Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, 410 N. 12th Street, 980533, Richmond, VA, 23298-0533, USA,
Lung. 2014 Aug;192(4):481-92. doi: 10.1007/s00408-014-9597-2. Epub 2014 May 16.
Although emphysema destroys alveolar structures progressively and causes death eventually, no drug has been discovered to prevent, intervene, and/or resolve this life-threatening disease. We recently reported that sulfated caffeic acid dehydropolymer CDSO3 is a novel potent triple-action inhibitor of elastolysis, oxidation, and inflammation in vitro, and therefore, a potential anti-emphysema agent. However, the in vivo therapeutic potency, duration and mode of actions, and effective route remain to be demonstrated.
Emphysema was induced in rats with human sputum elastase (HSE) combined with cigarette smoke extract (CSE). CDSO3 at 5, 30, or 100 μg/kg was dosed to the lung or injected subcutaneously at 2, 6, or 24 h before or 1 or 24 h or 1 week after the HSE/CSE instillation. At 1 h or 48 h or on day 21-22 or day 28, lungs were examined for airway-to-blood injurious barrier damage; their elastolytic, oxidative, and inflammatory activities; lung luminal leukocytes infiltration; functional treadmill exercise endurance; and/or morphological airspace enlargement.
CDSO3, when dosed to the lung at 30 or 100 μg/kg, but not via systemic subcutaneous injection, significantly (43-93 %) attenuated HSE/CSE-induced (1) barrier damage measured by luminal hemorrhage and protein leak; (2) elastolytic, oxidative, and inflammatory activities measured with elastase, reduced glutathione, and TNFα levels, respectively; (3) luminal neutrophil infiltration and tissue myeloperoxidase activity; (4) functional impairment of exercise endurance; and (5) airspace enlargement, in both preventive and interventional dosing protocols. Notably, the effects were shown to last for 24 h at the greater 100-μg/kg dose, and the 1-week-delayed administration was also capable of attenuating the development of emphysema.
CDSO3 is a novel, potent, long-acting, nonpeptidic macromolecule that inhibits HSE/CSE-induced elastolysis, oxidation, and inflammation in the lung and thereby attenuates the development of emphysema in rats, in both preventive and interventional manners, when administered locally to the lung.
尽管肺气肿逐渐破坏肺泡结构并最终导致死亡，但目前还没有发现可以预防、干预和/或解决这种危及生命的疾病的药物。我们最近报道，硫酸化咖啡酸脱水聚合物 CDSO3 是一种新型的强力三效弹性蛋白酶抑制剂、氧化抑制剂和炎症抑制剂，因此是一种有潜力的抗肺气肿药物。然而，其体内治疗效力、持续时间和作用模式以及有效途径仍有待证明。
用人痰弹性蛋白酶（HSE）联合香烟烟雾提取物（CSE）诱导大鼠肺气肿。CDSO3 以 5、30 或 100μg/kg 的剂量气管内给药或皮下注射，在 HSE/CSE 滴注前 2、6 或 24 小时，或滴注后 1 或 24 小时或 1 周时。在 1 小时或 48 小时或第 21-22 天或第 28 天，检查气道至血液损伤屏障损伤、弹性酶、氧化和炎症活性、肺腔白细胞浸润、功能跑步机运动耐力和/或形态性气腔扩大。
CDSO3 以 30 或 100μg/kg 的剂量气管内给药，但不是通过系统皮下注射，可显著（43-93%）减弱 HSE/CSE 诱导的（1）由管腔出血和蛋白渗漏测量的屏障损伤；（2）弹性酶、还原型谷胱甘肽和 TNFα 水平分别测量的弹性酶、氧化和炎症活性；（3）肺腔中性粒细胞浸润和组织髓过氧化物酶活性；（4）运动耐力的功能障碍；和（5）气腔扩大，在预防和干预给药方案中均有效。值得注意的是，在较大的 100μg/kg 剂量下，作用可持续 24 小时，1 周的延迟给药也能减轻肺气肿的发展。
CDSO3 是一种新型的、有效的、长效的非肽类大分子，可抑制 HSE/CSE 诱导的肺内弹性酶、氧化和炎症，从而在预防和干预两种方式下减轻大鼠肺气肿的发展，当局部给药到肺时。
