辛伐他汀对急性肺损伤及囊性纤维化跨膜传导调节体表达的影响

目的:探讨辛伐他汀对急性肺损伤大鼠囊性纤维化跨膜传导调节体(CFTR氯离子通道)的影响及其对减轻急性肺损伤的作用。方法:40只雄性SD大鼠随机分为空白组、模型组、辛伐他汀低剂量组(20 mg/kg)、辛伐他汀中剂量组(40 mg/kg)、辛伐他汀高剂量组(80 mg/kg);气道内滴注脂多糖(10 mg/kg)制备急性肺损伤模型。进行肺湿/干重比、肺泡灌洗液蛋白检测,HE染色观察肺组织的病理变化;实时荧光定量PCR检测肺组织匀浆CFTR mRNA表达。结果:结果显示,模型组的肺湿干重比,肺泡灌洗液蛋白较空白组高(P0.05),病理示肺泡膈增厚,大量炎性细胞浸润,肺泡腔内可见红细胞及血肿,提示模型复制成功。辛伐他汀低剂量组的肺湿/干重比、肺泡灌洗液蛋白与模型组相比无明显差异,病理可见肺损伤较重,与模型组相比无改善;CFTR mRNA表达与模型组相比稍高但无明显差异(P0.05)。辛伐他汀中高剂量组中肺湿/干重比、肺泡灌洗液蛋白与模型组相比有所降低,肺组织CFTRmRNA表达较模型组明显增加(P0.05),但中高剂量组之间无明显差异(P0.05);病理可见肺泡膈增厚,极少见炎性细胞浸润及透明膜,肺泡腔内未见明显出血和水肿,肺损伤程度较模型组减轻。结论:中高剂量的辛伐他汀(40 mg/kg)对急性肺损伤有一定保护作用,并上调CFTR的表达。     

Early intravenous unfractionated heparin and outcome in acute lung injury and acute respiratory distress syndrome -- a retrospective propensity matched cohort study

ABSTRACT: BACKGROUND: Acute lung injury (ALI) is characterized by a pro-coagulant state. Heparin is an anticoagulant with anti-inflammatory properties. Unfractionated heparin has been found to be protective in experimental models of ALI. We hypothesized that an intravenous therapeutic dose of unfractionated heparin would favorably influence outcome of critically ill patients diagnosed with ALI. METHODS: Patients admitted to the Intensive Care Unit (ICU) of a tertiary referral center in the Netherlands between November 2004 and October 2007 were screened. Patients who developed ALI (consensus definition) were included. In this cohort, the impact of heparin use on mortality was assessed by logistic regression analysis in a propensity matched case--control design. RESULTS: Of 5,561 admitted patients, 2,138 patients had a length of stay > 48 hours, of whom 723 were diagnosed with ALI (34 %), of whom 164 received intravenous heparin. In a propensity score adjusted logistic regression analysis, heparin use did not influence 28-day mortality (odds ratio 1.23 [confidence interval 95 % 0.80--1.89], nor did it affect ICU length of stay. CONCLUSIONS: Administration of therapeutic doses of intravenous unfractionated heparin was not associated with reduced mortality in critically ill patients diagnosed with ALI. Heparin treatment did not increase transfusion requirements. These results may help in the design of prospective trials evaluating the use of heparin as adjunctive treatment for ALI.     

The therapeutic effects of anti-oxidant and anti-inflammatory drug quercetin on aspiration-induced lung injury in rats

