NO-releasing xanthine KMUP-1 bonded by simvastatin attenuates bleomycin-induced lung inflammation and delayed fibrosis

Background and purposePulmonary fibrosis (PF) is a progressing lung injury initiated by pulmonary inflammation (PI). Bleomycin (BLM) is the most common pathogenesis of PF through early PI and extensive extracellular matrix deposition. This study is aimed to determine whether NO-releasing KMUP-1 inhibits PI and PF, and if so, the benefits of KMUP-1S resulted from simvastatin (SIM)-bonding to KMUP-1.Experiment approachC57BL/6 male mice were intra-tracheally administered BLM (4 U/kg) at day 0. KMUP-1 (1–5 mg/kg), KMUP-1S (2.5 mg/kg), SIM (5 mg/kg), Plus (KMUP-1 2.5 mg/kg + SIM 2.5 mg/kg), and clarithromycin (CAM, 10 mg/kg) were orally and daily administered for 7 and 28 days, respectively, to mice, sacrificed at day-7 and day-28 to isolate the lung tissues, for examining the inflammatory and fibrotic signaling and measuring the cell population and MMP-2/MMP-9 activity in broncholaveolar lavage fluid (BAL).Key resultsKMUP-1 and KUP-1S significantly decreased neutrophil counts in BAL fluid. Fibroblastic foci were histologically assessed by H&E and Masson's trichrome stain and treated with KMUP-1 and references. Lung tissues were determined the contents of collagen and the expressions of TGF-β, α-SMA, HMGB1, CTGF, eNOS, p-eNOS, RhoA, Smad3, p-Smad3, MMP-2 and MMP-9 by Western blotting analyses, respectively. These changes areregulated by NO/cGMP and inhibited by various treatments. KMUP-1 and KMUP-1S predominantly prevented HMGB1/MMP-2 expression at day-7 and reduced TGF-β/phosphorylated Smad3 and CTGF at day-28.Conclusions and implicationsKMUP-1 and KMUP-S restore eNOS, inhibit iNOS/ROCKII/MMP-2/MMP-9, attenuate histologic collagen disposition and reduce BALF inflammatory cells, potentially useful for the treatment of BLM-lung PF.     

Stress protein synthesis in human keratinocytes treated with sodium arsenite,phenyldichloroarsine, and nitrogen mustard

Cells from bacteria to man respond to sublethal thermal and certain chemical stresses by synthesis of heat shock, or stress, proteins. The human epidermal keratinocyte is a target for a variety of cytotoxic substances. One response of cells exposed to such agents may be the synthesis of stress proteins. Human epidermal keratinocytes were treated thermally (43°C) or chemically with sodium arsenite and the skin irritants phenyldichloroarsine and mechlorethamine. Proteins synthesized by keratinocytes were radiolabeled with [³⁵S]methionine, separated on polyacrylamide gels under denaturing conditions, and visualized by fluorography. Quantitation by computer-assisted densitometry of fluorograms revealed different patterns of synthesis of two heat shock proteins (hsp's) with apparent molecular weights of 70 and 90 kDa after treatment with heat, sodium arsenite, phenyldichloroarsine, or mechlorethamine. Sodium arsenite induced the highest levels of synthesis of these two proteins, approximately 10-fold and 3-fold increases in hsp-70 and hsp-90, respectively. Phenyldichloroarsine at 0.5 μm produced a 2-fold increase in hsp-70 but no significant increase in hsp-90. Mechlorethamine, in contrast, had an apparent inhibitory effect on hsp-70 synthesis. These results suggest that some but not all skin irritants induce the synthesis of heat shock proteins in human keratinocytes.     

别孕烯醇酮对6-羟基多巴胺损伤的细胞系SH-SY5Y的保护作用

目的 明确别孕烯醇酮(APα)对6-羟多巴胺(6-OHDA)损伤的SH-SY5Y细胞系的保护作用,并阐明可能的分子机制.方法 向体外培养的SH-SY5Y细胞系中分别加入6-OHDA、APα、γ-氨基丁酸A受体(GABAAR)拮抗剂荷包牡丹碱(Bic)和电压门控L型Ca2+通道拮抗剂硝苯地平(nifedipine),采用...     

