Airway hyperresponsiveness (AHR) is a characteristic feature of asthma, and generally correlates with severity of asthma. Understanding the protection mechanism against excessive airway narrowing and how it breaks dow...Airway hyperresponsiveness (AHR) is a characteristic feature of asthma, and generally correlates with severity of asthma. Understanding the protection mechanism against excessive airway narrowing and how it breaks down is fundamental to solving the problem of asthma. In this paper we have proposed a stochastic modeling the airway smooth muscle bundle for reproducing AHR such as an increased sensitivity of the airways to an inhaled constrictor agonist, a steeper slope of the dose-response curve, and a greater maximal response to agonist. A large number N of contractile muscle cells was assumed to repeat themselves in between contraction and relaxation asynchronously. Dynamic equilibrium of statistic physics was applied to the system of ASM bundle. Thus, the relation of dose to response of a piece of ASM bundle was described by Φ=tanh(βH) , where β was Boltzman factor and H represented energy of contraction induced by constrictor agents. Each of adjacent pair contractile cells was assumed to have Ising-type of antimagnetic interactions of preference energy J (for the condition of contraction-relaxation) between them. A motion equation for a piece of ASM bundle was described by Φ=N(H-zJΦ , which explained existence of combined tonic and phasic contractions. Based on observations of Venegas et al. [4], airway responsiveness was assumed to be assessable by total volume of the ventilation defects (TVD) of 13NN PET-CT images. Interactions via propagation of Ca ion waves between ASM bundles would cause percolation probability by PΦ=(1+tanh(βH))2/4 along the tree, then the relation of dose βH to TVD was described by TVD=PΦ[1-(1-PΦ)3/PΦ3]-TVD0. TVD0 represented the protection mechanism against excessive airway narrowing, which was determined by the ratio of amplitudes between tonic and phasic contractions, thus the balance of amplitudes between tonic and phasic contractions of peripheral lobular smooth muscles would be the determinant of AHR.展开更多
目的验证干预信号转导和转录激活因子-3(signal transducers and activators of transcription-3,STAT3)信号通路活化对慢性哮喘模型小鼠呼吸道炎症及气道重塑的影响。方法将30只Balb/c小鼠按数字法随机分为正常对照组、哮喘组、AG490...目的验证干预信号转导和转录激活因子-3(signal transducers and activators of transcription-3,STAT3)信号通路活化对慢性哮喘模型小鼠呼吸道炎症及气道重塑的影响。方法将30只Balb/c小鼠按数字法随机分为正常对照组、哮喘组、AG490干预组,每组10只;经鸡卵清蛋白(albumin,OVA)致敏激发建立慢性哮喘小鼠气道重塑模型,蛋白免疫印迹法检测肺组织STAT3磷酸化水平验证拮抗效果。形态学染色观察肺组织结构改变,免疫荧光方法观察气道平滑肌层增厚程度,采用小动物肺功能检测系统测定各组小鼠的气道阻力水平。体外分离各组小鼠气道平滑肌细胞,测定其胞内表型标志物蛋白水平。结果HE染色行肺组织形态学观察可见经OVA致敏激发后哮喘组小鼠可见明显气道结构病理改变。经AG490干预后,小鼠肺组织中STAT3蛋白活化水平(p-STAT3/STAT3比值)得到显著抑制[AG490干预组(0.46±0.22)vs.哮喘组(1.13±0.48),P=0.121;AG490干预组(0.46±0.22)vs.正常对照组(1.55±0.37),P=0.023]。AG490干预组小鼠气气道上皮下α-SMA阳性面积显著低于哮喘组[AG490干预组(1.56±0.24)vs.哮喘组(3.89±0.81),P=0.011]及正常对照组[AG490干预组(1.56±0.24)vs.正常对照组(1.10±0.32),P=0.012]。未观察到AG490干预对小鼠上皮杯状细胞增生的影响。与哮喘组相比,提前给予AG490干预可以显著降低小鼠的气道反应性的发生[AG490干预组(10.90±1.52)cm H2O·s/mL vs.哮喘组(13.99±2.52)cm H2O·s/mL,P=0.015],差异均有统计学意义。体外水平证实,AG490干预显著下调小鼠气道平滑肌细胞收缩表型蛋白α-SMA[AG490干预组(1.09±0.32)vs.哮喘组(0.39±0.12),P=0.002]和SM22α[AG490干预组(1.39±0.45)vs.哮喘组(2.59±0.34),P=0.014]表达。结论采用AG490干预哮喘小鼠STAT3信号通路活化,可以显著减轻慢性哮喘呼吸道重塑程度。展开更多