Aspiration pneumonitis refers to acute chemical lung injury caused by aspiration of sterile gastric contents. The aim of this study was to evaluate the role of quercetin (QC) in acid aspiration-induced lung injury in rats. Twenty-eight female Sprague–Dawley rats were used and divided into the following groups (n = 7): sham (aspirated normal saline, S), hydrochloric acid (aspirated HCl), S plus treatment with QC (S + QC), and HCl plus treatment with QC (HCl + QC). After aspiration, the treatment groups received QC 60 mg/kg/day intraperitoneally once a day for 7 days. As a result of acid aspiration, an increase was observed in the levels of serum clara cell protein-16 (CC-16) and advanced oxidation protein products, whereas there was a decrease in serum thiobarbituric acid-reactive substances, superoxide dismutase (SOD), and catalase levels. There was a significant decrease in peribronchial inflammatory cell infiltration, alveolar septal infiltration, alveolar edema, and alveolar exudate scores, except in the alveolar histiocytes in the HCl + QC group. The expression of nitric oxide synthase, which increased after aspiration in the HCl group, showed a statistically significant decrease after the QC treatment. After the treatment with QC, an increase in the serum SOD level was observed, whereas a significant decrease was determined in the serum CC-16 level relative to that of the aspiration group (HCl). The antioxidant QC is effective in the treatment of lung injury following acid aspiration and can be used as a serum CC-16 biomarker in predicting the severity of oxidative lung injury.     

Effects of pretreatment with anti-inflammatory drugs on ozone-induced lung damage in rats.

The effects of pretreatment with acetylsalicylic acid (aspirin), hydrocortisone, indomethacin, and heparin administered ip against the pulmonary edema produced by O3-exposure (4 ppm for 4 hr) were studied in rats. These anti-inflammatory drugs were found to alter the injurious effect of O3 on lung differently. First, aspirin at the high dose (125 mg/kg) accentuated O3-induced lung injury, and had no effect at the low dose (10 mg/kg); second, hydrocortisone (50 mg/kg) failed to have any effect; third, indomethacin at a high dose (20 mg/kg) offered a significant degree of protection, but had no effect at the low dose (2.5 mg/kg); and fourth, heparin (1000 units/kg) also offered a significant degree of protection against the lung damage normally induced by O3-exposure. Several mechanisms for the favorable and unfavorable interactions of anti-inflammatory drugs with O3-exposure are discussed.     

The involvement of nitric oxide,nitric oxide synthase,neutrophil elastase,myeloperoxidase and proinflammatory cytokines in the acute lung injury caused by phorbol myristate acetate

Phorbol myristate acetate (PMA) causes acute lung injury (ALI). The present study was designed to elucidate the role of nitric oxide (NO), inducible NO synthase (iNOS), neutrophil elastase (NE) and other mediators in the ALI caused by PMA. In isolated rat’s lungs, PMA at various doses (1, 2 and 4 μg/g lung weight) was added into the lung perfusate. Vehicle group received dimethyl sulfoxide (the solvent for PMA) 100 μg/g. We measured the lung weight changes, pulmonary arterial pressure, capillary filtration coefficient, exhaled NO, protein concentration in bronchoalveolar lavage (PCBAL) and Evan blue dye leakage. Nitrate/nitrite, methyl guanidine, proinflammatory cytokines, NE and myeloperoxidase (MPO) in lung perfusate were determined. Histopathological examination was performed. We detected the iNOS mRNA expression in lung tissue. PMA caused dose-dependent increases in variables for lung changes, and nitrate/nitrite, methyl guanidine, proinflammatory cytokines, NE and MPO in lung perfusate. The pathology was characterized by alveolar hemorrhagic edema with inflammatory cell infiltration. Scanning electron microscopy revealed endothelial damage. PMA upregulated the expression of iNOS mRNA. Our results suggest that neutrophil activation by PMA causes release of NE, upregulation of iNOS and a series of inflammatory responses leading to endothelial damage and ALI.     

Identification of ectonucleotidases CD39 and CD73 in innate protection during acute lung injury

Acute lung injury (ALI), such as that which occurs with mechanical ventilation, contributes to morbidity and mortality of critical illness. Nonetheless, in many instances, ALI resolves spontaneously through unknown mechanisms. Therefore, we hypothesized the presence of innate adaptive pathways to protect the lungs during mechanical ventilation. In this study, we used ventilator-induced lung injury as a model to identify endogenous mechanisms of lung protection. Initial in vitro studies revealed that supernatants from stretch-induced injury contained a stable factor which diminished endothelial leakage. This factor was subsequently identified as adenosine. Additional studies in vivo revealed prominent increases in pulmonary adenosine levels with mechanical ventilation. Because ectoapyrase (CD39) and ecto-5'-nucleotidase (CD73) are rate limiting for extracellular adenosine generation, we examined their contribution to ALI. In fact, both pulmonary CD39 and CD73 are induced by mechanical ventilation. Moreover, we observed pressure- and time-dependent increases in pulmonary edema and inflammation in ventilated cd39(-/-) mice. Similarly, pharmacological inhibition or targeted gene deletion of cd73 was associated with increased symptom severity of ventilator-induced ALI. Reconstitution of cd39(-/-) or cd73(-/-) mice with soluble apyrase or 5'-nucleotidase, respectively, reversed such increases. In addition, ALI was significantly attenuated and survival improved after i.p. treatment of wild-type mice with soluble apyrase or 5'-nucleotidase. Taken together, these data reveal a previously unrecognized role for CD39 and CD73 in lung protection and suggest treatment with their soluble compounds as a therapeutic strategy for noninfectious ALI.     

