严重急性呼吸综合征肺纤维化病理学探讨

目的 观察严重急性呼吸综合征(SARS)肺纤维化的表现，初步探讨SARS时肺纤维化的发病机制。方法 采用光镜、纤维化组织化学染色、免疫组织化学SP法以鼠抗Ⅲ型胶原、鼠抗α平滑肌肌动蛋白(α-SMA)、兔抗Fas、兔抗Fas；配体(FasL)、兔抗转化生长因子β1(TGF-β1)对4例SARS死亡病例的肺组织纤维化改变进行重点观察。结果 4例肺组织中存在不同程度的纤维化改变。表现为肺泡腔内纤维素性渗出物积聚及机化，甚而形成“团块状纤维样”结构；肺泡间隔增厚，成纤维细胞增生，可见胶原纤维条索；组织化学染色及Ⅲ型胶原染色证实以Ⅲ型和Ⅰ型胶原纤维增生为主；肺泡腔内的纤维化与肺泡外间质融合形成肺的实变。免疫组织化学检测成纤维细胞表达α-SMA、脱落的肺泡上皮细胞表达Fas、FasIL、肺泡上皮细胞和单核细胞的细胞浆内表达TGF-β1。结论 SARS患者的肺组织早期即有纤维化的征象，其纤维化的发生是各种效应细胞、炎症介质及细胞因子共同参与的结果。     

Spironolactone reduces fibrosis of dilated atria during heart failure in rats with myocardial infarction.

AIMS: Congestive heart failure (CHF) is associated with severe structural changes of atria, contributing to impaired atrial function and the risk of arrhythmia. This study investigated the effects of CHF treatments on atrial remodelling. METHODS AND RESULTS: Three months after myocardial infarction (MI), rats were treated for 1 month with spironolactone, lisinopril, or atenolol alone or in combination. Echocardiography-Doppler tissue imaging, haemodynamic measurements, and 24-h Holter monitoring were used to characterize the cardiomyopathy. Atrial fibrosis was quantified with Picrosirius Red staining. Left atrial diameter was increased (5.8+/-0.6 mm in MI vs. 3.6+/-0.3 mm in sham; P<0.0001), as was atrial fibrosis (26.7+/-3.8% in MI vs. 10.5+/-2.2% in sham; P<0.0001), which correlated with left ventricular (LV) dysfunction after 3 months of MI. P-wave duration was also increased and premature atrial beats were frequent on the 24-h electrocardiogram. Similar improvements in LV dysfunction were observed after 1 month of spironolactone, ACE-inhibitor, or beta-blocker therapy alone or in combination. Atrial hyperexcitability was reduced by all the treatments, but only spironolactone attenuated atrial fibrosis and reduced P-wave duration. CONCLUSION: Atrial fibrosis caused by chronic CHF is reduced by spironolactone.     

骨形成蛋白-7在慢性胰腺炎中的表达及意义

目的研究骨形成蛋白-7(BMP-7)在大鼠CP组织中的表达,探讨其在胰腺纤维化形成中的意义。方法每周2次腹腔内注射二乙基二硫代氨基甲酸盐(diethyldithiocarbamate,DDC)建立大鼠CP模型。HE染色观察正常组及造模后2、4、6、8周时大鼠胰腺病理学变化,VG染色观察胶原纤维含量,免疫组化检测BMP-7、TGF-β1、Smad2/3的表达。结果(1)正常组BMP-7在腺泡细胞的胞质中表达。造模后4周腺泡细胞及部分炎性细胞BMP-7阳性面积比及阳性灰度值较正常组减少(P<0.05)。造模后8周腺体萎缩几乎无BMP-7表达,残留腺泡中表达量较正常胰腺显著减少[阳性面积比:(5.63±1.65)%vs(36.51±3.76)%,P<0.01;灰度值:144.20±5.67vs174.54±1.22,P<0.01]。(2)TGF-β1和Smad2/3的表达在纤维化进展中变化一致。对照组小叶间结缔组织和部分腺泡间有少量表达。8周时小叶内纤维化区域及残留腺泡细胞间可见大量TGF-β1和Smad2/3表达,TGF-β1为(22.66±6.73)%;Smad2/3为(24.58±4.35)%,较正常组增加(P<0.01)。(3)TGF-β1与Smad2/3表达呈正相关(r=0.61,P=0.005),BMP-7与TGF-β1、Smad2/3表达均呈负相关(r值分别为-0.69和-0.68,P=0.001)。结论胰腺纤维化过程中TGF-β1/Smad2/3信号通路活化,可促进细胞外基质沉积和腺泡细胞萎缩。BMP-7的表达量可反映残存腺泡细胞的数量,可能对CP的进展具有潜在的保护作用。     

