白藜芦醇苷对慢性常压低氧性肺动脉高压模型中磷脂酶A2、一氧化氮和内皮素水平的影响

目的： 观察白藜芦醇苷（PD）对慢性常压低氧性肺动脉高压大鼠血浆及肺匀浆中磷脂酶A2(PLA2)、一氧化氮（NO）和内皮素1（ET-1）水平的影响，并探讨可能的机制。 方法: 29只健康SD大鼠随机分为正常对照组、单纯低氧组和低氧加PD组。右心导管法检测大鼠肺动脉平均压力（mPAP），观察右室/左室+室间隔重量比值（R/L+S）、血浆及肺匀浆中PLA2活性、NO和ET-1含量的变化。 结果: 低氧21 d后大鼠mPAP、R/L+S、血浆及肺匀浆中PLA2活性和ET-1含量显著高于对照组，NO含量显著低于对照组。PD预处理组上述变化可受抑制或减轻。 结论: PD可有效防治慢性常压低氧性大鼠肺动脉压力的升高，其机理与抑制PLA2活性及ET-1释放，促进NO产生有关。     

异甘草素对低氧诱导的大鼠肺动脉结构重建的影响

目的 观察异甘草素对缺氧性肺动脉高压（HPH）大鼠模型的肺动脉压力的变化,右心室肥厚程度及肺血管结构重建的影响,探讨异甘草素对HPH的抑制作用及其可能机制。方法 雄性SD大鼠30只随机分为对照组、HPH组、异甘草素组,每组各10只。HPH组和异甘草素组大鼠置于缺氧箱中建立大鼠HPH模型。异甘草素组中,每只大鼠腹腔注射异甘草素剂量为10 mg/(kg·d),从缺氧前1周开始给药直到缺氧结束。对照组和HPH组大鼠腹腔注射等体积0.5% DMSO。测定各组大鼠平均右心室压力(RVSP);称重法测得各组大鼠右心室游离壁（RV）及左心室加室间隔（LV+S）质量,以及RV/（LV+S）;HE染色观察肺动脉病理形态改变,计算血管厚度百分比(WT%)及面积百分比(WA%);ELISA法检测各组大鼠血清及肺组织中的超氧化物歧化酶(SOD)及丙二醛(MDA)的含量。Real-time PCR检测各组大鼠肺组织中的NADPH氧化酶4(NOX4) mRNA的表达。结果 HPH组大鼠RVSP、RV/LV+S、WT%,以及WA%明显高于对照组大鼠（P<0.01）,然而异甘草素组大鼠RVSP、RV/LV+S、WT%,以及WA%均明显低于HPH组大鼠（P<0.01）。HPH组大鼠肺组织及血清中的SOD含量较对照组明显降低,而MDA含量则明显增高（P<0.01）。异甘草素组大鼠肺组织及血清中的SOD含量较HPH组大鼠明显增高,而MDA含量则明显降低（P<0.01）。 Real time PCR结果显示,异甘草素有效抑制了低氧诱导的大鼠肺组织中NOX4 mRNA的高表达（P<0.01）。结论 异甘草素抑制由低氧诱导的HPH大鼠肺动脉压力升高、右心室肥厚,以及肺动脉管壁的增厚,可能与异甘草素抑制HPH大鼠体内的氧化损伤有关。     

