THERAPY FOR ACUTE LUNG INJURY WITH PROLIFERATION OF TYPE II PNEUMOCYTES AND REGULATION OF APOPTOSIS OF INFLAMMATORY

急性肺损伤的治疗包括[1]停止肺泡炎，[2]修复肺泡上皮，[3]预防肺纤维化。我们首先研究了罗利普兰(PDE-IV抑制剂)、利多卡因、咪达唑仑、异丙酚、氯胺酮(麻醉药)对中性粒细胞和肺泡II型肺泡细胞凋亡的影响。罗利普兰可促进抗Fas抗体诱导的中性粒细胞凋亡，而麻醉药对此无明显影响。罗利普兰和异丙酚可抑制内毒素诱导的II型肺泡细胞凋亡。我们继而评估了这些药物对培养的大鼠II型肺泡细胞增殖的影响。罗利普兰增加自发性增殖，增强KGF/HGF诱导的增殖。BrdU抗体的免疫组织化学分析显示，罗利普兰增加了KGF/HGF处理的小鼠II型肺泡细胞的DNA合成。采用小鼠腹腔注射内毒素(10 mg/kg)诱导急性肺损伤。罗利普兰可减轻肺损伤的病理改变。罗利普兰的这一成功结果可能是由于药物对中性粒细胞和肺泡上皮细胞的影响。

Therapy for acute lung injury consists of [1] cessation of alveolar inflammation, [2] repairment of alveolar epithelium, and [3] prevention of lung fibrosis. We first investigated the effects of rolipram (PDE-IV inhibitor), lidocaine, midazolam, propofol, ketamine (anesthetics) on apoptosis of neutrophils and alveolar type II pneumocytes. Anti-Fas antibody-induced apoptosis of neutrophils was enhanced by rolipram and not by the anesthetics. Endotoxin-induced apoptosis of type II pneumocytes was inhibited by rolipram and propofol. We secodly assessed the effects of these drugs on proliferation of rat cultured type II pneumocytes. Rolipram increased spontaneous proliperation and enhanced KGF/HGF-induced proliferation. Immunohistochemical analysis using BrdU antibody revealed that rolipram increased DNA synthesis in type II pneumocytes in mice treated with KGF/HGF. Acute lung injury was induced by intraperitoneal endotoxin (10 mg/kg) in mice. Rolipram attenuated the pathological changes of the lung injury. This successful result of rolipram may be due to the effect of the drug on neutrophils and the alveolar epithelial cells.