to 600?mg?×?min/m³ of soman. Results demonstrate that inhalational exposure to 600?mg?×?min/m³ soman produces notable alterations in various respiratory dynamic parameters at 24?h. The following multitude of physiological changes in respiratory dynamics highlights the need to develop countermeasures that protect against respiratory toxicity and lung injury.     

Protective effect of raloxifene on lipopolysaccharide and acid- induced acute lung injury in rats

Aim： To evaluate the protective effect of oral raloxifene on acute lung injury. Methods： Thirty adult, male Sprague-Dawley rats each weighing 180-210 g were used and divided into 3 groups： the raloxifene-lipopolysaccharide （LPS）-HCI group （n=10）, the LPS-raloxifene-HCl group （n=10）, and the placebo group （n=10）. All the rats were injected intraperitoneally （ip） with 5 mg/kg LPS, and raloxifene （30 mg/kg） was orally administered 1 h before and 14 h after LPS injection into the raloxifene-LPS-HCl and the LPS-raloxifene-HCl groups, respectively; the placebo group received nothing. Sixteen hours after LPS injection, all the animals were anesthetized and the femoral artery was cannulated. All the rats received a direct intratracheal （IT） injection ofHCl （pH 1.2; 0.5 mL/kg）. The mean arterial pressure （MAP） and blood gas concentrations were measured. Fifteen rats （5 in each group, respectively） underwent a micro positron emission tomography （microPET） scan of the thorax 4 h after HCI instillation. The wet/dry （W/D） weight ratio determination and histopathological examination were also performed. Results： The rats in the LPS-raloxifene-HCl group had a lower [^18F]fluorodeoxyglucose uptake compared with the rats in the placebo group （4.67±1.33 vs 9.01±1.58, respectively, P〈0.01）. The rats in the LPS-raloxifene-HCl group also had a lower histological lung injury score （8.20± 1.23 vs 12.6±0.97, respectively, P〈0.01） and W/D weight ratio （5.335±0.198 vs 5.886±0.257, respectively, P〈0.01） compared to the placebo group. The rats in this group also showed better pulmonary gas exchange and more stable mean arterial pressure （MAP） compared to the placebo group. Conclusion： Raloxifene provides a significant protective effect on acute lung injury in rats induced first by LPS ip injection and then by HCI IT instillation.     

特普他林对大鼠烟雾吸入伤后肺泡液体清除功能的影响

目的　观察特普他林对大鼠烟雾吸入伤后肺泡上皮液体清除能力变化的影响。方法　采用大鼠烟雾吸入性损伤模型。伤后 2 4h经气管滴注特普他林 ( 10 -4 mol·L-1)溶液 5ml·kg-1;1h后检测肺泡内液体清除率 (ALC)、总肺水量 (TLW )、肺血管外肺水量 (EVLW)和动脉血气指标。结果　大鼠伤后 2 4hALC降低 46 8% ,TLW和EVLW明显增加 ,出现严重的低氧血症。特普他林组ALC增高 5 7 6 % ,TLW和EVLW显著减少 ,低氧血症明显改善。钠转运特异性抑制剂阿咪洛利或哇巴因能部分抑制特普他林刺激肺泡内液体清除的作用。结论　特普他林通过上调钠主动转运机能 ,促进肺水肿液的吸收 ,从而改善换气功能 ,对吸入伤后肺水肿有一定的治疗作用     

Characterization of a nose-only inhaled phosgene acute lung injury mouse model

Abstract

Context: Phosgene’s primary mode of action is as a pulmonary irritant characterized by its early latent phase where life-threatening, non-cardiogenic pulmonary edema is typically observed 6‐24 h post-exposure.

Objective: To develop an inhaled phosgene acute lung injury (ALI) model in C57BL/6 mice that can be used to screen potential medical countermeasures.

Methods: A Cannon style nose-only inhalation exposure tower was used to expose mice to phosgene (8?ppm) or air (sham). An inhalation lethality study was conducted to determine the 8?ppm median lethal exposure (LCt₅₀) at 24 and 48 h post-exposure. The model was then developed at 1.2 times the 24 h LCt₅₀. At predetermined serial sacrifice time points, survivors were euthanized, body and lung weights collected, and lung tissues processed for histopathology. Additionally, post-exposure clinical observations were used to assess quality of life.

