Adawi A, Zhang Y, Baggs R, Finkelstein J, Phipps R P
University of Rochester Cancer Center and Department of Medicine, University of Rochester School of Medicine and Dentistry, New York 14642, USA.
Am J Pathol. 1998 Mar;152(3):651-7.
Oxygen therapy is a mainstay treatment for infants and adults with poor lung function. Unfortunately, oxygen itself is toxic and incites respiratory cell damage and inflammation. Therapies for oxygen-induced lung damage are nonexistent. Employing a mouse model of hyperoxic lung injury, a monoclonal anti-CD40 ligand (L) antibody (MR1), which disrupts CD40-CD40L interactions, was tested for the ability to reduce pulmonary injury. Intraperitoneal administration of MR1, either before or after oxygen exposure, was remarkably effective in reducing and in many cases preventing lung injury. The pro-inflammatory enzyme cyclooxygenase-2 (Cox-2), responsible for prostaglandin production, is massively up-regulated in the lungs after hyperoxic exposure. Immunohistochemical staining for Cox-2 revealed that MR1 greatly reduces the oxygen-induced induction of Cox-2. The remarkable effectiveness of MR1 in blunting hyperoxic lung injury in this preclinical model may be relevant to the hundreds of thousands of patients who require treatment with high oxygen and who are at risk for developing severe pulmonary inflammation and consequent fibrosis. Strategies to disrupt CD40-CD40L interactions may offer a new mode of intervention for oxygen-induced acute respiratory distress syndrome and other inflammatory lung disorders.
氧疗是治疗肺功能不佳的婴幼儿和成人的主要手段。不幸的是，氧气本身具有毒性，会引发呼吸细胞损伤和炎症。目前尚无针对氧诱导肺损伤的治疗方法。利用高氧肺损伤小鼠模型，测试了一种可破坏CD40-CD40L相互作用的单克隆抗CD40配体（L）抗体（MR1）减轻肺损伤的能力。在氧气暴露之前或之后腹腔注射MR1，在减轻肺损伤方面非常有效，并且在许多情况下可预防肺损伤。负责前列腺素生成的促炎酶环氧合酶-2（Cox-2）在高氧暴露后在肺中大量上调。Cox-2的免疫组织化学染色显示，MR1可大大降低氧气诱导的Cox-2表达。在这个临床前模型中，MR1在减轻高氧肺损伤方面的显著效果可能与数十万需要高氧治疗且有发生严重肺部炎症及随之而来的纤维化风险的患者有关。破坏CD40-CD40L相互作用的策略可能为氧诱导的急性呼吸窘迫综合征和其他炎症性肺部疾病提供一种新的干预模式。
