磷酸肌醇3-激酶信号通路参与肺损伤修复及机制探讨
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摘要
第一部分PI3K抑制剂对急性肺损伤的保护作用及机制
目的：探讨磷酸肌醇3-激酶(Phosphatidylinositol3-kinases, PI3K)抑制剂对肉毒素脂多糖(lipopolysaccharide, LPS)所致小鼠急性肺损伤的保护作用,并比较不同的给药方式、给药剂量、药物种类以及不同时间点的疗效差别。
方法：取6-8周龄的雄性CD-1小鼠,连续3天分别经鼻(0.5mg/kg)或经胃管(50mg/kg)滴入3种不同的P13K抑制齐(?)(LY294002,SHBM009,GDC0941)或PBS,随后经气道滴入LPS(1.25mg/kg)诱导肺损伤,分别在LPS滴入后4h和24h处死小鼠(每组每个时间点10只)。观察这3种P13K抑制剂对LPS刺激后小鼠肺毛细血管通透性、肺组织重量/体重比值、肺组织气体容量(excised lung gas volume, ELGV)、肺泡灌洗液蛋白渗出和炎症细胞浸润、肺泡灌洗液(Brochoalveolar lavage fluid,BALF)炎症因子水平的影响,并比较不同给药方式、不同时间点的疗效差别。A549上皮细胞分别在含有不同浓度SHBM1009(1或10ug/mL)的培养基中培养,然后用LPS(1ug/ml)或PBS刺激。在刺激后3,6,12,24收集培养液上清,4℃离心10000rpm10min,用ELISA方法测定培养液上清中角质细胞源性趋化因子(KC)、白三烯B4(LTB4)的水平。
结果：LPS刺激后4h和24h小鼠肺组织重量/体重的比值明显高于PBS刺激组(P<0.01),经鼻或经胃管滴入LY294002或GDC-0941能抑制肺组织重量/体重比值的升高(P<0.05),具有保护作用。经鼻滴入SHBM1009亦具有明显保护作用(P<0.01)。经鼻滴入LY294002或SHBM1009能明显抑制LPS刺激4h或24h后ELGV的增加(P<0.05)。经鼻滴入这3种P13K抑制剂均能抑制LPS刺激后4h肺泡灌洗液的白细胞浸润(P<0.01或0.05)。LPS刺激能明显增加4h和24h小鼠肺泡灌洗液角质细胞趋化因子(KC)的含量(P<0.01),只有SHBM1009经鼻滴入4h组显示出明显抑制作用(P<0.01)。利用伊文思蓝染色证明LPS能增加肺泡毛细血管通透性(P<0.01),而经鼻滴入SHBM1009具有明显保护作用(P<0.05)。通过肺组织免疫荧光染色方法发现经鼻滴入SHBM1009能抑制LPS所诱导的中性粒细胞(P<0.01)和巨噬细胞的浸润(P<0.05)。经LPS刺激的气道上皮细胞培养液上清中KC的水平在3-24h均有明显升高,而SHBM1009(1ug/ml和10ug/ml)能显著抑制上皮细胞分泌KC,且呈剂量依赖性(P值分别为P<0.05和P<0.01)。LPS刺激后24h,上清液中LTB4和LTB4的水平也有明显升高。
结论：P13K抑制剂能预防LPS所导致的小鼠急性肺损伤,主要通过保护毛细血管内皮屏障、抑制上皮细胞活化、抑制炎症细胞浸润和黏附能力、减少炎症因子释放等。局部给药的保护作用优于全身给药,且不同P13K抑制剂的保护作用也有差异,这可能和药物的化学结构、靶向部位以及药动学特点有关。
第二部分PI3K抑制剂对慢性气道炎症、组织损伤和气道重塑的治疗作用
目的：探讨P13K抑制剂对胰弹性蛋白酶(pancreatic elastase,PE)所诱导的大鼠慢性气道炎症、组织损伤和气道重塑的治疗作用。
方法：取180-200g的健康雄性Wistar大鼠,气道滴入PE(250IU/kg)诱导肺损伤模型,在随后的7天或28天内经鼻滴入PBS、SHBM1009或布地奈德(budesonide, Bud)观察其治疗作用。实验共分为6组：1)Sham组：PBS刺激+PBS治疗；2) Vehicle组：PE刺激+PBS治疗；3) SHBM1009对照组：PBS刺激+SHBM1009(10mg/kg);4) SHBM1009(?)(?)剂量组：PE刺激+SHBM1009(1mg/kg);5)SHBM1009高剂量组：PE刺激+SHBM1009(10mg/kg);6) Bud组：PE刺激+Bud (10mg/kg)。每组每个时间点6只大鼠。通过HE染色、电镜、Masson染色观察大鼠肺组织病理变化,同时测定大鼠ELGV、肺组织密度、肺组织重量/体重、BALF蛋白含量和细胞计数,ELISA方法检测肺泡灌洗液炎症因子IL-1β水平,RT-PCR方法检测肺组织Fibulin-5的表达。体外实验部分,A549细胞以合适密度接种于24孔培养板,以不同浓度PE(0.03U/ml,0.3U/ml,1U/ml,2U/m1)或Vehicle刺激与不同浓度的SHBM1009(0.01umol/L,0.1umol/L,1umol/L,10umol/L)或BEZ235(0.01umol/L,0.1umol/L,1umol/L,10umol/L)共培养,Cell-IQ细胞实时监测系统观察48h内细胞增生、分裂和凋亡情况。