低氧性肺动脉高压大鼠肺内5-HT_(1B)受体的分布和表达变化

目的:观察低氧性肺动脉高压(HPH)大鼠体内5-羟色胺(5-HT)水平及其肺内5-羟色胺1B(5-HT1B)受体的分布和表达变化,探讨低氧性肺动脉高压的形成机制。方法:40只健康雄性SD大鼠随机分为正常组(control)、低氧3周组、低氧4周组和低氧5周组。除正常组外,其余3组大鼠分别在低氧环境中饲养3周、4周和5周。测定各组大鼠的平均肺动脉压力(mPAP)、右心室收缩压(RVSP)、右心室肥厚度[RV/(LV+S)%]、血浆和肺组织中5-HT含量。应用免疫组织化学法观察大鼠肺组织中5-HT1B受体的分布和表达,Western blotting法测定大鼠肺组织中5-HT1B受体的蛋白含量。结果:和正常组相比,低氧3周组大鼠的mPAP、RVSP和右心室肥厚度均显著升高(均P0.05),并且随着低氧时间的延长而持续升高(均P0.05)。低氧大鼠血浆和肺组织中5-HT的含量均显著高于正常组大鼠(均P0.05),并随着低氧时间的延长而持续升高(均P0.05)。免疫组织化学结果显示:5-HT1B受体主要分布在正常大鼠肺动脉的内膜层,而平滑肌层中仅有少量表达;和正常组相比,低氧3周组大鼠肺动脉平滑肌层中5-HT1B受体的表达显著增多;随着低氧时间的延长,大鼠肺动脉平滑肌层中5-HT1B受体表达持续增多。Western blotting结果表明,大鼠肺组织中5-HT1B受体的蛋白含量变化和免疫组织化学结果相一致。结论:低氧性肺动脉高压大鼠体内5-HT水平显著升高,其肺动脉中5-HT1B受体呈过度表达,这可能是低氧性肺动脉高压形成的分子机制之一。     

慢性低氧性肺动脉高压大鼠肾上腺髓质素前体N端20肽的变化

目的：探讨慢性低氧性肺动脉高压和肺血管结构重建时肾上腺髓质素前体N端20肽（PAMP）的变化。方法:将18只雄性Wistar大鼠随机分为对照组和低氧组，每组各9只。常压低氧2周后，以右心导管法测定肺动脉平均压（mPAP），检测右心室与左心室加室间隔比值 ［RV/(LV+S)］，观测肺血管显微和超微结构的变化。并且以放免法测定血浆中PAMP含量，以免疫组化法检测肺组织中PAMP表达，以原位杂交检测肺组织中肾上腺髓质素（ADM） mRNA的表达。结果: 低氧组大鼠mPAP及RV/（LV+S）均明显高于对照组（均P<0.01）。光镜下，肺小血管肌化程度明显增强，肺中、小型肌型动脉相对中膜厚度明显增加。电镜下，肺腺泡内动脉内皮细胞增生、肿胀，内弹力层粗细不均，平滑肌细胞肥厚、向合成表型转化。并且低氧组大鼠血浆PAMP含量明显高于对照组（P<0.01），肺动脉PAMP表达和ADM mRNA表达均明显增强。结论：低氧后肺动脉PAMP表达和血浆PAMP含量的上调可能参与了慢性低氧性肺动脉高压和肺血管结构重建的形成。     

慢性低氧性肺动脉高压大鼠肺内肺动脉中尾加压素Ⅱ的变化

本实验旨在研究尾加压素Ⅱ（uⅡ）在慢性低氧性肺动脉高压及肺血管结构重构形成中的变化。应用免疫组化技术对慢性低氧性肺动脉高压大鼠不同节段肺内动脉uⅡ蛋白表达进行定位及半定量分析。结果显示：低氧1周和2周组大鼠肺动脉平均压（mPAP）、右心室肥厚指标R／（L＋S）、肺动脉相对中膜面积（RMA）和相对中膜厚度（RMT）均明显高于对照组（P＜0.001）。低氧2周组大鼠各节段肺内动脉内皮细胞中uⅡ表达较对照组分别下降27.75%、32.50%、39.63%（P均＜0.01）。相关分析显示：与呼吸性细支气管伴行的肺动脉内皮细胞uⅡ表达与mPAP呈显著负相关；各节段肺动脉内皮细胞uⅡ表达分别与各级肺动脉RMA、RMT呈明显负相关（P均＜0.05）。研究表明：低氧性肺动脉高压及肺血管结构重构形成过程中，肺内动脉内皮细胞uⅡ表达呈现明显下调；推测uⅡ在慢性低氧性肺动脉高压形成机制中具有重要的病理生理意义。     

