Comprehensive lipid profiling of bleomycin‐induced lung injury

Drug‐induced lung injury is an adverse effect of drug treatment that can result in respiratory failure. Because lipid profiling could provide cutting‐edge understanding of the pathophysiology of toxicological responses, we performed lipidomic analyses of drug‐induced lung injury. We used a mouse model of bleomycin‐induced lung injury and followed the physiological responses at the acute inflammatory (day 2), inflammatory‐to‐fibrosis (day 7) and fibrosis (day 21) phases. The overall lipid profiles of plasma, lung and bronchoalveolar lavage fluid (BALF) revealed that drastic changes in lipids occurred in the lung and BALF, but not in the plasma, after 7 and 21 days of bleomycin treatment. In the lung, the levels of ether‐type phosphatidylethanolamines decreased, while those of phosphatidylcholines, bismonophosphatidic acids and cholesterol esters increased on days 7 and 21. In BALF, the global lipid levels increased on days 7 and 21, but only those of some lipids, such as phosphatidylglycerols/bismonophosphatidic acids and phosphatidylinositols, increased from day 2. The lung levels of prostaglandins, such as prostaglandin D₂, were elevated on day 2, and those of 5‐ and 15‐lipoxygenase metabolites of docosahexaenoic acid were elevated on day 7. In BALF, the levels of 12‐lipoxygenase metabolites of polyunsaturated fatty acids were elevated on day 7. Our comprehensive lipidomics approach suggested anti‐inflammatory responses in the inflammatory phase, phospholipidosis and anti‐inflammatory responses in the inflammatory‐to‐fibrosis phase, and increased oxidative stress and/or cell phenotypic transitions in the fibrosis phase. Understanding these molecular changes and potential mechanisms will help develop novel drugs to prevent or treat drug‐induced lung injury.     

JAK/STAT1信号转导通路在博莱霉素致肺纤维化大鼠中的作用

目的 探讨蛋白酪氨酸激酶(JAK)信号传导子和转录活化子1(STAT1)信号转导通路在肺纤维化中的作用机制.方法 将30只Wistar大鼠随机分为博莱霉素(BLM)组和生理盐水(NS)组,分别于气管内灌注BLM及NS后第7、14、28天处死.右肺支气管肺泡灌洗,进行细胞分类、计数;左肺组织匀浆测定胶原含量;免疫组化法测定STAT1、血小板源性生长因子(PDGF)和纤溶酶原激活物抑制剂1(PAI-1)蛋白的表达.结果 BLM组肺组织胶原含量在7、14、28 d均明显高于NS组(P<0.01);BLM组肺组织STAT1、PDGF蛋白表达在第7天达高峰,之后下降,第28天时仍高于NS组(P<0.05),且与支气管肺泡灌洗液中的细胞总数呈正相关(r=0.880,P均<0.01);BLM组肺组织中PAI-1表达在第7天开始升高,第28天达高峰,且与肺组织中胶原含量呈正相关(r＝0.952,P<0.01).结论 JAK/STAT1信号转导通路可能通过调节STAT1、PDGF和PAI-1表达,参与肺纤维化的形成.     

基于二氧化硅、百草枯、博莱霉素建立3种大鼠肺纤维模型的差异蛋白质组学分析

目的 以二氧化硅、百草枯、博莱霉素诱导的大鼠肺纤维化(PF)模型为研究对象,以期在3种大鼠PF模型中探究存在差异表达的参与PF发生、发展相关的关键蛋白.方法 应用同位素标记相对与绝对定量技术(iTRAQ)结合液相色谱-串联质谱(LC-MS/MS)分析3种大鼠PF模型肺组织蛋白表达谱;采用Proteome Discove...     

系统性硬化症动物模型

系统性硬化症是一种自身免疫病,以多系统纤维化、小血管病变、血清自身抗体阳性为主要特点。目前其病因尚未十分清楚,越来越多的证据显示可能有血管病变、炎性反应、纤维化、自身免疫四大机制参与并相互作用。在研究系统性硬化症的发病机制、探索新药治疗效果时需要用到动物模型来模拟病理生理过程,而每一种模型都有其特点却又不完美。本文将根据建模方法分类介绍一些经典的和创新的模型,以及它们各自的特点、应用价值,为研究者选择最合适的动物模型提供帮助。     

静脉注射不同剂量博莱霉素诱导小鼠肺纤维化的比较研究

目的寻求建立小鼠肺纤维化模型的改良方案。方法雄性C57BL/6小鼠随机分为单次和多次注射模型组。单次注射模型组分为博莱霉素100、150、200 mg/kg组及对照组1;多次注射模型组分为博莱霉素50 mg/kg组及对照组2。取小鼠肺组织行病理检查,免疫组化检测肺Ⅰ型胶原蛋白、TGF-β1和α-SMA的表达。结果在单次注射模型组中,100、150、200 mg/kg组的肺泡炎均于第2周达峰(P0.01);肺纤维化分别在第2、4、4周达峰(P0.01)。在多次注射模型组中,50 mg/kg组肺泡炎和肺纤维化均在第10周达峰(P0.05)。TGF-β1和α-SMA在肺泡炎和纤维化部位表达明显增加。结论尾静脉单次注射博莱霉素200mg/kg可有效诱导肺纤维化,复制一个相对稳定的肺纤维化模型。     