Results and discussion: The 24-hour LCt₅₀ was 226?ppm*min (8?ppm for 28.2?min) and the 48-hour LCt₅₀ was 215?ppm*min (8?ppm for 26.9?min). The phosgene exposed animals had a distinct progression of clinical signs, histopathological changes and increased lung/body weight ratios. Early indicators of a 1.2 times the 24-hour LCt₅₀ phosgene exposure were significant changes in the lung-to-body weight ratios by 4 h post-exposure. The progression of clinical signs and histopathological changes were important endpoints for characterizing phosgene-induced ALI for future countermeasure studies.

Conclusion: An 8?ppm phosgene exposure for 34?min (1.2?×?LCt₅₀) is the minimum challenge recommended for evaluating therapeutic interventions. The predicted higher mortality in the phosgene-only controls will help demonstrate efficacy of candidate treatments and increase the probability that a change in survival rate is statistically significant.     

Delayed low-dose supplemental oxygen improves survival following phosgene-induced acute lung injury

Phosgene is a chemical widely used in the plastics industry and has been used in warfare. It produces life-threatening pulmonary edema within hours of exposure; no antidote exists. This study examines pathophysiological changes seen following treatment with elevated inspired oxygen concentrations (Fio₂), in a model of phosgene-induced acute lung injury. Anesthetized pigs were exposed to phosgene (Ct 2500?mg min m^?3) and ventilated (intermittent positive pressure ventilation, tidal volume 10?ml kg^?1, positive end-expiratory pressure 3?cm H₂O, frequency 20 breaths min^?1). The Fio₂ was varied: group 1, Fio₂ 0.30 (228?mm Hg) throughout; group 2, Fio₂ 0.80 (608?mm Hg) immediately post exposure, to end; group 3, Fio₂ 0.30 from 30?min post exposure, increased to 0.80 at 6?h post exposure; group 4, Fio₂ 0.30 from 30?min post exposure, increased to 0.40 (304?mm Hg) at 6?h post exposure. Group 5, Fio₂ 0.30 from 30?min post exposure, increased to 0.40 at 12?h post exposure. The current results demonstrate that oxygen is beneficial, with improved survival, arterial oxygen saturation, shunt fraction, and reduced lung wet weight to body weight ratio in all treatment groups, and improved arterial oxygen partial pressure in groups 2 and 3, compared to phosgene controls (group 1) animals. The authors recommend that treatment of phosgene-induced acute lung injury with inspired oxygen is delayed until signs or symptoms of hypoxia are present or arterial blood oxygenation falls. The lowest concentration of oxygen that maintains normal arterial oxygen saturation and absence of clinical signs of hypoxia is recommended.     

Effects of inhaled aerosolized carfentanil on real-time physiological responses in mice: a preliminary evaluation of naloxone

This study examined the real-time exposure–response effects of aerosolized carfentanil (CRF) on opioid-induced toxicity, respiratory dynamics and cardiac function in mice. Unrestrained, conscious male CD-1 mice (25–30?g) were exposed to 0.4 or 4.0?mg/m³ of aerosolized CRF for 15?min (Ct?=?6 or 60?mg?min/m³) in a whole-body plethysmograph chamber. Minute volume (MV), core body temperature (T_c), mean arterial blood pressure (MAP) and heart rate (HR) were evaluated in animals exposed to CRF or sterile H₂O. Loss of consciousness and Straub tail were observed in before 1?min following initiation of exposure to 6 or 60?mg?min/m³ of CRF. Clinical signs of opioid-induced toxicity were observed in a dose-dependent manner. Exposure to 6 or 60?mg?min/m³ of CRF resulted in significant decrease in MV as compared to the controls. MAP, HR and T_c decreased 24?h in animals exposed to either 6 or 60?mg?min/m³ of CRF as compared to the controls. Post-exposure administration of naloxone (NX, 0.05?mg/kg, i.m.) did not increase the MV of animals exposed to CRF to control levels within 24?h, but decreased clinical signs of opioid-induced toxicity and the duration of respiratory depression. This is the first study to evaluate real-time respiratory dynamics and cardiac function during exposure and up to 24?h post-exposure to CRF. The evaluation of toxicological signs and respiratory dynamics following exposure to CRF will be useful in the development of therapeutic strategies to counteract the ongoing threat of abuse and overuse of opioids and their synthetic variants.     