西拉普利对低氧大鼠肺动脉和心肌细胞增殖的抑制作用

目的：探索cilazapril 对低氧大鼠肺血管和心肌细胞增殖的抑制机理。 方法： 采用生化、放射免疫、免疫组织化学、细胞凋亡标记和血流动力学技术研究低氧肺血管及心肌细胞增殖和结构重建。 结果： （1）低氧大鼠mPAP显著增高，伴有肺动脉血管管腔狭窄、管壁增厚，心肌肥大，R/L+S增高。（2）B组、C组大鼠肺动脉和右心肌细胞增殖指数（PI）均分别明显高于A组，而C组明显低于B组。ET-1免疫组化染色阳性细胞主要分布在肺动脉血管壁和心肌细胞上，染色程度由强到弱依次为B组>C组>A组。（3）B组大鼠ET-1水平和ACE活性明显高于A组，而C组显著低于B组。（4）直线相关分析显示ET-1、ACE分别与R/(L+S)、mPAP、肺动脉PI、心肌PI呈正相关；多元回归分析显示ET-1和ACE可能是影响PI的主要因素。 结论： 低氧大鼠存在细胞过度增殖状态，继发肺血管、右心结构重建是低氧性肺动脉高压发病机理之一。Cilazapril通过抑制ACE和ET-1的促增殖作用，阻止肺血管及心肌重建，对低氧性肺动脉高压的防治有一定作用。     

慢性低氧对大鼠肺血管L-精氨酸

目的:探讨慢性低氧对大鼠肺血管L-精氨酸/一氧化氮(L-Arg/NO)途径的影响。方法:采用慢性低氧性肺动脉高压(HPH)大鼠肺血管孵育,测定慢性HPH对大鼠肺动脉L-Arg转运,一氧化氮合酶(NOS)活性和NO生成释放的影响。结果:(1)低氧4周大鼠肺动脉平均压(mPAP)比对照组高33.7%(P＜0.01),右心室(RV)和左室加室间隔(LV+S)重量比值(RV/LV+S)高44.2%(P＜0.01)。(2)低氧对血浆L-Arg含量无明显影响。(3)低氧大鼠离体孵育的肺动脉摄取低浓度(0.2mmol/L)和高浓度(5.0mmol/L)[³H]-L-Arg分别低于对照组15.8%(P＜0.05)和27.2%(P＜0.01)。(4)低氧大鼠肺动脉tNOS、iNOS和cNOS活性较对照组高38.0%、32.8%和53.0%(P＜0.01)。(5)低氧大鼠血浆NO含量低于对照组,与mPAP和RV/LV+S呈负相关(P＜0.01)。结论:慢性HPH时NOS活性代偿性增强,但L-Arg转运受损使血浆NO生成仍减少,说明L-Arg转运是NO生成的重要限速步骤。     

三七总皂苷对低氧大鼠肺动脉压和肺组织p38 MAPK表达的影响

目的:探讨三七总皂苷(PNS)对低氧大鼠p38丝裂原活化蛋白激酶(p38 MAPK)表达的影响,及预防低氧性肺动脉高压(HPH)的作用和机制。方法:将30只SD大鼠随机分为3组:正常对照组、低氧组和低氧+PNS组。观察各组大鼠平均肺动脉压(mPAP)、平均颈动脉压(mCAP)和右心室/(左心室+室间隔重量)比[RV/(LV+S)],免疫组化法和RT-PCR法分别检测肺小血管壁磷酸化p38 MAPK(p-p38 MAPK)蛋白和肺组织中mRNA的含量。结果:与对照组相比,低氧组大鼠mPAP、RV/(LV+S)明显升高,肺小动脉p-p38 MAPK及肺组织p38 MAPK mRNA含量显著升高(P0.05)。低氧+PNS组mPAP、RV/(LV+S)、肺小动脉p-p38 MAPK及肺组织p38 MAPK mRNA含量明显低于低氧组(P0.05)。结论:PNS具有显著预防HPH的作用,其机制可能与其降低p38 MAPK mRNA的表达有关。     

低氧性肺动脉高压大鼠红细胞的变形性,膜流动性及外形变化

为探讨红细胞变形性变化在低氧性肺动脉高压形成中的作用及低氧时红细胞变形性变化机制，本文观察了低氧1、3、5周大鼠红细胞的变形性、膜流动性、红细胞形态、红细胞平均体积（MCV）及红细胞平均血红蛋白浓度（MCHC）变化。结果：（1）低氧1周红细胞变形性即明显下降（即红细胞滤过指数FI增高），低氧时间越长红细胞变形性下降越明显；且与肺动脉压、右心室压升高及右心室肥厚呈负相关。（2）低氧3周及5周大鼠异常形态红细胞数明显增多。（3）低氧5周大鼠红细胞膜流动性明显下降。提示：低氧大鼠红细胞形态异常及红细胞膜流动性下降可使红细胞变形性下降。红细胞变形性下降可能在低氧性肺动脉高压及右室肥厚的发生及发展中起一定的作用。     