结果：组织病理学HE染色可见PE刺激后28天,肺泡壁断裂,肺泡腔明显扩大,电镜观察可发现肺泡II型上皮细胞微结构变化、间质胶原沉积及成纤维细胞增生、气血屏障破坏,Masson染色可见Vehicle治疗组胶原含量明显增多,而SHBM1009或Bud治疗能保护肺组织结构的破坏。Vehicle治疗组在7天和28天肺组织重量和ELGV值较Sham组和SHBM1009对照组明显升高(分别为P<0.05和P<0.01)。PE刺激能诱导肺组织重量增加,虽SHBM1009(1mg/kg)和Bud (10mg/kg)治疗组在第7天和28天肺组织重量较vehicle治疗组明显减轻,但与Sham组相比仍有明显升高(P<0.05or0.01)。在PE刺激后第7天,大鼠肺组织密度明显升高,第28天时,肺组织密度明显减轻,SHBM1009或Bud治疗具有明显保护作用(P<0.01)。PE刺激后第7天,Vehicle组肺泡灌洗液蛋白含量明显增加(P<0.01),SHBM1009或Bud治疗均具有明显抑制作用(P<0.05orP<0.01)。PE刺激后第7天和第28天,BALF细胞计数明显增多(P<0.01),SHBM1009或Bud治疗均具有明显抑制作用(P<0.05or0.01)。PE刺激能诱导BALF炎症因子IL-1p水平的升高,SHBM1009或Bud治疗均具有明显抑制作用(P<0.05or0.01)。Fibulin-5mRNA的水平在Vehicle组明显升高,SHBM10091mg/kg或10mg/kg治疗组在第28天均显示出治疗作用,Bud治疗组在第7天和28天均显示出治疗作用。PE刺激能明显抑制气道上皮细胞的增生和分裂,且呈剂量和时间依赖效应,而对细胞凋亡的影响较小。当PE浓度为1U/ml时,BEZ235在浓度0.1-1.0uM或SHBM1009在浓度0.01-10uM具有明显保护作用。而当PE浓度为0.3U/ml时,BEZ2350.01或0.1uM/ml或SHBM10090.01-1.0uM时保护作用较明显。
结论：P13K参与了肺损伤的发生和发展过程,包括早期的炎症反应、肺水肿,以及后期的组织修复、气道重塑和肺气肿,其机制主要通过促进上皮细胞的增生分裂,修复损伤的上皮,并能抑制成纤维母细胞增生和胶原沉积,从而减轻气道重塑。P13K抑制剂可能成为慢性气道疾病的一个治疗的新靶点。
第三部分KGF-2对大鼠原位肺缺血再灌注损伤的保护作用及机制
目的：探讨角质细胞生长因子-2(keratinocyte growth factor-2,KGF-2)对大鼠原位肺缺血再灌注损伤的保护作用,及对内皮细胞屏障功能的影响。
方法：健康雄性SD大鼠250g左右,分成6组,每组15只,分组如下:1)Sham组：手术开胸但不经历缺血-再灌注；3)缺血再灌注(ischemia-reperfusion, IR)组(I/R)：动物经开胸后,左肺门夹闭60min,再灌注180min；3),4)和5)KGF-2低、中、高剂量治疗组：动物在手术前72h气道滴入KGF-22.5mg/kg,5mg/kg和10mg/kg,之后行缺血再灌注手术；6)地塞米松(dexamethasone, DXM)组：在缺血再灌注手术前2h腹腔注射地塞米松5mg/kg。在缺血再灌注损伤前后分别采集血标本行血气分析,动物处死后HE染色行肺组织形态学测量,计算肺湿干重比值,收集肺泡灌洗液进行细胞计数和蛋白水平检测,肺组织提取RNA和蛋白进行后续分子生物学分析。体外培养人肺微血管内皮细胞(human pulmonary microvascular endothelial cell, HPMEC)进一步探讨KGF-2对内皮细胞保护作用的机制。Cell-IQ. Brdu细胞增殖实验检测KGF-2对细胞增殖和凋亡的影响；FITC标记白蛋白的通透性及跨膜电阻抗检测内皮细胞屏障功能。
结果：肺组织形态学观察显示IR组肺组织出血、水肿和炎症反应明显较Sham组严重,KGF-2和DXM均具有预防作用,其中KGF-22.5mg/kg和5mg/kg的保护作用最明显(P<0.01)。IR组肺组织湿/干重比值明显增大,KGF-22.5mg/kg,5mg/kg和DXM5mg/kg具有保护作用(P<0.05)。缺血再灌注之前,所有组血氧分压无明显差别,IR之后,IR组、KGF-210mg/kg组及DXM组血氧分压均明显降低(P<0.05),而KGF-22.5mg/kg和5mg/kg预处理显示出明显保护作用(P<0.05)。IR之后,大鼠肺泡灌洗液细胞计数和蛋白水平均明显增加,KGF-2和DXM均显示出不同程度的保护作用(P<0.05或P<0.01)。RT-PCR检测显示KGF-2能促进肺泡表面蛋白C (surfactant protein C, SPC)的表达,而对SPA的表达量无明显影响。体外实验发现,在无损伤刺激的情况下,KGF-2不促进内皮细胞的过度增殖,但可维持损伤情况下细胞总数的稳定增长。此外,KGF-2还可保护内皮细胞的正常屏障功能。
结论：KGF-2预处理能保护缺血再灌注所致肺损伤,减轻炎症反应、水肿和出血。其保护作用机制可能包括促进肺泡表面活性物质的表达、维持气血屏障的正常结构和功能。
Part1Preventive Effects of Phosphatidylinositol3-kinases Inhibitors on Lipopolysaccharide induced Acute Lung Injury in Mice
Objective:To investigated the preventive effects of Phosphatidylinositol3-kinases (PI3K) inhibitors and compared the efficacy of intratracheal and intragastrical deliveries on lung edema and gas volume, leukocyte recruitment, and chemokine production at4and24h after LPS induced ALI in mice. In vitro studies were further conducted to investigate whether the PI3K inhibitor has direct effects on epithelial cells and neutrophils.