氨溴索与肝素联合应用对急性肺损伤兔TNF-α和IL-1β的影响

目的：探讨联合应用氨溴索与小剂量肝素对急性肺损伤（ALI）时氧化应激,TNF-α和IL-1β变化的干预及其机制。方法：健康日本大耳白兔24只,随机分成3组（n=8）：①生理盐水对照组（NC）,②油酸损伤组（OA）,③氨溴索＋小剂量肝素治疗组（AH）。各组分别在给药前和给药后6 h采血及测定动脉血氧分压（PaO2）、肿瘤坏死因子-α（TNF-α）、白介素-1β（IL-1β）的含量,实验结束后肉眼观察肺病理改变,测定支气管肺泡灌洗液（BALF）以及肺组织匀浆中TNF-α、IL-1β、超氧化物歧化酶（SOD）、丙二醛（MDA）、黄嘌呤氧化酶（XO）、谷胱甘肽过氧化物酶（GSH-Px）的含量,检测肺组织原位凋亡细胞变化、肺组织湿干比（W/D）,光镜观察肺组织病理改变,电镜观察肺组织超微结构变化。结果：①光镜,电镜观察结果以及W/D提示氨溴索＋小剂量联合治疗减轻了ALI造成的肺组织形态学改变。②OA组中显著降低的PaO2均在AH组明显升高（P〈0.01）。③抗氧化指标GSH-Px和SOD活力检测,发现AH组比OA组有不同程度升高（P〈0.01或P〈0.05）,而氧化性指标XO活力和MDA含量则较OA组显著降低（P〈0.01）。④除给药前IL-1β外,在OA组中IL-1β、TNF-α含量均显著高于NC组（P均〈0.01）,但在AH组中有显著的降低（P〈0.01）。⑤AH组凋亡指数（AI）比OA组显著降低（P〈0.01）。结论：在OA致ALI时,TNF-α和IL-1β明显升高,参与了ALI的发生与发展。联合应用氨溴索与小剂量肝素可减轻氧化应激反应,抑制促炎细胞因子TNF-α和IL-1β释放,发挥对ALI的治疗作用。     

VEGF, Bcl-2 and Bad regulated by angiopoietin-1 in oleic acid induced acute lung injury

Molecular mechanisms of acute lung injury (ALI) are poorly defined. Our previous study demonstrated that recombinant angiopoietin-1 (Ang1) can protect against oleic acid (OA) induced ALI at an early stage. The purpose of this study was to elucidate whether vascular endothelial growth factor (VEGF), Bcl-2, and Bad, phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) play any role in the protective mechanism of recombinant Ang1 in OA-induced ALI. All BALB/C mice were administered a single dose of OA to induce lung injury. Lungs, bronchoalveolar lavage fluid (BALF), and serum were harvested at certain time points. The expression of VEGF, Bcl-2, Bad, PI3K/Akt, and the histological changes in the lung, and the levels of VEGF, IL-6, and IL-10 in serum and BALF were examined. A second cohort of mice was followed for survival for 7 days. We observed increased expression of VEGF in BALF and serum and reduced expression of VEGF in lung tissue. Recombinant Ang1 treatment, however, up-regulated VEGF expression and p-Akt/Akt in lung tissue but down-regulated VEGF expression in BALF and serum. OA led to a decrease of anti-apoptotic marker Bcl-2 and a marked increase of pro-apoptotic marker Bad. Compared with the ALI group, in the recombinant Ang1 treated group, Bcl-2 expression was restored, and Bad expression was clearly attenuated. In addition, recombinant Ang1 attenuated the lung pathological changes and improved the survival of mice. These findings suggest that recombinant Ang1 may be a promising potential treatment for ALI. It seems that VEGF is mediated by PI3K/Akt pathway which is required for Ang1-mediated protection of lung injury. Activation of Akt stimulates expression of Bcl-2 and inhibits the expression of Bad, thus inhibiting the execution of apoptosis.     