大鼠腹壁浅动脉穿支皮瓣的解剖学

目的探讨大鼠腹壁浅动脉穿支皮瓣的解剖学特点,为该皮瓣切取提供解剖学依据。方法 SD大鼠27只,7只行大体解剖,描述该皮瓣的解剖学特点;20只经颈总动脉行明胶-氧化铅灌注,并通过图片处理技术测量相关数据。结果腹壁浅动脉由股动脉发出后在穿浅筋膜处发出第1个分支,随即分为内外侧支,分别与胸外侧动脉和胸背动脉吻合。其外径在股动脉发出处为(0.46±0.02)mm,在穿经浅筋膜处为(0.46±0.02)mm,其营养面积为(18.37±3.67)cm2,其与胸背动脉的吻合区距离腋下水平线和腹中线分别为(5.34±0.86)cm和(4.38±0.38)cm;与胸外侧动脉的吻合区距离腋下水平线和腹中线分别为(6.28±0.69)cm和(2.04±0.33)cm。结论大鼠腹壁浅动脉解剖位置和外径恒定,是游离皮瓣移植、皮瓣动脉增压、血流动力学研究等的理想模型。     

小腿经络区体被组织的血管形态学研究

目的：观察小腿经络区的体被组织内血管的分布。方法：采用巨微解剖、全身动脉放射显影及图像分析技术，解剖12只下肢的体被组织，观察分析小腿经络沿线的体被组织内血管来源、分支和吻合情况。结果：足三阴经、胆经、膀胱经线区的小腿体被组织血管密度明显高于其他部位，在动脉显影X绒图像上分别形成一条明显的营养血管链；胃经沿线血管密度未见增高，也未见明显的营养血管链。结论：除胃经外，小腿经络区体被组织内均形成一条明显的皮神经营养血管链。     

Ⅱ型与Ⅴ型腓骨瓣修复跟骨缺失初期再造跟骨稳定性的比较

目的 比较Ⅱ型、Ⅴ型腓骨瓣重建跟骨缺损的临床效果.方法 建立Ⅴ型和Ⅱ型的简化模型,分别模拟采用Ⅱ型Ｖ型腓骨瓣重建跟骨缺损,以结构力学计算得到的位移作为评价足功能指标,进行理论分析进而比较两者的稳定性.结果 建立了Ⅱ型腓骨瓣与Ⅴ型腓骨瓣修复简化模型并得到分析后的理论数据.理论计算表明,Ⅱ型腓骨瓣的稳定性优于Ⅴ型.两种重建...     

穿支皮瓣Choke区动、静脉血流阻力对皮瓣存活的影响

目的　通过在同一组皮瓣中对choke血管的动、静脉阻力进行比较研究,探究血流跨过choke血管的动、静脉阻力大小关系及其对皮瓣存活的影响。 方法　将34只SD大鼠随机分成两组,A组保留右侧肋间后动脉+左侧肋间后静脉,B组保留右侧肋间后动脉+右侧髂腰静脉。测量保留的动、静脉之间的距离。术后7天,统计皮瓣存活率以及血管造影观察皮瓣区微血管形态;choke区取材,H&E染色,计算平均微血管密度;尾静脉采血,检测乳酸含量。 结果　A组保留的动、静脉之间的距离比B组短[(2.5±0.3) cm vs (3.7±0.2) cm,t=14.608,P<0.05）]。术后7 d,A组皮瓣存活率为100%,B组1号血管体区存活率为（67.0±13.1）%,4号血管体区的为100%,整块皮瓣存活率为（88.0±6.8）%;A组比B组血管增生明显[（24.0±3.9）vs (17.6±4.3),t=2.727,P=0.021];A组与B组乳酸均接近术前水平,差异无统计学意义[（8.0±0.8）mmol/L vs (8.4±0.4) mmol/L vs (7.5±0.6) mmol/L,P>0.05]。 结论　①血流跨过choke血管的静脉阻力大于动脉阻力;②缩短跨choke区的动、静脉血流单向距离有利于减小跨choke区所受的静脉阻力,提高皮瓣的存活率。