Methods:Male CD-1mice aged6-8weeks were selected and administered3different PI3K inhibitors (LY294002, GDC0941and SHBM1009) either intranasally or intragastrically once a day for3days before intratracheal instillation of lipopolysaccharide at4h and24h. Animal bodyweight (BW) was measured both before the experiment and at termination. After termination, the lung weight/body weight (LW/BW) ratio, gas volume, and total number of leukocytes and levels of KC in Brochoalveolar lavage fluid (BALF) were measured. Excised lung gas volume (ELGV) was measured based on the Archimedes principle. Effects of SHBM1009on lipopolysaccharide (LPS)-induced capillary permeability were evaluated by Evans blue dye, leukocyte distribution and activation were measured. The number of neutrophils and macrophages in the lung tissue was measured as the average cell number per cross-section of lungs based on evaluating10lung areas per specimen. For the in vitro study, the CD-1mouse airway epithelial cells and circulating neutrophils were isolated, purified, and cultured cultured in the presence or absence of LPS at1mg/mL and SHBM1009at1or10mg/mL. The production of KC and LTB4was evaluated using ELISA kit at3,6,12, and24h after LPS challenge. Neutrophil adhesion was measured. The direct inhibitory effects of LY294002and SHBM1009at different concentrations on the superoxide generation from mouse neutrophils stimulated by LPS at1mg/mL for24h were measured as described previously.
Results:LW/BW ratio in animals pretreated with vehicle and challenged with LPS were significantly higher than those challenged with PBS at4and24h (P<0.01), which was prevented by intranasal or intragastrical pretreatment with LY294002, intragastrically with GDC-0941, and intranasally with SHBM1009(P<0.05and P<0.01, respectively). Levels in animals with LY294002(intranasally at24h) and GDC-0941(intranasally at4h and intragastrically at4and24h) were still significantly higher than those without LPS (P<0.05for both). Intranasal pretreatment with either LY294002or SHBM1009significantly prevented LPS-induced increase of ELGV at4or24h after LPS challenge (P<0.05). Intranasal pretreatment with all PI3K inhibitors significantly prevented LPS-induced leukocyte influx in BALF at4h (P<0.05and P<0.01, respectively). Intranasal pretreatment with LY294002or SHBM1009at4or24h showed partially preventive effects on LPS-induced KC production (P<0.05). LPS significantly increased Evans blue dye leakage in the airway and lung (P<0.01vs control subjects), which was prevented by intranasal delivery of SHBM1009(P<0.05vs animals with vehicle and LPS). Pretreatment with SHBM1009prevented LPS-increased number of neutrophils (P<0.01) and macrophages (P<0.05). Levels of KC in the mouse epithelial cell supernatant were significantly higher from3h after LPS challenge compared with the control or those treated with SHBM1009at1or10mg/mL (P<0.05and P<0.01, respectively). The adhesion rate of mouse neutrophils stimulated by KC, LTB4, or LPS was inhibited by SHBM1009at different concentrations. The inhibitory potency of SHBM1009depended on stimuli. LY294002or SHBM1009significantly inhibited superoxide production from LPS-stimulated mouse neutrophils, and the50%inhibitory dose of SHBM1009was much lower than that of LY294002.
Conclusion:Local delivery of PI3K inhibitors played more effective roles in the prevention of endotoxin-induced lung injury than the systemic delivery. The preventive effects of PI3K inhibitors varied most likely because of chemical properties, targeting sites, and pharmacokinetics. The protective effects of PI3K inhibitors on ALI may through direct inhibition of airway epithelial cells, neutrophils, and macrophages. PI3K may be a therapeutic target for acute lung injury, and local delivery of PI3K inhibitors may be one of the optimal approaches for the therapy.
Part2Roles and mechanism of phosphoinositide3-kinase in acute and chronic lung inflammation, tissue injury, remodeling and emphysema in rats
Objective:To evaluate the therapeutic effects of SHBM1009, a new PI3K/mTOR inhibitor, on chronic lung inflammation, tissue injury and remodeling7and28days after the intratracheal instillation of pancreatic elastase (PE), and potential mechanisms by which PI3K may be involved in the inflammation or biological functions of airway epithelial cells or pulmonary myofibroblasts.
Methods:Adult male Wister rats, weighing180-200g, were intratracheally instilled with PE (0.2mL,100IU) or PBS, followed by7or28days of continuously intranasal instillation of SHBM1009or budesonide (the reference drug). The animals were divided randomly into six experimental groups:1) animals were challenged with vehicle and treated with vehicle at0.2ml;2) animals were challenged with PE and treated with vehicle;3) animals were challenged with vehicle and treated with SHBM1009at10mg-kg-1,4and5) animals were challenged with PE and treated with SHBM1009at1and10mg-kg-1or6) animals were challenged with PE and treated with budesonide at1mg-kg-1, respectively. There were12animals per group and6in each time point. Lung weight, body weight and lung density were measured for each rat. Excised lung gas volume (ELGV) was measured by Archimedes' principle. The bronchoalveolar lavage fluid was harvested for evaluating cell count, protein concentration, levels of IL-1β and TGF-β1. HE staining, scanning electron microscopy and Masson staining were used to evaluate lung morphometry. Besides, cellular biological functions were monitored and determined with Cell-IQ, an integrated, fully automated system which can monitor and record the cell number, proliferation, differentiation, apoptosis or movement without use of labels or markers. The cells were plated onto24-well plates with an appropriate density and challenged with PE at concentrations of0.03,0.30,1.00, or2.00U/ml, respectively, to evaluate damaging effects of PE per se. In order to determine protective and dose-associated effects of PI3K inhibitors, cells were co-cultured with BEZ235at concentrations of0.01,0.10,1.00or10μM, or SHBM1009at concentrations of0.01,0.10,1.00, or10μM, respectively, under PE at1.00U/ml. The effects of BEZ235or SHBM1009at concentrations of0.01,0.10, or1.00μM were furthermore evaluated under PE challenge at0.3U/ml.