Protective effect of magnolol-loaded polyketal microparticles on lipopolysaccharide-induced acute lung injury in rats

Magnolol has shown inhibitory effects on NO production and TNF-alpha production in lipopolysaccharide (LPS)-activated macrophages and LPS-induced acute lung injury; however, the poor solubility of magnolol has hindered its clinical success. In this study, magnolol-loaded microparticles were prepared via single emulsion method from a polyketal polymer, termed PK3. The particle sizes of magnolol-loaded PK3 microparticle is 3.73?±?0.41?μm, and was suitable for phagocytosis by macrophages and pulmonary drug delivery. PK3 microparticles exhibited excellent biocompatibility both in vitro and in vivo. More importantly, intratracheal delivery of these magnolol-loaded microparticles significantly reduced the lung inflammatory responses at low dosage of magnolol (0.5?mg/kg), and have great clinical potential in treating acute lung injury.     

Comparisons of acute inflammatory responses of nose-only inhalation and intratracheal instillation of ammonia in rats

Objective: To establish a rat model with respiratory and pulmonary responses caused by inhalation exposure to non-lethal concentrations of ammonia (NH₃) that can be used for evaluation of new medical countermeasure strategies for NH₃-induced acute lung injury (ALI). This is of great value since no specific antidotes of NH₃-induced injuries exist and medical management relies on supportive and symptomatically relieving efforts.

Methods: Female Sprague-Dawley rats (8–9?weeks old, 213g?±?2g) were exposed to NH₃ using two different exposure regimens; nose-only inhalation or intratracheal instillation. The experiment was terminated 5?h, 24?h, 14 and 28?days post-exposure.

Results: Nose-only inhalation of NH₃ (9000–15 000?ppm) resulted in increased salivation and labored breathing directly post-exposure. Exposure did not increase inflammatory cells in bronchoalveolar lavage fluid but exposure to 12 000?ppm NH₃ during 15?min reduced body weight and induced coagulation abnormalities by increasing serum fibrinogen levels. All animals were relatively recovered by 24?h. Intratracheal instillation of NH₃ (1%) caused early symptoms of ALI including airway hyperresponsiveness, neutrophilic lung inflammation and altered levels of coagulation factors (increased fibrinogen and PAI-1) and early biomarkers of ALI (IL-18, MMP-9, TGFβ) which was followed by increased deposition of newly produced collagen 14?days later. Histopathology analysis at 5?h revealed epithelial desquamation and that most lesions were healed after 14?days.

Conclusions: This study demonstrates that intratracheal instillation can reproduce several early hallmarks of ALI. Our findings therefore support that the intratracheal instillation exposure regimen can be used for new medical countermeasure strategies for NH₃-induced ALI.     

Assessment of early acute lung injury in rodents exposed to phosgene

Phosgene is a highly reactive oxidant gas used in the chemical industry. Phosgene can cause life-threatening pulmonary edema by reacting with peripheral lung compartment tissue components. Clinical evidence of edema is not usually apparent until well after the initial exposure. This study was designed to investigate early signs of acute lung injury in rodents within 45–60 min after the start of exposure. Male mice, rats, or guinea pigs were exposed to 87 mg/m³ (22 ppm) phosgene or filtered room air for 20 min followed by room air washout for 5 min. This concentration-time exposure causes a doubling of lung wet weight within 5 h. After exposure, animals were immediately anesthetized i.p., with pentobarbital. Bronchoalveolar lavage (BAL) was performed and fluid analyzed for total glutathione (GSH), lipid peroxidation thiobarbituric acid reactive substances (TBARS), and protein concentration. Lungs were perfused with saline to remove blood, freeze-snapped in liquid N₂, analyzed for tissue GSH, and TBARS. Lung edema was assessed gravimetrically by measuring tissue wet/dry (W/D) weight ratios and tissue wet weights (TWW). W/D and TWW were significantly higher in mice for phosgene vs air (P=0.001, P<0.0001, respectively), but not in rats or guinea pigs. Tissue TBARS was significantly higher in phosgene-exposed guinea pigs, P=0.027; however, BAL TBARS was higher in both rats and guinea pigs, P=0.013 and P=0.006, respectively. Tissue GSH was significantly lower in phosgene-exposed rats and guinea pigs but not mice, whereas BAL GSH was higher in rats, P<0.0001. There were significantly higher BAL protein levels in all phosgene-exposed species: mice, P<0.0001; rats, P<0.0001; and guinea pigs, P=0.002. Although there appears to be a species-specific biochemical effect of phosgene exposure for some biochemical indices, measurement of BAL protein in all three species is a better indicator of ensuing edema formation. Received: 30 June 1997 / Accepted: 5 January 1998     

Combined inhaled diesel exhaust particles and allergen exposure alter methylation of T helper genes and IgE production in vivo.