Losartan对慢性低氧大鼠肺动脉压力及管壁胶原的影响

目的：探讨氯沙坦（losartan）对慢性低氧大鼠肺动脉压力及管壁胶原的影响。方法：将二级SD大鼠分为：对照组（A）、低氧组（B）、低氧+losartan组（C），低氧时间为4周。采用透射电镜、免疫组化、原位杂交等方法观察losartan对慢性低氧大鼠肺动脉平均压（mPAP）、右心室重量比（RV/LV+S）、肺细小动脉超微结构、肺动脉管壁Ⅰ、Ⅲ胶原和Ⅰ、Ⅲ前胶原基因的影响。结果：①B组mPAP、RV/LV+S显著高于A组（P<0.01），C组mPAP、RV/LV+S显著低于B组（P<0.01）。②电镜检查显示B组肺动脉胶原纤维较A组明显为多，C组较B组明显为少。③免疫组化、原位杂交显示B组肺细小动脉(直径约100-200μm)Ⅰ型胶原及Ⅰ型前胶原mRNA平均吸光度值显著高于A组（均P<0.01），C组肺细小动脉Ⅰ型胶原及Ⅰ型前胶原mRNA平均吸光度值明显低于B组（均P<0.01），Ⅲ型胶原及Ⅲ型前胶原mRNA平均吸光度值各组间无明显差异（均P>0.05）。结论：losartan可预防慢性低氧肺动脉高压的形成和肺动脉管壁胶原的生成、沉积。     

P63 in pulmonary epithelium,pulmonary squamous neoplasms,and other pulmonary tumors

p63 is a p53-homologous nuclear protein that appears to play a crucial role in regulation of stem cell commitment in squamous and other epithelia. In this study, p63 expression was examined in benign lung and in neoplasms of pulmonary origin. Eighty sections from routinely fixed and processed archival bronchoscopic biopsy or lobectomy specimens were pretreated with citric acid (pH 6.0) for antigen retrieval, then incubated overnight with anti-p63 monoclonal antibody 4A4. Slides were stained using a streptavidin-biotin kit and diaminobenzidine as chromagen, and were counterstained with hematoxylin. In normal lung, p63 intensely stained nuclei of bronchial reserve cells but did not stain ciliated cells, alveolar epithelial cells, or nonepithelial cells. The lower strata of squamous metaplastic bronchial epithelium stained positively. All squamous-cell carcinomas stained positively (n = 30). In some well-differentiated carcinomas, staining was found at the periphery of tumor nests but was negative in central zones showing squamous maturation. Poorly differentiated carcinomas showed very high proportions (80% to 100%) of p63-positive nuclei. All small-cell carcinomas were p63 negative (n = 9). Staining of bronchioloalveolar carcinomas (n = 7) and adenocarcinomas (n = 23) was variable: some tumors showed no detectable staining, others showed heterogeneously positive staining. Adenosquamous carcinomas (n = 5) displayed a unique basalar staining pattern. Carcinoid tumors were almost entirely negative (n = 5). We conclude that p63 is expressed in benign bronchial stem cells, in neoplastic cells with either squamous differentiation or squamous differentiating potential, and in a subpopulation of adenocarcinomas. p63 immunostaining may also aid in some histopathologic distinctions, such as in small biopsies where the differential diagnosis is poorly differentiated squamous carcinoma versus small-cell carcinoma. A stem cell biology-based classification system for squamous carcinomas is proposed.     