Lung inflammation and endothelial cell damage are decreased after treatment with phototherapy (PhT) in a model of acute lung injury induced by Escherichia coli lipopolysaccharide in the rat

Lipopolysaccharide (LPS) mimics the symptoms of acute lung injury (ALI), which is characterized by the accumulation in the lungs of neutrophils producing inflammatory mediators. Because of the lack of information about phototherapy (PhT) effects on ALI, we investigated whether PhT (685 nm InGaAlP) attenuates LPS-induced ALI. PhT reduced lung edema, the accumulation of TNF-α in the lung, and myeloperoxidase (MPO) activity. However, PhT was not efficient in reducing of TNF-α concentration in both serum and neutrophils of blood after LPS. In another series of experiments, in vitro assays of the effects of PhT effect on mouse pulmonary arterial endothelium cells (MPAECs) after TNF-α showed that the laser restores the MPAECs damage induced at 6 or 24 h after TNF-α. These results suggest the PhT effect on ALI is partly due to inhibition of TNF-α release from neutrophils and lung cells.     

Cyclooxygenase 2 plays a pivotal role in the resolution of acute lung injury

Acute lung injury (ALI) is a severe illness with excess mortality and no specific therapy. In its early exudative phase, neutrophil activation and accumulation in the lung lead to hypoxemia, widespread tissue damage, and respiratory failure. In clinical trials, inhibition of proinflammatory mediators has not proven effective. In this study, we pursued a new investigative strategy that emphasizes mediators promoting resolution from lung injury. A new spontaneously resolving experimental murine model of ALI from acid aspiration was developed to identify endogenous proresolving mechanisms. ALI increased cyclooxygenase 2 (COX-2) expression in murine lung. Selective pharmacologic inhibition or gene disruption of COX-2 blocked resolution of ALI. COX-2-derived products increased levels of the proresolving lipid mediators lipoxin A4 (LXA4) and, in the presence of aspirin, 15-epi-LXA4. Both LXA4 and 15-epi-LXA4 interact with the LXA4 receptor (ALX) to mediate anti-inflammatory actions. ALX expression was markedly induced by acid injury and transgenic mice with increased ALX expression displayed dramatic protection from ALI. Together, these findings indicate a protective role in ALI for COX-2-derived mediators, in part via enhanced lipoxin signaling, and carry potential therapeutic implications for this devastating clinical disorder.     

Effect of cyclooxygenase inhibition on ethchlorvynol-induced acute lung injury in dogs

In anesthetized dogs ethchlorvynol (ECV, 9 mg/kg) was selectively administered into the right pulmonary circulation to produce unilateral acute lung injury (ALI) characterized by nonhydrostatic pulmonary edema and systemic hypoxemia. To investigate the hypothesis that products of cyclooxygenase activity are mediators of the arterial hypoxemia, but not the edema formation in this injury, animals were pretreated with one of two chemically dissimilar cyclooxygenase inhibitors, indomethacin (5 mg/kg), or ibuprofen (12.5 mg/kg), or vehicle (0.1 M sodium carbonate) prior to the administration of ECV. Pretreatment with either inhibitor prevented the ECV-induced systemic hypoxemia observed in animals pretreated with vehicle (P less than 0.01). Despite this protection of systemic oxygenation, there was no redistribution of blood flow to the uninjured lung following unilateral ECV administration. Cyclooxygenase inhibition prior to ALI did not attenuate the accumulation of lung water. In the ibuprofen group, left atrial pressure increased significantly following ECV administration. We conclude that a product(s) of cyclooxygenase-mediated arachidonic acid metabolism is responsible for the altered vascular reactivity and consequent systemic hypoxemia in this model, but that the edema formation following ECV is not related to cyclooxygenase activity. In addition, ibuprofen, administered prior to the induction of ALI, exhibits properties not shared by indomethacin but is not different in its capacity to attenuate hypoxemia or in its failure to limit edema formation.     