Results:Intratracheal instillation of SHBM1009at the dose of lmg/kg and budesonide can prevent PE-increased lung weights on7and28days, respectively. Values of lung densities in animals with PE and vehicle7days after the challenge were significantly higher than those without PE, which were significantly attenuated by the treatment with SHBM1009or budesonide (p<0.01). PE instillation increased the lung density at7days while decreased it at28days, while the treatment with SHBM100910mg/kg and budesonide can significantly attenuate such reduction (p<0.01). Levels of total protein in BALF significantly increased7days after the challenge with PE (p<0.01), which was prevented by the treatment with SHBM1009at1or10mg/kg and budesonide (p<0.01or0.05, respectively). Treatment with SHBM1009or budesonide significantly inhibited PE-increased inflammatory cells in BALF on both7and28days (p<0.05or0.01, respectively). Levels of IL-1in BALF or serum harvested from animals with PE challenge and vehicle treatment were significantly higher than from those without PE on7and28days (p<0.01, Fig2C), and were significantly attenuated by treatment with SHBM1009and budesonide (p<0.05or0.01, respectively). For the morphologic changes, alveolar walls and airspace were compromised and enlarged, the thickness of remained alveolar walls increased, and the number of monocytes with the wall elevated in PE-challenged animals treated with vehicle. PE-induced lung injury was protected by the treatment with SHBM1009or Budesonide, while therapeutic effects of SHBM1009at10mg/kg were better than at1mg/kg. Intratracheal instillation of PE induced a significant increase in the area of collagen-positive staining in the lung, while the treatment with SHBM1009or budesonide significantly inhibited the deposition of collagen. Total number of lung epithelial cells significantly decreased when the co-culture with PE in a dose-dependent pattern. PE (1U/ml)-induced reductions of total cell number were partially prevented by the addition of BEZ at0.1-1.0uM or SHBM1009at0.01-10uM, while SHBM1009at0.01-1.0uM or BEZ at0.01and0.1uM fully prevented from decreased total cell number by PE at0.3U/ml. Altered number of stable, differentiated and death cells co-cultured with PE alone or PE at1.0or0.3U/ml plus BEZ or SHBM1009at the different concentrations was similar to the pattern of total cell number.
Conclusion:PI3K plays a critical role in the development of both acute and chronic lung injury and the progress of tissue remodeling and emphysema. The mechanisms include promoting proliferation and differentiation of epithelial cells, inhibiting the proliferation and differential of fibroblasts and collagen deposition. PI3K inhibitors may be considered as one of new therapeutic alternatives for chronic lung diseases e.g. COPD or emphysema, or at least as a candidate of therapeutic combination.
Part3Protective effects of keratinocyte growth factor-2on warm ischemia reperfusion induced lung injury in rats
Objectives:The purpose of this study was to investigate whether KGF-2had a beneficial effect on IR-induced ALI. In addition, the effect of KGF-2on endothelial cells was also investigated to provide insight into the possible molecular mechanisms involved in the action of KGF-2.
Methods:SD rats were randomly divided into seven experimental groups (n=15):1) Sham group:animals undergoing a sham operation and pre-treated with vehicle;2) IR group:animals with I/R-ALI and pre-treated with vehicle;3),4) and5) KGF-2low, middle, and high treatment group:animals were intratracheally instilled with2.5mg/kg,5mg/kg and10mg/kg KGF-272hours prior to IR surgery;7) dexamethasone (DXM) group:DXM at a dose of5mg/kg was administered introperitoneally2hours prior to IR. Keratinocyte growth factor-2(2.5,5, or10mg/kg) was administered intratracheally to rats3days before surgery. Then the left lung in rats was subjected to ischemia for60minutes and reperfusion for as long as180minutes. Lung morphology, blood gas analysis, total cell number and protein concentration in the bronchoalveolar lavage fluid were measured to evaluate the lung injury. The protective effects of keratinocyte growth factor-2on human pulmonary microvascular endothelial cells and related mechanisms were evaluated in vitro. Cell-IQ was applied to monitoring biological behavior; Brdu proliferation assay was used to assess cell proliferation; measurement of the permeability of FITC-labeled albumin and transendothelial electrical resistence to assesse barrier function of the endothelial.
Results:Pre-treatment with keratinocyte growth factor-2at the doses of2.5mg and-5mg/kg effectively inhibited lung edema, inflammatory cell infiltration, protein exudation and the release of inflammatory cytokines. In vitro study demonstrated that keratinocyte growth factor-2could inhibit endothelial cell apoptosis, enhancing migration, and maintaining the integrity of the blood-gas barrier. Phosphoinositide3-kinase inhibitors attenuated the protective effect of Keratinocyte growth factor-2in endothelial cells.
Conclusion:Keratinocyte growth factor-2pre-treatment reduced ischemia reperfusion-induced acute lung injury. The protective effects of keratinocyte growth factor-2may contribute to its protective effects on both epithelial and endothelial cells.