Effect of emodin on pancreatic fibrosis in rats

AIM： To establish the rats model of chronic fibrosing pancreatitis and to prove the anti-fibrotic effect of emodin in chronic pancreatitis with fibrosis.
METHODS： Fifty rats were randomly divided into five groups, 10 rats in each group. Trinitrobenzene sulfonic acid （TNBS） was infused into the pancreatic duct to induce chronic pancreatitis in rats （except for normal group）. Emodin-treated rats were fed with different doses of emodin （20, 40 and 80 mg/kg body weight） for 28 d, while normal group and control group received 0.9% sodium chloride solution. Serum levels of hyaluronic acid （HA） and laminin （LN） were determined by radioimmunoassay. Histopathological alterations were studied by optical microscopy. Expression of collagen was also examined while transforming growth factor- beta-1 （TGF-131） was localized by immunochemistry. RESULTS： In emodin-treated rats, the serum levels of HA and LN were decreased significantly （HA, 62.2 ± 19.3 μg/L vs 112.7 ± 26.5μg/L, P 〈 0.05; LN 44.3 ± 10.4 μg/L vs 86.2 ± 16.5 μg/L, P 〈 0.05）; the degree of fibrosis was ameliorated observably; the expression of collagen in pancreatic tissue was reduced especially in high-dose emodin-treated group （36% ± 5% vs 42% ± 6%, P 〈 0.05）; with the increased doses of emodin, the expression of TGF-β1 was declined, compared with those in control group.
CONCLUSION： Emodin has an anti-fibrotic effect on pancreatic fibrosis in rats. Because of its anti-fibrotic effect, it could be a potential herb for the treatment of chronic pancreatitis.     

肝素对肝纤维化大鼠模型作用的疗效观察

目的建立肝纤维化大鼠模型,对肝素、干扰素和复方丹参的抗肝纤维的疗效进行评价。方法应用CCl4建立肝纤维化大鼠模型,分别给予不同剂量的肝素、干扰素和丹参进行抗肝纤维化干预治疗。8周后处死大鼠,留取血清检测HA、IV-C、LN、PCⅢ等,留取肝组织,行HE和Massson三色染色。结果肝素治疗组、复方丹参治疗组的各项血清学指标水平与肝纤维化大鼠造模组相比均有显著性差异。α干扰素治疗组与肝纤维化大鼠造模组相比,HA和PCⅢ水平有显著性下降,ⅣC、LN水平无显著性差异。肝素治疗组的HA、ⅣC、LN、PCⅢ水平均较复方丹参治疗组、α干扰素治疗组为低。胶原纤维染色显示,肝素可明显抑制肝纤维化的发展,作用效果优于干扰素和复方丹参。结论肝素、α干扰素、丹参具有抗肝纤维化作用,但以肝素的作用效果为最强。     

Evaluating Liver Fibrosis by Transient Elastometry in Patients With HIV-HCV Coinfection and Monoinfection

Background:

Due to the high efficacy of combination antiretroviral therapy (cART), the number of patients living with HIV is increasing. Chronic HCV infection has become a leading cause of non-AIDS related morbidity and mortality in patients with HIV infection.

Objectives:

The aim of this cross-sectional study was to identify factors associated with liver fibrosis (LF) in patients with HIV monoinfection and HIV-HCV coinfection.

Patients and Methods:

We analyzed LF by transient elastometry ([TE], Fibroscan) in three groups of patients (HIV, HIV-HCV and HCV) followed at the Infectious Diseases Department of University of Ancona, Italy, between October 2009 and November 2012.