Hypoxia enhances unilateral lung injury by increasing blood flow to the injured lung

We hypothesized that in unilateral lung injury, bilateral hypoxic ventilation would induce vasoconstriction in the normal lung, redirect blood flow to the injured lung, and cause enhanced edema formation. Unilateral left lung injury was induced by intrabronchial instillation of 1.5 ml/kg of 0.1 N HCl. After HCl injury, blood flow to the injured left lung decreased progressively from 0.70 +/- 0.04 to 0.37 +/- 0.05 l/min and percent of flow to the injured left lung (QL/QT) decreased from 37.7 +/- 2.2 to 23.6 +/- 2.2% at 240 min. Exposure to hypoxia (12% O2) for three 10-min episodes did not affect QL/QT in normal animals, but after unilateral HCl injury, it caused blood flow to the injured left lung to increase significantly. A concomitant decrease in blood flow occurred to the noninjured right lung, resulting in a significant increase in QL/QT. The enhanced blood flow to the injured lung was associated with a significant increase in the wet-to-dry lung weight ratio in the dependent regions of the injured lung. These findings demonstrate that in unilateral HCl-induced lung injury, transient hypoxia can enhance blood flow to the areas of injury and increase lung edema formation.     

Contribution of neutrophils to acute lung injury

Treatment of acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), remain unsolved problems of intensive care medicine. ALI/ARDS are characterized by lung edema due to increased permeability of the alveolar-capillary barrier and subsequent impairment of arterial oxygenation. Lung edema, endothelial and epithelial injury are accompanied by an influx of neutrophils into the interstitium and broncheoalveolar space. Hence, activation and recruitment of neutrophils are regarded to play a key role in progression of ALI/ARDS. Neutrophils are the first cells to be recruited to the site of inflammation and have a potent antimicrobial armour that includes oxidants, proteinases and cationic peptides. Under pathological circumstances, however, unregulated release of these microbicidal compounds into the extracellular space paradoxically can damage host tissues. This review focuses on the mechanisms of neutrophil recruitment into the lung and on the contribution of neutrophils to tissue damage in ALI.     

Hyperoxia causes angiopoietin 2-mediated acute lung injury and necrotic cell death

The angiogenic growth factor angiopoietin 2 (Ang2) destabilizes blood vessels, enhances vascular leak and induces vascular regression and endothelial cell apoptosis. We considered that Ang2 might be important in hyperoxic acute lung injury (ALI). Here we have characterized the responses in lungs induced by hyperoxia in wild-type and Ang2-/- mice or those given either recombinant Ang2 or short interfering RNA (siRNA) targeted to Ang2. During hyperoxia Ang2 expression is induced in lung epithelial cells, while hyperoxia-induced oxidant injury, cell death, inflammation, permeability alterations and mortality are ameliorated in Ang2-/- and siRNA-treated mice. Hyperoxia induces and activates the extrinsic and mitochondrial cell death pathways and activates initiator and effector caspases through Ang2-dependent pathways in vivo. Ang2 increases inflammation and cell death during hyperoxia in vivo and stimulates epithelial necrosis in hyperoxia in vitro. Ang2 in plasma and alveolar edema fluid is increased in adults with ALI and pulmonary edema. Tracheal Ang2 is also increased in neonates that develop bronchopulmonary dysplasia. Ang2 is thus a mediator of epithelial necrosis with an important role in hyperoxic ALI and pulmonary edema.     