目的：探讨磷酸肌醇3-激酶(Phosphatidylinositol3-kinases, PI3K)抑制剂对肉毒素脂多糖(lipopolysaccharide, LPS)所致小鼠急性肺损伤的保护作用,并比较不同的给药方式、给药剂量、药物种类以及不同时间点的疗效差别。
方法：取6-8周龄的雄性CD-1小鼠,连续3天分别经鼻(0.5mg/kg)或经胃管(50mg/kg)滴入3种不同的P13K抑制齐(?)(LY294002,SHBM009,GDC0941)或PBS,随后经气道滴入LPS(1.25mg/kg)诱导肺损伤,分别在LPS滴入后4h和24h处死小鼠(每组每个时间点10只)。观察这3种P13K抑制剂对LPS刺激后小鼠肺毛细血管通透性、肺组织重量/体重比值、肺组织气体容量(excised lung gas volume, ELGV)、肺泡灌洗液蛋白渗出和炎症细胞浸润、肺泡灌洗液(Brochoalveolar lavage fluid,BALF)炎症因子水平的影响,并比较不同给药方式、不同时间点的疗效差别。A549上皮细胞分别在含有不同浓度SHBM1009(1或10ug/mL)的培养基中培养,然后用LPS(1ug/ml)或PBS刺激。在刺激后3,6,12,24收集培养液上清,4℃离心10000rpm10min,用ELISA方法测定培养液上清中角质细胞源性趋化因子(KC)、白三烯B4(LTB4)的水平。
结果：LPS刺激后4h和24h小鼠肺组织重量/体重的比值明显高于PBS刺激组(P<0.01),经鼻或经胃管滴入LY294002或GDC-0941能抑制肺组织重量/体重比值的升高(P<0.05),具有保护作用。经鼻滴入SHBM1009亦具有明显保护作用(P<0.01)。经鼻滴入LY294002或SHBM1009能明显抑制LPS刺激4h或24h后ELGV的增加(P<0.05)。经鼻滴入这3种P13K抑制剂均能抑制LPS刺激后4h肺泡灌洗液的白细胞浸润(P<0.01或0.05)。LPS刺激能明显增加4h和24h小鼠肺泡灌洗液角质细胞趋化因子(KC)的含量(P<0.01),只有SHBM1009经鼻滴入4h组显示出明显抑制作用(P<0.01)。利用伊文思蓝染色证明LPS能增加肺泡毛细血管通透性(P<0.01),而经鼻滴入SHBM1009具有明显保护作用(P<0.05)。通过肺组织免疫荧光染色方法发现经鼻滴入SHBM1009能抑制LPS所诱导的中性粒细胞(P<0.01)和巨噬细胞的浸润(P<0.05)。经LPS刺激的气道上皮细胞培养液上清中KC的水平在3-24h均有明显升高,而SHBM1009(1ug/ml和10ug/ml)能显著抑制上皮细胞分泌KC,且呈剂量依赖性(P值分别为P<0.05和P<0.01)。LPS刺激后24h,上清液中LTB4和LTB4的水平也有明显升高。
结论：P13K抑制剂能预防LPS所导致的小鼠急性肺损伤,主要通过保护毛细血管内皮屏障、抑制上皮细胞活化、抑制炎症细胞浸润和黏附能力、减少炎症因子释放等。局部给药的保护作用优于全身给药,且不同P13K抑制剂的保护作用也有差异,这可能和药物的化学结构、靶向部位以及药动学特点有关。
第二部分PI3K抑制剂对慢性气道炎症、组织损伤和气道重塑的治疗作用
目的：探讨P13K抑制剂对胰弹性蛋白酶(pancreatic elastase,PE)所诱导的大鼠慢性气道炎症、组织损伤和气道重塑的治疗作用。
方法：取180-200g的健康雄性Wistar大鼠,气道滴入PE(250IU/kg)诱导肺损伤模型,在随后的7天或28天内经鼻滴入PBS、SHBM1009或布地奈德(budesonide, Bud)观察其治疗作用。实验共分为6组：1)Sham组：PBS刺激+PBS治疗；2) Vehicle组：PE刺激+PBS治疗；3) SHBM1009对照组：PBS刺激+SHBM1009(10mg/kg);4) SHBM1009(?)(?)剂量组：PE刺激+SHBM1009(1mg/kg);5)SHBM1009高剂量组：PE刺激+SHBM1009(10mg/kg);6) Bud组：PE刺激+Bud (10mg/kg)。每组每个时间点6只大鼠。通过HE染色、电镜、Masson染色观察大鼠肺组织病理变化,同时测定大鼠ELGV、肺组织密度、肺组织重量/体重、BALF蛋白含量和细胞计数,ELISA方法检测肺泡灌洗液炎症因子IL-1β水平,RT-PCR方法检测肺组织Fibulin-5的表达。体外实验部分,A549细胞以合适密度接种于24孔培养板,以不同浓度PE(0.03U/ml,0.3U/ml,1U/ml,2U/m1)或Vehicle刺激与不同浓度的SHBM1009(0.01umol/L,0.1umol/L,1umol/L,10umol/L)或BEZ235(0.01umol/L,0.1umol/L,1umol/L,10umol/L)共培养,Cell-IQ细胞实时监测系统观察48h内细胞增生、分裂和凋亡情况。