肺部超声对重症肺部感染患者肺通气的评估价值

目的:探讨肺部超声评价重症肺部感染患者通气情况的应用价值。方法:选取88例重症肺部感染患者,采用半定量方法对肺部超声征象进行评分,以CT检查结果为金标准,分析肺部超声评分与患者肺通气的关系;同时分析存活和死亡患者临床资料、肺部超声评分的差异,以及肺部超声评分预测患者死亡的价值。结果:88例患者全肺超声评分平均为（18.50±2.12）分,全肺CT值平均为（-620.50±88.13） HU,不通气/低通气肺组织比例平均为（10.41±3.35）%,正常通气肺组织比例平均为（71.54±6.69）%,过度通气肺组织比例平均为（17.65±4.11）%;患者肺部超声评分与全肺CT值、不通气/低通气肺组织比例呈正相关（r=0.775、0.648, P<0.05）,与正常通气肺组织比例、过度通气肺组织比例无明显相关性（r=-0.170、0.046, P>0.05）;死亡组患者年龄、糖尿病比例、APACHEⅡ评分、肺泡-动脉氧分压差、机械通气治疗和肺部超声评分分别为（59.28±8.12）岁、44.83%、（22.19±2.40）分、（344.40±82.29） mmHg、72.41%和（20.20±1.72）分,明显高于存活组（P<0.05）,而氧合指数为（104.42±21.18）,明显低于存活组（P<0.05）;Logistic回归分析结果显示:年龄、APACHEⅡ、肺部超声评分是重症肺部感染患者死亡的影响因素（OR=1.758、2.841、2.440, P<0.05）;肺部超声评分预测重症肺部感染患者死亡的ROC曲线下面积为0.901（95%CI:0.836~0.966）,截断值为20分,灵敏性和特异性分别为82.80%和84.70%。结论:肺部超声可以作为重症肺部感染患者肺通气的评估指标,同时其在预测患者预后方面有一定应用价值。     

The pulmonary matrix, glycosaminoglycans and pulmonary emphysema

This paper reviews recent evidence of the effect of intratracheal hyaluronan (HA) to limit the induction of experimental emphysema in hamsters. Experimental emphysema was induced by both neutrophil and pancreatic elastase instilled intratracheally. Emphysema was quantified anatomically by measurement of alveolar mean linear intercept. Hyaluronidase, instilled intratracheally, enhanced the induction of experimental emphysema. Air-space size measured one week after intratracheal instillation of elastase showed that administration of 1 mg HA immediately following elastase administration resulted in a marked reduction in air-space enlargement (82 microM vs 122 microM, p < 0.01). Similarly, animals given either 1 or 2 mg HA 2 h before elastase or 2mg HA 1 h after elastase showed a significant decrease in air-space enlargement compared to controls (96 microM, 88 microM vs 120 microM and 66 microM vs 104 microM, respectively; p < 0.05. Experimental emphysema induced by neutrophil elastase was also limited by the administration of 1 or 4 mg of HA, administered 2 h prior to elastase (57 and 59 microM, respectively vs 64 for controls, p < 0.05). Characterization of administered HA showed a mean molecular weight of 104,800 Da, less than 5% protein and a uronic acid/hexosamine ratio of 1, which is characteristic of HA. Studies using fluorescein-labeled hyaluronan (HA) showed fluorescence associated with interstitial, pleural and vascular elastic fibers. The mechanism of attachment of the administered HA to elastin remains unknown. Fluorescein labeling of elastin was visible for at least 4 h post-instillation. These studies indicate a protective effect of hyaluronan against elastase degradation of pulmonary elastin in vivo by both pancreatic and neutrophil elastases. The anatomical studies further suggest a mechanism of protective coating of hyaluronan which may limit access to pulmonary elastin from neutrophils and alveolar macrophages. Results also suggest that a reduction in pulmonary hyaluronan content increases the susceptibility of elastin to degradation by elastases. These studies provide evidence for an antielastase effect of hyaluronan which is not dependent upon enzyme inhibition but on anatomical protection of pulmonary elastin by other mechanisms.     

Changes in pulmonary hemodynamics in acute pulmonary edema

Summary Experiments were made on dogs to study the hemodynamic changes following intravenous injections of chloramine and adrenaline. Chloramine injections were followed by the development of a severe pulmonary edema in an of the dogs. In most of them, however, the capillary pressure in the pulmonary circulation increased, but insignificantly. The great increase in the pulmonary capillary pressure following adrenaline injection did not culminate in the development of edema or caused very slight edema. The conclusion is drawn that increase of filtration pressure is not an indispensable decisive factor for the development of pulmonary edema, even if it is concurrent with considerable disturbances in the pulmonary circulation.(Presented by Academician V. V. Parin) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 60, No. 8, pp. 25–29, August, 1965     