Changes in methylation of CpG sites at the interleukin (IL)-4 and interferon (IFN)-gamma promoters are associated with T helper (Th) 2 polarization in vitro. No previous studies have examined whether air pollution or allergen exposure alters methylation of these two genes in vivo. We hypothesized that diesel exhaust particles (DEP) would induce hypermethylation of the IFN-gamma promoter and hypomethylation of IL-4 in CD4+ T cells among mice sensitized to the fungus allergen Aspergillus fumigatus. We also hypothesized that DEP-induced methylation changes would affect immunoglobulin (Ig) E regulation. BALB/c mice were exposed to a 3-week course of inhaled DEP exposure while undergoing intranasal sensitization to A. fumigatus. Purified DNA from splenic CD4+ cells underwent bisulfite treatment, PCR amplification, and pyrosequencing. Sera IgE levels were compared with methylation levels at several CpG sites in the IL-4 and IFN-gamma promoter. Total IgE production was increased following intranasal sensitization A. fumigatus. IgE production was augmented further following combined exposure to A. fumigatus and DEP exposure. Inhaled DEP exposure and intranasal A. fumigatus induced hypermethylation at CpG(-45), CpG(-53), CpG(-205) sites of the IFN-gamma promoter and hypomethylation at CpG(-408) of the IL-4 promoter. Altered methylation of promoters of both genes was correlated significantly with changes in IgE levels. This study is the first to demonstrate that inhaled environmental exposures influence methylation of Th genes in vivo, supporting a new paradigm in asthma pathogenesis.     

Adverse respiratory effects in rats following inhalation exposure to ammonia: respiratory dynamics and histopathology

Acute respiratory dynamics and histopathology of the lungs and trachea following inhaled exposure to ammonia were investigated. Respiratory dynamic parameters were collected from male Sprague–Dawley rats (300–350?g) during (20?min) and 24?h (10?min) after inhalation exposure for 20?min to 9000, 20,000, and 23,000?ppm of ammonia in a head-only exposure system. Body weight loss, analysis of blood cells, and lungs and trachea histopathology were assessed 1, 3, and 24?h following inhalation exposure to 20,000?ppm of ammonia. Prominent decreases in minute volume (MV) and tidal volume (TV) were observed during and 24?h post-exposure in all ammonia-exposed animals. Inspiratory time (IT) and expiratory time (ET) followed similar patterns and decreased significantly during the exposure and then increased at 24?h post-exposure in all ammonia-exposed animals in comparison to air-exposed controls. Peak inspiratory (PIF) and expiratory flow (PEF) significantly decreased during the exposure to all ammonia doses, while at 24?h post-exposure they remained significantly decreased following exposure to 20,000 and 23,000?ppm. Exposure to 20,000?ppm of ammonia resulted in body weight loss at 1 and 3?h post-exposure; weight loss was significant at 24?h compared to controls. Exposure to 20,000?ppm of ammonia for 20?min resulted in increases in the total blood cell counts of white blood cells, neutrophils, and platelets at 1, 3, and 24?h post-exposure. Histopathologic evaluation of the lungs and trachea tissue of animals exposed to 20,000?ppm of ammonia at 1, 3, and 24?h post-exposure revealed various morphological changes, including alveolar, bronchial, and tracheal edema, epithelial necrosis, and exudate consisting of fibrin, hemorrhage, and inflammatory cells. The various alterations in respiratory dynamics and damage to the respiratory system observed in this study further emphasize ammonia-induced respiratory toxicity and the relevance of efficacious medical countermeasure strategies.     

脓毒症相关性急性肺损伤发病机制研究进展

急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）是临床上常见的危重病之一,病因多、影响因素复杂、救治困难,病死率高。脓毒症是危重病最主要的死亡原因,也是引起ALI/ARDS的最常见的病因,尽管对脓毒症致ALI/ARDS的机制研究较多,其确切机制尚不完全清楚。本文就脓毒症致急性肺损伤的发病机制进行综述。     

