Molecular and genetic studies on patho genesis and patho plrysiolegy of emphysema

黄帽大鼠(FHR)是一种以远端空气空间扩大为特征的品系，尽管没有肺泡壁的破坏，但肺的扩张性增加。为了分析肺实质结构变化对机械性能的影响，利用计算机控制的小动物呼吸机(Flexivent，Scireq，Canada)测量了呼吸阻抗(Z)，并与同龄的Wistar京都大鼠(WKY)进行了比较。测量的阻抗Z符合恒时相模型(Z=R+j(27πf)i+(Gtis-htis)/(2πf)α)，其中R为气道阻力，Gtis为组织阻力，Htis为组织弹性。FHR的TLC明显大于WKR(2.60±39vs1.97±0.22，p&lt；0.01)，形状常数(K)值高于WKY(0.219±0.018 vs0.117±0.011，p&lt；0.01)。虽然两组间的R(呼吸道阻力)无显著差异，但di…与WKY组相比，低肺容量组(p&lt；0.05)的GTIS和HTI明显减少(p&lt；0.05)，而高肺容量组(p&lt；0.05)的GTIS和HTI增加(p&lt；0.05)。这些结果表明，FHR具有更高的TLC，降低了肺弹性反冲，这些表观结构变化导致FHR的双相机械特性与肺容量的关系。我们试图通过至少16周的香烟烟雾暴露来诱导FHR发生肺气肿，然后分析支气管肺泡灌洗液中的细胞数量、肺力学和肺的病理。另一方面，结合人巨噬细胞样细胞系(U937和THP-1)产生的基质金属蛋白酶(MMPs)，分析了香烟烟雾对肺实质蛋白水解酶-抗水解酶平衡的影响。当D-尼古丁或香烟烟雾提取物(CSE)刺激U937细胞时，D-尼古丁不影响U937细胞产生MMP2，但CSE呈剂量依赖性地促进U937细胞产生MMP2。全反式维甲酸和9-顺式维甲酸均抑制维甲酸诱导的细胞产生基质金属蛋白酶-9，Northern印迹分析显示维甲酸诱导的RAR-α和FAR-γ表达增加，提示这两种视黄酸受体通过直接调节基因表达参与类视黄醇对基质金属蛋白酶-9产生的调节。较少

Fawn-hooded rat (FHR) is a strain characterized by a distal air-space enlargement with increased lung distensibility although there was no alveolar wall destruction. In order tO analyze the effect of structural changes of lung parenchyma on the mechanical properties, the respiratory impedance (Z) was examined by utilizing a computer-controlled small-animal ventilator (Flexivent, Scireq, Canada) and compared with those of age-matched Wister kyoto control rats (WKY). The measured impedance Z was fit by the constant-phase model (Z=R+j(27πf)I+(Gtis-Htis)/(2πf)α), where R is airway resistance, Gtis is tissue resistance, and Htis is tissue elastance. TLC was significantly larger in FOR than in WKR (2.60±39 vs 1.97±0.22, p<0.01) and a leftward arid upward shift of the pressure-volume curve was observed in FHR with higher shape constant (K) value as compared with WKY (0.219±0.018 vs 0.117±0.011, p<0.01). Although there was no significant difference in R (airway resistance) between 2 groups, di … More minished Gtis and Htis were observed in FUR at low lung volume (p<0.05), but increased Gtis and Htis were observed at high lung volume (p<0.05) as compared with the WKY.These results suggest that FHR has a higher TLC with reduced lung elastic recoil and that these parechymal structural changes result in biphasic mechanical properties against lung volume in FHR.We are now trying to induce to develop pulmonary emphysema in FHR by exposing cigarette smoke for at least 16 weeks and then analyze cell population in bronchoalveolar lavage fluid, lung mechanics, arid pathology of the lungs. On the other hand, the effect of cigarette smoke on proteaseantiprotease balance in lung parenchyma was analyzed with special reference to matrix metalloproteinases (MMP) production from human macrophage-like cell lines (U937 and THP-1). When U937 cells were stimulated with D-nicotine or cigarette smoke extract (CSE), MMP-2 production by U937 was not affected by D-nicotine but increased by CSE in a dose-dependent manner. THP-1 cells showed increased MMP-9 production by CSE.All-trans retinoic acid and 9-cis retinoic acid suppressed PMA-mediated MMP-9 production by both cell lines and northern blot analysis revealed increased expression of RAR-α and FAR-γ by retinoid, suggesting that both RARs are involved in retinoid-mediated regulation of MMP-9 production by directly modulating gene expression. Less