T-cell signature cytokines distinguish pulmonary sarcoidosis from pulmonary tuberculosis

Sarcoidosis is a systemic inflammatory disorder characterized by tissue infiltration due to mononuclear phagocytes and lymphocytes and associated noncaseating granuloma formation. Pulmonary sarcoidosis (PS) shares a number of clinical, radiological, and histopathological characteristics with that of pulmonary tuberculosis (PTB). Due to this, clinicians face issues in differentiating between PS and PTB in a substantial number of cases. There is a lack of any specific biomarker that can diagnose PS distinctively from PTB. We compared T-cell-based signature cytokines in patients with PS and PTB. In this study, we proposed a serum biomarker panel consisting of cytokines from cells: T helper (Th) 1 [interferon-gamma (IFN-γ); tumor necrosis factor-alpha (TNF-α)], Th9 [interleukin (IL)-9], Th17 [IL-17], and T regulatory (Treg) [IL-10; transforming growth factor-beta (TGF-β)]. We performed the principal component analysis that demonstrated that our serum cytokine panel has a significant predictive ability to differentiate PS from PTB. Our results could aid clinicians to improve the diagnostic workflow for patients with PS in TB endemic settings where the diagnosis between PS and PTB is often ambiguous.     

Mycobacterial pulmonary infections in patients with idiopathic pulmonary fibrosis

Patients with idiopathic pulmonary fibrosis (IPF) have an increased risk for developing tuberculosis (TB). However, no studies have been reported regarding the development of nontuberculous mycobacterium (NTM) lung disease (NTMLD). We reviewed 795 patients with IPF from five university hospitals who were diagnosed by histological or radio-clinical criteria. In the 795 patients with IPF, pulmonary infections with mycobacterium tuberculosis (MTB) and NTM were found in 35 (4.4%) and 16 patients (2.0%), respectively, which was a higher frequency than that found in the general population. TB was more common in patients treated with immunosuppressants than in those who did not receive immunosuppressants (2.6% vs 1.4%, P = 0.12). Among the IPF patients who had mycobacterial infections,immunosuppressant users developed TB or NTMLD within 1 yr after treatment with immunosuppressants,while those occurred later than 2 yr after diagnosis of IPF in the subjects that did not receive immunosuppressants. Among 51 IPF patients who had mycobacterial infections, 9 (18%) died during follow-up. Of these, three died due to progression of pulmonary tuberculosis. TB and NTMLD is relatively common in patients with IPF in Korea and may be fatal in some groups. Careful evaluation of TB and NTMLD is necessary not only for immunosuppressant users, but also for nonusers with IPF.     

A case of pulmonary capillary hemangiomatosis with pulmonary fibrosis associated with MMP-9 related pulmonary remodeling

Pulmonary capillary hemangiomatosis (PCH) is a rare cause of pulmonary hypertension. It is characterized capillary proliferation within the alveolar septa. Here, we report a case of PCH with extensive pulmonary fibrosis. A 52-year-old man with a clinical diagnosis of non-specific interstitial pneumonia died of respiratory failure with severe pulmonary hypertension. Autopsy revealed pronounced right ventricle hypertrophy and pulmonary fibrosis. Consistent with clinical diagnosis, histological examination revealed diffuse pulmonary fibrosis, in addition, it also disclosed marked capillary proliferation within the alveolar septa as well as the fibrotic pulmonary stroma, suggesting the presence of PCH. Hemosiderin-laden macrophages had accumulated in the capillary proliferative area, and bronchiolar-type metaplasia was conspicuous in the fibrotic lesion. Proliferated capillaries were surrounded by fine collagen and α-smooth muscle actin-positive myofibroblasts. Immunohistochemistry revealed that type IV collagen around capillaries in the area of the PCH without inflammation disappeared in the area with inflammation. In addition, the PCH lesion contained significant numbers of macrophages expressing matrix metalloproteinase (MMP) 9 and type II pneumocytes positive for vascular endothelial growth factor. Although pulmonary fibrosis is a distinctive disease entity, different from PCH, MMP-9-driven destruction of the basement membrane may promote unusual pulmonary remodeling, which, in this case, resulted in extensive pulmonary fibrosis.