α_1-ANTITRYPSIN ATTENUATES ENDOTOXIN-INDUCED ACUTE LUNG INJURY IN RABBITS

Objective To investigate whether pretreatment with α 1-AT can attenuate acute lung injury (ALI) in rabbits induced with endotoxin. Methods Thirty-two New Zealand rabbits were randomly assigned to four groups(n=8):1.Infusion of endotoxin(Lipopolysaccharide,LPS 500μg/kg)without α 1-AT (group LPS).2.Infusion α 1-AT 120mg/kg at 15min before challenge with LPS(group LAV).3.Infusion of α 1-AT 120mg/kg(group AAT).4 Infusion of saline 4ml/kg as control (group NS).Arterial blood gases,peripheral leukocyte counts and airway pressure were recorded every 1h.Physiologic intrapulmonary shunting (Qs/Qt) was measured every 4h.After 8h the bloods were collected for measurement of plasma concentration and activity of α 1-AT.Then bronchoalveolar lavage fluid (BALF)was collected for measurement of concentrations of total protein (TP),interleukin-8(IL-8),tumor necrosis factor(TNF-α),the activities of elastase-like and α 1-AT,total phospholipids(TPL) and disaturated phosphatidylcholine (DSPC).In addition,the wet-to-dry lung weight ratio(W/D) was measured. Results After infusion of endotoxin,it was observed that PaO 2,peripheral luekocyte counts,total respiratory compliance progressively decreased and P peak and Qs/Qt increased comparing with the baseline values.In contrast to group NS,the increased plasma concentration but reduced activity of α 1-AT was found in group LPS.In the BALF,the activity of α 1-AT,TPL,DSPC/TPL were lower,but the concentrations of albumin,IL-8,TNF-α,and the activity of NE were higher.The ratio of W/D also increased.The pretreatment of α 1-AT attenuated the deterioration of oxygenation,the reduction of compliance and the deterioration of other physiological,biochemical parameters mentioned above. Conclusion Pretreatment with α 1-AT could attenuate endotoxin-induced lung injury in rabbits.Those beneficial effects of α 1-AT might be due in part to the inhibitory effect on neutrophil elastase.

Protective effects of α_1 -antitrypsin on acute lung injury in rabbits induced by endotoxin

Objective To investigate whether pretreatment with α1,-antitrypsin (AAT) can attenuate acute lung injury (ALI) in rabbits induced with endotoxin.Methods Thirty-two healthy adult New Zealand rabbits were anaesthetized, tracheotomized and mechanically ventilated. They were then randomly divided into four groups (n =8): (1) Infusion of Escherichia coli endotoxin [ Lipopolysaccharide (LPS) 500μg/kg ] without AAT (Group LPS). (2) Infusion of AAT 120 mg/kg at 15 minutes after LPS (Group LAV). (3) Infusion of AAT 120 mg/kg without endotoxin (Group AAT). (4) Infusion of saline 4 ml/kg as control (Group NS). Arterial blood gases, peripheral leukocyte counts and airway pressure were recorded every hour for eight hours. Physiologic intrapulmonary shunting (Qs/Qt) was measured every four hours. After eight hours, blood samples were collected for measurement of plasma concentration and activity of AAT. Then, the animals were sacrificed, and bronchoalveolar lavage fluid (BALF) was collected for measurement of concentrations of total protein (TP), interleukin-8 (IL-8), tumor necrosis factor (TNFa, the activities of NE and AAT, total phospholipids (TPL) and disaturated phosphatidylcholine (DSPC). In addition, the wet-to-dry lung weight ratio (W/D) was measured.Results The infusion of endotoxin induced decreases in arterial oxygen pressure (PaO2), peripheral leukocyte counts, total respiratory compliance (TLC) and the increases in peak pressure (Ppeak), Qs/ Qt compared with the baseline values ( P < 0. 05). The increased plasma concentration but reduced activity of AAT was also found in contrast to that in Group NS (P<0. 05). In the BALF, the activity of AAT, TPL, DSPC/TPL were lower than those in Group NS (P<0. 05), but the concentrations of albumin, IL-8, TNFα, the activity of NE and the ratio of W/D were higher than those in Group NS (P <0. 05). The pretreatment of AAT attenuated the deterioration of oxygenation, the reduction of compliance and the deterioration of other physiological and biochemical parameters mentioned above.Conclusion Pretreatment with AAT could attenuate endotoxin-induced lung injury in rabbits. Those beneficial effects of AAT might be due, in part, to reduction in the levels of mediators that could activate neutrophils, in addition to the direct inhibitory effect on neutrophil elastase.

慢性阻塞性肺疾病中蛋白酶与抗蛋白酶系统的研究进展

COPD是一种以气流受限为特征，并伴有肺功能进行性降低的异常炎症反应相关的疾病。其主要原因是细胞外基质在气道壁过度沉积，引起气道阻塞和肺弹性基质的降解。COPD的发生中，气道炎症、氧化／抗氧化失衡、蛋白酶／抗蛋白酶失衡起着重要的作用。其中，α1-抗胰蛋白酶（α1—antitrypsin，α1-AT）缺乏症与COPD有着重要联系，本文主要就目前对于蛋白酶／抗蛋白酶系统中起主要作用的中性粒细胞弹性蛋白酶／α1—AT、基质金属蛋白酶／基质金属蛋白酶组织抑制物的结构、功能、诊断与治疗作一综述。