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

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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