PB方案在宫颈癌介入化疗中的应用

目的 探讨顺铂＋博莱霉素（PB）治疗方案在宫颈癌介入化疗中的应用效果。方法 采用P B方案,对64例ⅠB～ⅡB期宫颈癌病人术前均行双侧子宫动脉介入化疗栓塞术,观察化疗前后宫颈肿瘤体积变化及化疗后反应,评价介入化疗的效果。比较介入化疗后手术病人（观察组）与直接手术病人（对照组）术中情况及切除组织病理情况,评价介入化疗的近期疗效。长期随访病人,评价介入化疗的远期效果。结果 PB方案病人介入化疗的有效率为87.5%,缓解率为96.9%,34.4%的病人出现了发热反应,未见其他明显不良反应。观察组和对照组手术时间和术中出血量比较差异有显著性（t=9 0.99、9 1.02,P〈0.05）;两组术后盆腔淋巴结转移、脉管浸润、宫旁浸润及阴道切缘受累方面比较差异均有显著性（V2=5.037、7.246,P〈0.05）;观察组5年生存率及2、5年复发率与对照组比较,差异有显著性（V2=4 5.85～7.246,P〈0.05）。结论 PB介入化疗方案有效、低毒,对ⅠB～ⅡB期宫颈癌具有较好的疗效。PB方案是值得推广的介入化疗方案。     

参龙煎剂对博来霉素致肺纤维化大鼠肺组织基质金属蛋白酶2与金属蛋白酶组织抑制剂1表达的影响

目的：观察博来霉素致肺纤维化大鼠肺组织中基质金属蛋白酶2（matrixmetalloproteinase-2,MMP-2）和金属蛋白酶组织抑制剂1（tissue inhibitor of metallo proteinase-1,TIMP-1）mRNA的表达,探讨中药复方参龙煎剂防治大鼠肺纤维化的作用机制。方法：230只健康雄性Wistar大鼠随机分为正常对照组、模型组、泼尼松组和参龙煎剂低、中、高剂量组,采用气管内注入博来霉素的方法建立Wistar大鼠肺纤维化模型。正常对照组和模型组大鼠第2日起每日予生理盐水灌胃,其余各组大鼠按配好的参龙煎剂以等容药品灌胃。苏木素-伊红染色和Masson染色观察不同时间点大鼠肺组织病理变化,以评价模型是否成功。逆转录聚合酶链反应检测大鼠肺组织MMP-2和TIMP-1mRNA的表达水平。结果：各组大鼠肺组织在各个时间点均有MMP-2和TIMP-1mRNA表达。与正常对照组大鼠比较,模型组大鼠在第7天时MMP-2和TIMP-1mRNA基因转录水平均显著增高,尤以MMP-2mRNA增加明显,差异均有统计学意义（P〈0.05或P〈0.01）;在第14天时,MMP-2和TIMP-1mRNA的基因转录表达继续增高,但TIMP-1mRNA增加更显著,差异均有统计学意义（P〈0.05或P〈0.01）;第28天时,MMP-2已有所下降,但TIMP-1mRNA表达仍持续性增高,差异均有统计学意义（P〈0.05或P〈0.01）。与模型组大鼠比较,治疗组大鼠第7天MMP-2和TIMP-1mRNA基因转录水平降低,尤其是MMP-2的表达降低更明显,第28天时这种降低作用仍持续存在,以参龙煎剂中剂量组大鼠表现最明显,差异均有统计学意义（P〈0.05或P〈0.01）。结论：参龙煎剂可能是通过上调TIMP-1mRNA的表达来抑制MMP-2mRNA表达水平,从而起到延缓肺纤维化的作用。     

In vivo MRI of altered proton signal intensity and T2 relaxation in a bleomycin model of pulmonary inflammation and fibrosis

Purpose:

To investigate the ability of proton (¹H) magnetic resonance imaging (MRI) to distinguish between pulmonary inflammation and fibrosis.

Materials and Methods:

Three groups of Sprague‐Dawley rats (n = 5) were instilled intratracheally with bleomycin (2.5 U/kg or 3.5 U/kg) in saline or with saline only. Rats were imaged at 2.0 Tesla using a multi‐slice Carr‐Purcell‐Meilboom‐Gill (CPMG) sequence with 6 ms echo spacing. Signal intensity (S₀) and T₂ were calculated on a pixel‐by‐pixel basis using images collected before dosing and 1, 2, 4, and 7 weeks after. At each time point, data from dosed animals were compared with controls, and bivariate statistical analysis was used to classify image pixels containing abnormal tissue. At week 7, pulmonary function tests were performed, then all rats were killed, left lungs were formalin fixed and tri‐chrome stained for histological analysis of collagen content, and right lungs were used to measure water and hydroxyproline (collagen) content.

Results:

The product S₀×T₂ significantly correlated with water and collagen content in the high‐dose group (P = 0.004 and P = 0.03, respectively). However, S₀ and T₂ of abnormal tissue were correlated for all time points (r = 0.93, P < 0.001), and could not distinguish inflammation from fibrosis.

Conclusion:

MRI can be used to confidently localize pulmonary inflammation and fibrosis, but it lacks specificity. J. Magn. Reson. Imaging 2010;31:1091–1099. © 2010 Wiley‐Liss, Inc.     

Complete resolution of recalcitrant periungual/subungual wart with recovery of normal nail following “prick” method of administration of bleomycin 1%

We report a case of 14 year old girl with recalcitrant subungual wart which responded dramatically to bleomycin with normal nail regrowth.