Ursodeoxycholic acid protects against lung injury induced by fat embolism syndrome

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life‐threatening disease with a high mortality rate, which was a common complication of fat embolism syndrome (FES). Ursodeoxycholic acid (UDCA) has been reported to exert potent anti‐inflammatory effects under various conditions. In vivo, perinephric fat was injected via tail vein to establish a rat FES model, the anti‐inflammatory effects of UDCA on FES‐induced lung injury were investigated through histological examination, ELISA, qRT‐PCR, Western blot and immunofluorescence. In vitro, human lung microvascular endothelial cells (HPMECs) were employed to understand the protective effects of UDCA. The extent of ALI/ARDS was evaluated and validated by reduced PaO₂/FiO₂ ratios, increased lung wet/dry (W/D) ratios and impaired alveolar‐capillary barrier, up‐regulation of ALI‐related proteins in lung tissues (including myeloperoxidase [MPO], vascular cell adhesion molecule 1 [VCAM‐1], intercellular cell adhesion molecule‐1 [ICAM‐1]), elevated protein concentration and increased proinflammatory cytokines levels (TNF‐α and IL‐1β) in bronchoalveolar lavage fluid (BALF). Pre‐treatment with UDCA remarkably alleviated these pathologic and biochemical changes of FES‐induced ALI/ARDS; our data demonstrated that pre‐treatment with UDCA attenuated the pathologic and biochemical changes of FES‐induced ARDS, which provided a possible preventive therapy for lung injury caused by FES.     

Extracellular heat shock protein 72 is a marker of the stress protein response in acute lung injury

Previous studies have shown that heat shock protein 72 (Hsp72) is found in the extracellular space (eHsp72) and that eHsp72 has potent immunomodulatory effects. However, whether eHsp72 is present in the distal air spaces and whether eHsp72 could modulate removal of alveolar edema is unknown. The first objective was to determine whether Hsp72 is released within air spaces and whether Hsp72 levels in pulmonary edema fluid would correlate with the capacity of the alveolar epithelium to remove alveolar edema fluid in patients with ALI/ARDS. Patients with hydrostatic edema served as controls. The second objective was to determine whether activation of the stress protein response (SPR) caused the release of Hsp72 into the extracellular space in vivo and in vitro and to determine whether SPR activation and/or eHsp72 itself would prevent the IL-1beta-mediated inhibition of the vectorial fluid transport across alveolar type II cells. We found that eHsp72 was present in plasma and pulmonary edema fluid of ALI patients and that eHsp72 was significantly higher in pulmonary edema fluid from patients with preserved alveolar epithelial fluid clearance. Furthermore, SPR activation in vivo in mice and in vitro in lung endothelial, epithelial, and macrophage cells caused intracellular expression and extracellular release of Hsp72. Finally, SPR activation, but not eHsp72 itself, prevented the decrease in alveolar epithelial ion transport induced by exposure to IL-1beta. Thus SPR may protect the alveolar epithelium against oxidative stress associated with experimental ALI, and eHsp72 may serve as a marker of SPR activation in the distal air spaces of patients with ALI.     

Effect of heparin and related glycosaminoglycan on PDGF-induced lung fibroblast proliferation, chemotactic response and matrix metalloproteinases activity

Fibroblast migration, proliferation, extracellular matrix protein synthesis and degradation are the key events in various biological and pathological processes in pulmonary fibrosis. In addition, biopsy specimens from the lungs of patients with pulmonary fibrosis show increased numbers of mast cells which have metachromatic granules containing heparin, histamine and proteases. Little is known about how these products influence pulmonary fibrosis. In the present study, we investigated the effect of heparin and related glycosaminoglycans on PDGF-induced lung fibroblast proliferation and chemotactic response in vitro. In addition, we examined the effect of heparin on both the induction of matrix metalloproteinases (MMPs) and MMPs activity in lung fibroblasts in vitro. Heparin, de-N-sulphated heparin but not heparan sulphate inhibited PDGF-induced lung fibroblast proliferation. In contrast, only heparin inhibited PDGF-stimulated human lung fibroblast chemotaxis. Negatively charged poly-L-glutamic acid had no effect on either fibroblast proliferation or chemotaxis. Thus the negative charge alone cannot account for the ant-proliferative and anti-chemotactic effects of heparin. Furthermore, heparin and heparan sulphate also had no inhibitory effect on induction of MMPS, including MMP-1 (interstitial collagenase), MMP-2 (gelatinase A) and MMP-9 (gelatinase B). Only heparin inhibited both MMP-1 and MMP-2/MMP-9 activity. Additionally, tissue inhibitor of metalloproteinase type 1 (TIMP-1) and type 2 (TIMP-2) inhibited PDGF-stimulated human lung fibroblast chemotaxis. The ability of heparin to inhibit fibroblast chemotaxis may account for the inhibitory effect of heparin on MMP activity. The above results suggested that heparin and related glycosaminoglycans differentially regulate PDGF-induced lung fibroblast proliferation, chemotaxis and MMPs activity and further that these effects may have a key role in extracellular matrix remodeling in inflammatory lung disease.     