L-硝基精氨酸对大鼠内毒素性肺损伤治疗作用及其机制的研究

目的探讨L-硝基精氨酸（NG—nitro-L—arginine,L—NA）对内毒素性肺损伤大鼠肺表面活性物质（PS）和细胞凋亡的影响,探讨L—NA对肺损伤的保护作用及其机制。方法健康雄性SD大鼠采用舌下静脉注射脂多糖（LPS）复制肺损伤模型,分别于给予LPS 1h和6b后给予0．9％氯化钠溶液（对照纽及LPS组,静脉给药）和L-NA（20mg／kg,静脉给药）（L-NA治疗组）,治疗3h,取肺组织,原位杂交法（ISH）测定肺组织肺表面活性物质蛋白A（SP-A）mRNA;流式细胞术（FCM）检测肺细胞凋亡率;Western blot法检测Caspase-3蛋白的表达;免疫组化法测定Bcl-2和Bax蛋白的表达。结果与对照组比较,大鼠肺损伤后SP-A mRNA表达明显下降（P〈0．01）;细胞凋亡率、Caspase-3和Bax蛋白表达明显升高（P〈0．01）,Bcl-2蛋白表达和Bcl-2／Bax降低（P〈0．01）;肺损伤1h用L—NA治疗3h后,SP-A mRNA阳性细胞表达明显增强（P〈0．05）,细胞凋亡率降低（P〈0．05）;但Caspase-3、Bax、Bcl-2蛋白表达、Bcl-2／Bax与LPS组比较没有明显的变化（P〈0．05）,肺组织病理改变减轻,肺损伤6h用L—NA治疗3h对LPS引起的以上变化没有明显影响。结论肺损伤1h后给予L—NA可减轻内毒素性肺损伤,增强PS表达,减少细胞凋亡是其机制之一。     

二甲基阿米洛利对大鼠油酸性急性肺损伤的保护作用

The effect of Na⁺/H⁺ exchange inhibitor dimethyl amiloride(DMA) on rat acute lung injury induced by oleic acid was studied. Five hours after administration (iv) of oleic acid (10 mL·kg^-1), pulmonary coefficient, lung wet/dry weight ratio and protein content, lactic acid dehydrogenase(LDH) activity, total white blood cell(WBC) and polymorphonuclear leukocyte(PMN) in bronchoalveolar lavage(BAL) of rat were increased significantly. However, after pretreatment with DMA(0.2 mg·kg^-1 iv) for 10 min, the pulmonary coefficient and lung wet/dry weight ratio were decreased from 1.12±0.06 to 0.87±0.05 and 5.8±0.5 to 4.5±0.3, respectively. The protein content, LDH activity, total WBC and PMN in BAL were also reduced from (1.69±0.15) g·L^-1 to (1.05±0.13) g·L^-1, (3.37±0.25) μmol·min^-1·L^-1 to (0.81±0.08) μmol·min^-1·L^-1, (4.3±0.9) ×10⁶·L^-1 to (2.4±0.8) ×10⁶·L^-1 and (2.4±0.4) ×10⁶·L^-1 to (1.6±0.4) ×10⁶·L^-1, respectively. These results suggest that activation of Na⁺/H⁺ exchange be involved in the acute rat lung injury induced by oleic acid and that inhibitor of sodium-hydrogen exchange prevent the rat lungs from this injury.     

大剂量呋塞米持续静脉泵入对早期急性肾损伤伴急性肺水肿的临床疗效

目的 研究大剂量呋塞米持续静脉泵入对早期急性肾损伤伴急性肺水肿的临床疗效。方法 选择2012年2月~2015年12月在陕西省人民医院进行诊治的早期急性肾损伤伴急性肺水肿患者180例,所有患者均先持续静脉泵入1~2 mg/min呋塞米,再按照患者尿量的多少调整呋塞米的用药剂量。分别在治疗前和治疗后6、12、24、48、72 h,观察并记录患者的血肌酐、血尿素氮、氧合指数、血钾、机械通气时间、pH值、预后情况和不良反应发生情况。结果 呋塞米用药剂量开始减少的时间平均为（12.15±3.12）h;呋塞米的应用时间平均为（46.31±4.89）h;治疗后各时间点患者的血肌酐、血尿素氮、氧合指数、pH值和血钾均与治疗前有明显差异（P<0.05）,且治疗后各时间点上述观察指标均有明显差异（P<0.05）;180例患者中,治疗后有161例肾功能恢复,占89.44%,呼吸困难的症状得到明显减轻,X线胸片发现肺水肿有明显好转,成功停止机械通气,机械通气时间平均为（35.28±11.37）h;在治疗过程中,180例患者血流动力学稳定,均未出现低血压、耳聋和耳鸣等不良反应。结论 给予大剂量呋塞米治疗早期急性肾损伤伴急性肺水肿,能明显增加尿量,改善肾功能、内环境紊乱和预后,提高救治成功率。     