结果：组织病理学HE染色可见PE刺激后28天,肺泡壁断裂,肺泡腔明显扩大,电镜观察可发现肺泡II型上皮细胞微结构变化、间质胶原沉积及成纤维细胞增生、气血屏障破坏,Masson染色可见Vehicle治疗组胶原含量明显增多,而SHBM1009或Bud治疗能保护肺组织结构的破坏。Vehicle治疗组在7天和28天肺组织重量和ELGV值较Sham组和SHBM1009对照组明显升高(分别为P<0.05和P<0.01)。PE刺激能诱导肺组织重量增加,虽SHBM1009(1mg/kg)和Bud (10mg/kg)治疗组在第7天和28天肺组织重量较vehicle治疗组明显减轻,但与Sham组相比仍有明显升高(P<0.05or0.01)。在PE刺激后第7天,大鼠肺组织密度明显升高,第28天时,肺组织密度明显减轻,SHBM1009或Bud治疗具有明显保护作用(P<0.01)。PE刺激后第7天,Vehicle组肺泡灌洗液蛋白含量明显增加(P<0.01),SHBM1009或Bud治疗均具有明显抑制作用(P<0.05orP<0.01)。PE刺激后第7天和第28天,BALF细胞计数明显增多(P<0.01),SHBM1009或Bud治疗均具有明显抑制作用(P<0.05or0.01)。PE刺激能诱导BALF炎症因子IL-1p水平的升高,SHBM1009或Bud治疗均具有明显抑制作用(P<0.05or0.01)。Fibulin-5mRNA的水平在Vehicle组明显升高,SHBM10091mg/kg或10mg/kg治疗组在第28天均显示出治疗作用,Bud治疗组在第7天和28天均显示出治疗作用。PE刺激能明显抑制气道上皮细胞的增生和分裂,且呈剂量和时间依赖效应,而对细胞凋亡的影响较小。当PE浓度为1U/ml时,BEZ235在浓度0.1-1.0uM或SHBM1009在浓度0.01-10uM具有明显保护作用。而当PE浓度为0.3U/ml时,BEZ2350.01或0.1uM/ml或SHBM10090.01-1.0uM时保护作用较明显。
结论：P13K参与了肺损伤的发生和发展过程,包括早期的炎症反应、肺水肿,以及后期的组织修复、气道重塑和肺气肿,其机制主要通过促进上皮细胞的增生分裂,修复损伤的上皮,并能抑制成纤维母细胞增生和胶原沉积,从而减轻气道重塑。P13K抑制剂可能成为慢性气道疾病的一个治疗的新靶点。
第三部分KGF-2对大鼠原位肺缺血再灌注损伤的保护作用及机制
目的：探讨角质细胞生长因子-2(keratinocyte growth factor-2,KGF-2)对大鼠原位肺缺血再灌注损伤的保护作用,及对内皮细胞屏障功能的影响。
方法：健康雄性SD大鼠250g左右,分成6组,每组15只,分组如下:1)Sham组：手术开胸但不经历缺血-再灌注；3)缺血再灌注(ischemia-reperfusion, IR)组(I/R)：动物经开胸后,左肺门夹闭60min,再灌注180min；3),4)和5)KGF-2低、中、高剂量治疗组：动物在手术前72h气道滴入KGF-22.5mg/kg,5mg/kg和10mg/kg,之后行缺血再灌注手术；6)地塞米松(dexamethasone, DXM)组：在缺血再灌注手术前2h腹腔注射地塞米松5mg/kg。在缺血再灌注损伤前后分别采集血标本行血气分析,动物处死后HE染色行肺组织形态学测量,计算肺湿干重比值,收集肺泡灌洗液进行细胞计数和蛋白水平检测,肺组织提取RNA和蛋白进行后续分子生物学分析。体外培养人肺微血管内皮细胞(human pulmonary microvascular endothelial cell, HPMEC)进一步探讨KGF-2对内皮细胞保护作用的机制。Cell-IQ. Brdu细胞增殖实验检测KGF-2对细胞增殖和凋亡的影响；FITC标记白蛋白的通透性及跨膜电阻抗检测内皮细胞屏障功能。
结果：肺组织形态学观察显示IR组肺组织出血、水肿和炎症反应明显较Sham组严重,KGF-2和DXM均具有预防作用,其中KGF-22.5mg/kg和5mg/kg的保护作用最明显(P<0.01)。IR组肺组织湿/干重比值明显增大,KGF-22.5mg/kg,5mg/kg和DXM5mg/kg具有保护作用(P<0.05)。缺血再灌注之前,所有组血氧分压无明显差别,IR之后,IR组、KGF-210mg/kg组及DXM组血氧分压均明显降低(P<0.05),而KGF-22.5mg/kg和5mg/kg预处理显示出明显保护作用(P<0.05)。IR之后,大鼠肺泡灌洗液细胞计数和蛋白水平均明显增加,KGF-2和DXM均显示出不同程度的保护作用(P<0.05或P<0.01)。RT-PCR检测显示KGF-2能促进肺泡表面蛋白C (surfactant protein C, SPC)的表达,而对SPA的表达量无明显影响。体外实验发现,在无损伤刺激的情况下,KGF-2不促进内皮细胞的过度增殖,但可维持损伤情况下细胞总数的稳定增长。此外,KGF-2还可保护内皮细胞的正常屏障功能。
结论：KGF-2预处理能保护缺血再灌注所致肺损伤,减轻炎症反应、水肿和出血。其保护作用机制可能包括促进肺泡表面活性物质的表达、维持气血屏障的正常结构和功能。
Part1Preventive Effects of Phosphatidylinositol3-kinases Inhibitors on Lipopolysaccharide induced Acute Lung Injury in Mice
Objective:To investigated the preventive effects of Phosphatidylinositol3-kinases (PI3K) inhibitors and compared the efficacy of intratracheal and intragastrical deliveries on lung edema and gas volume, leukocyte recruitment, and chemokine production at4and24h after LPS induced ALI in mice. In vitro studies were further conducted to investigate whether the PI3K inhibitor has direct effects on epithelial cells and neutrophils.