Production of leukotrienes in phorbol ester-induced acute lung injury

Leukotrienes, when administered into the pulmonary circulation of intact animals or isolated perfused lungs, have been associated with the formation of pulmonary edema. In addition, leukotrienes were identified in edema fluid and in bronchoalveolar lavage fluid (BALF) both from patients with the adult respiratory distress syndrome (ARDS) and from dogs with ethchlorvynol-induced acute lung injury (ALI). To determine whether the identification of leukotrienes in BALF was a finding common to ALI, etiology notwithstanding, we produced acute lung injury in dogs with phorbol myristate acetate (PMA). PMA produces a model of ALI thought to differ mechanistically from ethchlorvynol-induced ALI. Leukotriene C4 (LTC4), D4 (LTD4) and B4 (LTB4) were measured in BALF before and after PMA administration in intact pentobarbital-anesthetized dogs. The intravenous administration of 20 or 30 micrograms/kg of PMA produced increases in pulmonary vascular resistance (PVR) and extravascular lung water (EVLW), whereas, 10 or 15 micrograms/kg caused only a modest increase in PVR with no increase in EVLW. LTD4 and LTB4 were increased in BALF solely in those animals that developed increases in EVLW. These results, when viewed together with those reported in humans with ARDS and in dogs with ethchlorvynol-induced ALI, support the hypothesis that leukotriene detection in BALF is a feature common to ALI, etiology notwithstanding.     

复方清下汤对脓毒症大鼠细胞因子调控及其肺损伤的作用

目的盲肠结扎穿孔导致大肠埃希菌腹膜炎进而建立脓毒症肺损伤大鼠模型,检测炎性反应时,细胞因子的调控变化,探讨肺水肿的形成机制。经复方清下汤处理后检测上述变化,以期为脓毒症肺损伤的防治提出可能的新途径。方法将健康SD大鼠随机分为4组,每组10只：假手术组（SHAM组）,只翻动盲肠,不做其他处理;脓毒症肺损伤组（模型组）,盲肠结扎穿孔诱发AL（急性肺损伤）I模型;盲肠结扎穿孔＋复方清下汤组（造模后立即灌胃给药,造模后8 h再次灌胃1次,剂量为10 m l/kg）;盲肠结扎穿孔＋头孢哌酮/舒巴坦组（抗生素舒普深）（造模后立即静脉注射1次,造模后8 h再次静脉注射1次,剂量为0.2 g/kg）造模24 h后收集标本。分别观察大鼠的一般状态,肺组织匀浆MPO的测定,留取下腔静脉血清进行TNF-α的测定。镜下观察肺组织病理形态学改变,测量肺湿/干比值的变化。结果与SHAM组比较,模型组MPO、TNF-α水平明显升高（P〈0.01）,肺间质和肺泡内水肿,伴大量红细胞渗出（出血）和纤维素沉积,肺泡间隔毛细血管内皮细胞高度肿胀。肺湿/干比值明显增加（P〈0.01）,抗生素及中药处理组与模型组比较,MPO、TNF-α水平明显降低（P〈0.01）,肺湿/干比值明显降低（P〈0.01）,肺组织镜下表现：中药处理组及抗生素组较模型组肺泡间隔变窄,毛细血管内皮细胞肿胀减轻,出血减轻,纤维素渗出明显减少。结论脓毒症大鼠肺损伤时细胞因子TNF-α过度表达,炎性介质的过度表达可能是造成脓毒症肺损伤的重要原因,而复方清下汤可以减轻脓毒症时的肺损伤和抑制TNF-α的表达,它们之间可能存在一定的联系。