Early lung injury contributes to lung fibrosis via AT1 receptor in rats

AIM: Angiotensin II is believed to play an important role in tissue repair and remodeling in lungs by the angiotensin type I (AT1) receptor via a number of potential mechanisms. However, the role of the AT1 receptor in early lung injury has not been characterized. METHODS: Bleomycin-induced pulmonary fibrosis (PF) in rats was utilized to value the treatment with valsartan, an AT1 receptor antagonist, by measurement of body weight, wet weight of the left lung, hydroxy-proline content, mRNA expression of collagen I/III, and the degree of fibrosis in lung tissues on d 21. Tissue injury in the early phase was assessed on d 1, 3 and 7 by apoptosis, malondialdehyde content, myeloperoxidase activity, inflammatory cell count and protein content. Angiotensin converting enzyme (ACE) activity and the AT1 receptor in lung tissues were analyzed by biochemistry method and Western blotting, respectively. RESULTS: Valsartan ameliorated PF induced by bleomycin in the rats on d 21. After bleomycin was injected intratracheally, increases in the lung AT1 receptor and ACE activity were observed by d 1, 3 and 7. Lung injury deteriorated in the early phase. Valsartan reduced the increase of the AT1 receptor, ACE activity and lung injury induced by bleomycin in the early phase. CONCLUSION: These observations suggest that angiotensin II may play a potent role in early lung injury via the AT1 receptor. AT1 receptor antagonists should be assessed as potential new therapies for fibrotic lung disease.     

二甲基阿米洛利对大鼠油酸性急性肺损伤的保护作用

呼吸窘迫综合征（ｒｅｓｐｉｒａｔｏｒｙｄｉｓｔｒｅｓｓｓｙｎｄｒｏｍｅ,ＲＤＳ）是一种死亡率高达５０％以上的以肺泡毛细血管损伤为特征的疾病［１］．油酸（ｏｌｅｉｃａｃｉｄ,ＯＡ）性肺损伤动物模型产生与ＲＤＳ病人相似的表现,已被广泛用于ＲＤＳ发病机理和...     

白藜芦醇对脂多糖诱导小鼠急性肺损伤的保护作用

目的研究白藜芦醇对脂多糖(LPS)致小鼠急性肺损伤(ALI)的保护作用,探讨其可能的作用机制。方法以小鼠气道滴注LPS制备急性肺损伤模型,检测气道吸气阻力(Ri)、气道呼气阻力(Re)和动态肺顺应性(Cdyn)的变化,测定支气管肺泡灌洗液(BALF)中白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)和肿瘤坏死因子-α(TNF-α)的含量,检测肺湿/干比值和毛细血管通透性,观察组织病理学变化。结果白藜芦醇能明显抑制Ri、Re增长和Cdyn降低,降低BALF中IL-1βI、L-6、TNF-α的含量,降低肺湿/干比值和渗透性,减轻肺组织病理学的损伤。结论白藜芦醇对LPS诱导的ALI具有保护作用,作用机制可能与抑制炎症因子的合成与释放有关。     

重症急性胰腺炎大鼠肺损伤的病理生理变化及机制研究

目的观察重症急性胰腺炎大鼠肺损伤的病理生理变化并探讨其发生机制。方法选取2008年1月至2009年1月健康雄性SD(Sprague-Dawley)大鼠240只,按照随机数字表随机均分为8组,每组30只,即重症急性胰腺炎(SAP)不同时间点组(SAP 1 h、3 h、6 h、9 h、12 h、18 h、24 h组)和对照组。比较各组血清淀粉酶、肺组织湿/干重比、肺髓过氧化物酶(myeloperoxidase,MPO)活性、肺通透性指数的变化。结果观察组大鼠肺损伤组织评分、肺组织湿干重比以及肺髓过氧化物酶(MPO)水平随着时间的延续逐渐升高,各时间点组均明显高于对照组(P<0.05),观察组肺通透性指数随时间延续呈逐渐降低趋势,均低于对照组,差异均有统计学意义(P<0.05)。肺组织MPO水平与肺损伤评分存在正相关(r=0.946,P<0.01),肺湿干重比与肺损伤评分呈正相关(r=0.879,P<0.01),肺通透性指数与肺损伤评分存在负相关(r=-0.859,P<0.01)。结论重症急性胰腺炎大鼠肺损伤的损伤程度随SAP病程延长而逐渐增加,肺组织MPO水平持续升高。