Methods:Male CD-1mice aged6-8weeks were selected and administered3different PI3K inhibitors (LY294002, GDC0941and SHBM1009) either intranasally or intragastrically once a day for3days before intratracheal instillation of lipopolysaccharide at4h and24h. Animal bodyweight (BW) was measured both before the experiment and at termination. After termination, the lung weight/body weight (LW/BW) ratio, gas volume, and total number of leukocytes and levels of KC in Brochoalveolar lavage fluid (BALF) were measured. Excised lung gas volume (ELGV) was measured based on the Archimedes principle. Effects of SHBM1009on lipopolysaccharide (LPS)-induced capillary permeability were evaluated by Evans blue dye, leukocyte distribution and activation were measured. The number of neutrophils and macrophages in the lung tissue was measured as the average cell number per cross-section of lungs based on evaluating10lung areas per specimen. For the in vitro study, the CD-1mouse airway epithelial cells and circulating neutrophils were isolated, purified, and cultured cultured in the presence or absence of LPS at1mg/mL and SHBM1009at1or10mg/mL. The production of KC and LTB4was evaluated using ELISA kit at3,6,12, and24h after LPS challenge. Neutrophil adhesion was measured. The direct inhibitory effects of LY294002and SHBM1009at different concentrations on the superoxide generation from mouse neutrophils stimulated by LPS at1mg/mL for24h were measured as described previously.
Results:LW/BW ratio in animals pretreated with vehicle and challenged with LPS were significantly higher than those challenged with PBS at4and24h (P<0.01), which was prevented by intranasal or intragastrical pretreatment with LY294002, intragastrically with GDC-0941, and intranasally with SHBM1009(P<0.05and P<0.01, respectively). Levels in animals with LY294002(intranasally at24h) and GDC-0941(intranasally at4h and intragastrically at4and24h) were still significantly higher than those without LPS (P<0.05for both). Intranasal pretreatment with either LY294002or SHBM1009significantly prevented LPS-induced increase of ELGV at4or24h after LPS challenge (P<0.05). Intranasal pretreatment with all PI3K inhibitors significantly prevented LPS-induced leukocyte influx in BALF at4h (P<0.05and P<0.01, respectively). Intranasal pretreatment with LY294002or SHBM1009at4or24h showed partially preventive effects on LPS-induced KC production (P<0.05). LPS significantly increased Evans blue dye leakage in the airway and lung (P<0.01vs control subjects), which was prevented by intranasal delivery of SHBM1009(P<0.05vs animals with vehicle and LPS). Pretreatment with SHBM1009prevented LPS-increased number of neutrophils (P<0.01) and macrophages (P<0.05). Levels of KC in the mouse epithelial cell supernatant were significantly higher from3h after LPS challenge compared with the control or those treated with SHBM1009at1or10mg/mL (P<0.05and P<0.01, respectively). The adhesion rate of mouse neutrophils stimulated by KC, LTB4, or LPS was inhibited by SHBM1009at different concentrations. The inhibitory potency of SHBM1009depended on stimuli. LY294002or SHBM1009significantly inhibited superoxide production from LPS-stimulated mouse neutrophils, and the50%inhibitory dose of SHBM1009was much lower than that of LY294002.
Conclusion:Local delivery of PI3K inhibitors played more effective roles in the prevention of endotoxin-induced lung injury than the systemic delivery. The preventive effects of PI3K inhibitors varied most likely because of chemical properties, targeting sites, and pharmacokinetics. The protective effects of PI3K inhibitors on ALI may through direct inhibition of airway epithelial cells, neutrophils, and macrophages. PI3K may be a therapeutic target for acute lung injury, and local delivery of PI3K inhibitors may be one of the optimal approaches for the therapy.
Part2Roles and mechanism of phosphoinositide3-kinase in acute and chronic lung inflammation, tissue injury, remodeling and emphysema in rats
Objective:To evaluate the therapeutic effects of SHBM1009, a new PI3K/mTOR inhibitor, on chronic lung inflammation, tissue injury and remodeling7and28days after the intratracheal instillation of pancreatic elastase (PE), and potential mechanisms by which PI3K may be involved in the inflammation or biological functions of airway epithelial cells or pulmonary myofibroblasts.
Methods:Adult male Wister rats, weighing180-200g, were intratracheally instilled with PE (0.2mL,100IU) or PBS, followed by7or28days of continuously intranasal instillation of SHBM1009or budesonide (the reference drug). The animals were divided randomly into six experimental groups:1) animals were challenged with vehicle and treated with vehicle at0.2ml;2) animals were challenged with PE and treated with vehicle;3) animals were challenged with vehicle and treated with SHBM1009at10mg-kg-1,4and5) animals were challenged with PE and treated with SHBM1009at1and10mg-kg-1or6) animals were challenged with PE and treated with budesonide at1mg-kg-1, respectively. There were12animals per group and6in each time point. Lung weight, body weight and lung density were measured for each rat. Excised lung gas volume (ELGV) was measured by Archimedes' principle. The bronchoalveolar lavage fluid was harvested for evaluating cell count, protein concentration, levels of IL-1β and TGF-β1. HE staining, scanning electron microscopy and Masson staining were used to evaluate lung morphometry. Besides, cellular biological functions were monitored and determined with Cell-IQ, an integrated, fully automated system which can monitor and record the cell number, proliferation, differentiation, apoptosis or movement without use of labels or markers. The cells were plated onto24-well plates with an appropriate density and challenged with PE at concentrations of0.03,0.30,1.00, or2.00U/ml, respectively, to evaluate damaging effects of PE per se. In order to determine protective and dose-associated effects of PI3K inhibitors, cells were co-cultured with BEZ235at concentrations of0.01,0.10,1.00or10μM, or SHBM1009at concentrations of0.01,0.10,1.00, or10μM, respectively, under PE at1.00U/ml. The effects of BEZ235or SHBM1009at concentrations of0.01,0.10, or1.00μM were furthermore evaluated under PE challenge at0.3U/ml.