文摘Airway hyperresponsiveness (AHR) is a characteristic feature of asthma, and generally correlates with severity of asthma. Understanding the protection mechanism against excessive airway narrowing and how it breaks down is fundamental to solving the problem of asthma. In this paper we have proposed a stochastic modeling the airway smooth muscle bundle for reproducing AHR such as an increased sensitivity of the airways to an inhaled constrictor agonist, a steeper slope of the dose-response curve, and a greater maximal response to agonist. A large number N of contractile muscle cells was assumed to repeat themselves in between contraction and relaxation asynchronously. Dynamic equilibrium of statistic physics was applied to the system of ASM bundle. Thus, the relation of dose to response of a piece of ASM bundle was described by Φ=tanh(βH) , where β was Boltzman factor and H represented energy of contraction induced by constrictor agents. Each of adjacent pair contractile cells was assumed to have Ising-type of antimagnetic interactions of preference energy J (for the condition of contraction-relaxation) between them. A motion equation for a piece of ASM bundle was described by Φ=N(H-zJΦ , which explained existence of combined tonic and phasic contractions. Based on observations of Venegas et al. [4], airway responsiveness was assumed to be assessable by total volume of the ventilation defects (TVD) of 13NN PET-CT images. Interactions via propagation of Ca ion waves between ASM bundles would cause percolation probability by PΦ=(1+tanh(βH))2/4 along the tree, then the relation of dose βH to TVD was described by TVD=PΦ[1-(1-PΦ)3/PΦ3]-TVD0. TVD0 represented the protection mechanism against excessive airway narrowing, which was determined by the ratio of amplitudes between tonic and phasic contractions, thus the balance of amplitudes between tonic and phasic contractions of peripheral lobular smooth muscles would be the determinant of AHR.
文摘目的验证干预信号转导和转录激活因子-3(signal transducers and activators of transcription-3,STAT3)信号通路活化对慢性哮喘模型小鼠呼吸道炎症及气道重塑的影响。方法将30只Balb/c小鼠按数字法随机分为正常对照组、哮喘组、AG490干预组,每组10只;经鸡卵清蛋白(albumin,OVA)致敏激发建立慢性哮喘小鼠气道重塑模型,蛋白免疫印迹法检测肺组织STAT3磷酸化水平验证拮抗效果。形态学染色观察肺组织结构改变,免疫荧光方法观察气道平滑肌层增厚程度,采用小动物肺功能检测系统测定各组小鼠的气道阻力水平。体外分离各组小鼠气道平滑肌细胞,测定其胞内表型标志物蛋白水平。结果HE染色行肺组织形态学观察可见经OVA致敏激发后哮喘组小鼠可见明显气道结构病理改变。经AG490干预后,小鼠肺组织中STAT3蛋白活化水平(p-STAT3/STAT3比值)得到显著抑制[AG490干预组(0.46±0.22)vs.哮喘组(1.13±0.48),P=0.121;AG490干预组(0.46±0.22)vs.正常对照组(1.55±0.37),P=0.023]。AG490干预组小鼠气气道上皮下α-SMA阳性面积显著低于哮喘组[AG490干预组(1.56±0.24)vs.哮喘组(3.89±0.81),P=0.011]及正常对照组[AG490干预组(1.56±0.24)vs.正常对照组(1.10±0.32),P=0.012]。未观察到AG490干预对小鼠上皮杯状细胞增生的影响。与哮喘组相比,提前给予AG490干预可以显著降低小鼠的气道反应性的发生[AG490干预组(10.90±1.52)cm H2O·s/mL vs.哮喘组(13.99±2.52)cm H2O·s/mL,P=0.015],差异均有统计学意义。体外水平证实,AG490干预显著下调小鼠气道平滑肌细胞收缩表型蛋白α-SMA[AG490干预组(1.09±0.32)vs.哮喘组(0.39±0.12),P=0.002]和SM22α[AG490干预组(1.39±0.45)vs.哮喘组(2.59±0.34),P=0.014]表达。结论采用AG490干预哮喘小鼠STAT3信号通路活化,可以显著减轻慢性哮喘呼吸道重塑程度。
