Elucidation of roles of platelet-activating factor receptor by gene targeting.

血小板活化因子(PAF)是参与炎症和过敏反应的一种有效的磷脂介质。也有报道称，PAF在内毒素诱导的致死、生殖和脑发育中起重要作用。为了确定PAF及其受体在体内的作用，我们通过荣誉重组的方法产生了PAF受体缺陷小鼠。后代的分布符合孟德尔分布。它们正常生长，在所检查的任何器官中都没有观察到发育变化。血液免疫球蛋白水平和细胞分类计数未见异常。用卵清蛋白致敏和激发后，野生型小鼠出现明显的支气管收缩、肺水肿、低血压和死亡。另一方面，PAF受体缺陷小鼠对这些治疗只表现出中等反应。内毒素激发后，两组间差异无统计学意义。因此，我们得出结论，PAF与过敏反应密切相关，而在内毒素诱导的病理和致死性反应中起着较小的作用。考虑到PAF拮抗剂对内毒素休克有一定的保护作用，即使在PAF受体基因敲除的小鼠中，也可能存在PAF受体拮抗剂的其他靶点，以保护生命系统免受内毒素所致的紊乱。

Platelet-activating factor (PAF) is a potent phospholipid mediator involved in inflammatory and allergic responses. It is also reported that PAF plays major roles in endotoxin-induced lethality, reproduction and brain development. To determine the role of PAF and its receptor in vivo, we generated a PAF receptor-deficient mice, by honologous recombination. Offspring were obtained with a Menderian distribution. They grow up normally, and no developmental changes are observed in any organs examined. The level of blood immunoglobulins and differential cell counts show no abnormality.When the mice were sensitized and challenged with ovalbumin, the wild type mice showed a marked bronchial constriction, pulmonary edema, hypotension and death. On the other hand, the PAF receptor-deficient mice showed only moderate response to these treatments. Upon challenging with endotoxin, no significant difference was observed in both groups. Thus, we concluded that PAF is deeply involved in anaphylactic responses, while it shows minor role in the endotoxin-induced pathologies and lethality. Considering PAF antagonists show some protective effects on endotoxin-shock, even in PAF receptor knock-out mice, there may exist other targets of PAF receptor antagonists to protect the living system from endotoxin-induced disorders.