Results:

In total, 354 adults including 98 HIV, 70 HIV-HCV and 186 HCV patients were studied. HIV-HCV patients had a longer duration of HIV (P < 0.006) and HCV (P < 0.001) infections. Additionally, they were receiving cART therapy for a longer period (P < 0.001); they had higher prevalence of lipodystrophy (P < 0.001) and higher HCV load (P = 0.004). LF was significantly more pronounced in HCV and HIV-HCV compared to HIV patients (P < 0.001). A total of 13.3%, 39.2% and 51.4% of HIV, HCV and HIV-HCV, respectively, showed a LF ≥ F2. Additionally, a severe LF (F = 4) was significantly more frequent among HIV-HCV compared to other groups. A longer exposure to didanosine, stavudine, lopinavir/ritonavir and fosamprenavir resulted in increased LF by univariate analysis (P ranging from < 0.001 to 0.007). By logistic regression analysis, the only variables significantly associated with increased LF were HCV coinfection, older age, and high AST values (P ranging from < 0.001 to 0.036).

Conclusions:

HCV coinfection, older age and AST were associated with LF in patients with HIV infection.     

胰腺弹力蛋白酶在大鼠肝纤维化组织中的表达

目的:观察胰腺丝氨酸弹力蛋白酶的基因、蛋白及活性在大鼠肝纤维化中的表达,探讨弹力蛋白酶在肝纤维化形成中的作用.方法:采用二甲基亚硝胺(DMN)4周12次腹腔注射制备Wistar雄性大鼠肝纤维化模型,以正常组作对照.观察肝功能,肝脏病理组织学,肝组织羟脯氨酸含量以及肝组织弹力蛋白酶mRNA、蛋白及其活性的表达.结果:弹力蛋白酶mRNA、蛋白及其活性在正常大鼠肝组织均有一定程度的表达,在肝纤维化模型组,假小叶内肝细胞弹力蛋白酶mRNA表达有所减少,弹力蛋白酶活性在正常组和模型组分别为(11.43±2.35)U/g、(8.02±1.62)U/g,模型组显著降低(P＜0.05).结论:某种程度的弹力蛋白酶表达是维持正常细胞外基质合成与降解动态平衡的需要;在肝纤维化形成过程中,大鼠胰腺丝氨酸弹力蛋白酶的表达下降是促进肝纤维化形成的因素之一.     

Leptin and acetaldehyde synergistically promotes αSMA expression in hepatic stellate cells by an interleukin 6-dependent mechanism

Background: The mechanisms whereby patients with obesity/overweight are more susceptible to alcohol‐associated liver fibrosis are unclear. Leptin, a peptide hormone secreted by white adipose tissue is increased in association with overweight/obesity and is recognized as mediator of liver fibrosis. We sought to assess whether leptin contributes to alcoholic liver fibrosis by in vitro studies in hepatic stellate cells (HSC). Methods: Rat HSCs in second or third passage were utilised. Leptin, Acetaldehyde or combination with leptin and acetaldehyde were incubated for specific periods in cultured HSCs. Profibrogenic gene and protein expression were determined and associated‐signalling pathways were assessed. Interleukin 6 (IL‐6) antibody neutralization was used to evaluate the role of IL‐6. Results: Leptin did not promote acetaldehyde‐induced gene expression of collagen I, transforming growth factor β1 (TGFβ1) and tissue inhibitor of metalloproteinase 1 (TIMP1) in vitro. However, combined treatment of leptin with acetaldehyde synergistically enhanced the protein expression of smooth muscle actin (αSMA), an activation marker of HSCs, and of Interleukin‐6 (IL‐6). The combination of leptin and acetaldehyde also augmented MAPK/p38 and MAPK/ERK1/2 phosphoprotein expression. IL‐6 neutralization down‐regulated protein expression of pp38, pERK1/2 and αSMA, while exogenous rat recombinant IL‐6 administration up‐regulated αSMA. Similarly, MAPK/p38 and MAPK/ERK1/2 inhibition attenuated αSMA expression. H₂O₂ induction by acetaldehyde was not potentiated by co‐treatment with leptin nor did IL‐6 neutralization reduce acetaldehyde‐induced H₂O₂ production. Conclusions: We conclude that leptin potentiates acetaldehyde‐induced HSC activation and αSMA expression by an IL‐6‐dependent mechanism.