Results:Intratracheal instillation of SHBM1009at the dose of lmg/kg and budesonide can prevent PE-increased lung weights on7and28days, respectively. Values of lung densities in animals with PE and vehicle7days after the challenge were significantly higher than those without PE, which were significantly attenuated by the treatment with SHBM1009or budesonide (p<0.01). PE instillation increased the lung density at7days while decreased it at28days, while the treatment with SHBM100910mg/kg and budesonide can significantly attenuate such reduction (p<0.01). Levels of total protein in BALF significantly increased7days after the challenge with PE (p<0.01), which was prevented by the treatment with SHBM1009at1or10mg/kg and budesonide (p<0.01or0.05, respectively). Treatment with SHBM1009or budesonide significantly inhibited PE-increased inflammatory cells in BALF on both7and28days (p<0.05or0.01, respectively). Levels of IL-1in BALF or serum harvested from animals with PE challenge and vehicle treatment were significantly higher than from those without PE on7and28days (p<0.01, Fig2C), and were significantly attenuated by treatment with SHBM1009and budesonide (p<0.05or0.01, respectively). For the morphologic changes, alveolar walls and airspace were compromised and enlarged, the thickness of remained alveolar walls increased, and the number of monocytes with the wall elevated in PE-challenged animals treated with vehicle. PE-induced lung injury was protected by the treatment with SHBM1009or Budesonide, while therapeutic effects of SHBM1009at10mg/kg were better than at1mg/kg. Intratracheal instillation of PE induced a significant increase in the area of collagen-positive staining in the lung, while the treatment with SHBM1009or budesonide significantly inhibited the deposition of collagen. Total number of lung epithelial cells significantly decreased when the co-culture with PE in a dose-dependent pattern. PE (1U/ml)-induced reductions of total cell number were partially prevented by the addition of BEZ at0.1-1.0uM or SHBM1009at0.01-10uM, while SHBM1009at0.01-1.0uM or BEZ at0.01and0.1uM fully prevented from decreased total cell number by PE at0.3U/ml. Altered number of stable, differentiated and death cells co-cultured with PE alone or PE at1.0or0.3U/ml plus BEZ or SHBM1009at the different concentrations was similar to the pattern of total cell number.
Conclusion:PI3K plays a critical role in the development of both acute and chronic lung injury and the progress of tissue remodeling and emphysema. The mechanisms include promoting proliferation and differentiation of epithelial cells, inhibiting the proliferation and differential of fibroblasts and collagen deposition. PI3K inhibitors may be considered as one of new therapeutic alternatives for chronic lung diseases e.g. COPD or emphysema, or at least as a candidate of therapeutic combination.
Part3Protective effects of keratinocyte growth factor-2on warm ischemia reperfusion induced lung injury in rats
Objectives:The purpose of this study was to investigate whether KGF-2had a beneficial effect on IR-induced ALI. In addition, the effect of KGF-2on endothelial cells was also investigated to provide insight into the possible molecular mechanisms involved in the action of KGF-2.
Methods:SD rats were randomly divided into seven experimental groups (n=15):1) Sham group:animals undergoing a sham operation and pre-treated with vehicle;2) IR group:animals with I/R-ALI and pre-treated with vehicle;3),4) and5) KGF-2low, middle, and high treatment group:animals were intratracheally instilled with2.5mg/kg,5mg/kg and10mg/kg KGF-272hours prior to IR surgery;7) dexamethasone (DXM) group:DXM at a dose of5mg/kg was administered introperitoneally2hours prior to IR. Keratinocyte growth factor-2(2.5,5, or10mg/kg) was administered intratracheally to rats3days before surgery. Then the left lung in rats was subjected to ischemia for60minutes and reperfusion for as long as180minutes. Lung morphology, blood gas analysis, total cell number and protein concentration in the bronchoalveolar lavage fluid were measured to evaluate the lung injury. The protective effects of keratinocyte growth factor-2on human pulmonary microvascular endothelial cells and related mechanisms were evaluated in vitro. Cell-IQ was applied to monitoring biological behavior; Brdu proliferation assay was used to assess cell proliferation; measurement of the permeability of FITC-labeled albumin and transendothelial electrical resistence to assesse barrier function of the endothelial.
Results:Pre-treatment with keratinocyte growth factor-2at the doses of2.5mg and-5mg/kg effectively inhibited lung edema, inflammatory cell infiltration, protein exudation and the release of inflammatory cytokines. In vitro study demonstrated that keratinocyte growth factor-2could inhibit endothelial cell apoptosis, enhancing migration, and maintaining the integrity of the blood-gas barrier. Phosphoinositide3-kinase inhibitors attenuated the protective effect of Keratinocyte growth factor-2in endothelial cells.
Conclusion:Keratinocyte growth factor-2pre-treatment reduced ischemia reperfusion-induced acute lung injury. The protective effects of keratinocyte growth factor-2may contribute to its protective effects on both epithelial and endothelial cells.
引文
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