Han Eun D, MacFarlane Ryan C, Mulligan Aideen N, Scafidi Jennifer, Davis Alvin E
Center for Blood Research, Harvard Medical School, 800 Huntington Avenue, Boston, MA 02115, USA.
J Clin Invest. 2002 Apr;109(8):1057-63. doi: 10.1172/JCI14211.
Heterozygosity for C1 inhibitor (C1INH) deficiency results in hereditary angioedema. Disruption of the C1INH gene by gene trapping enabled the generation of homozygous- and heterozygous-deficient mice. Mating of heterozygous-deficient mice resulted in the expected 1:2:1 ratio of wild-type, heterozygous, and homozygous-deficient offspring. C1INH-deficient mice showed no obvious phenotypic abnormality. However, following injection with Evans blue dye, both homozygous and heterozygous C1INH-deficient mice revealed increased vascular permeability in comparison with wild-type littermates. This increased vascular permeability was reversed by treatment with intravenous human C1INH, with a Kunitz domain plasma kallikrein inhibitor (DX88), and with a bradykinin type 2 receptor (Bk2R) antagonist (Hoe140). In addition, treatment of the C1INH-deficient mice with an angiotensin-converting enzyme inhibitor (captopril) increased the vascular permeability. Mice with deficiency of both C1INH and Bk2R demonstrated diminished vascular permeability in comparison with C1INH-deficient, Bk2R-sufficient mice. These data support the hypothesis that angioedema is mediated by bradykinin via Bk2R.
C1抑制剂（C1INH）缺乏的杂合性会导致遗传性血管性水肿。通过基因捕获破坏C1INH基因可产生纯合和杂合缺陷型小鼠。杂合缺陷型小鼠交配产生的野生型、杂合型和纯合缺陷型后代的比例符合预期的1:2:1。C1INH缺陷型小鼠未表现出明显的表型异常。然而，注射伊文思蓝染料后，纯合和杂合C1INH缺陷型小鼠与野生型同窝小鼠相比，血管通透性均增加。静脉注射人C1INH、含库尼茨结构域的血浆激肽释放酶抑制剂（DX88）和缓激肽2型受体（Bk2R）拮抗剂（Hoe140）可逆转这种增加的血管通透性。此外，用血管紧张素转换酶抑制剂（卡托普利）治疗C1INH缺陷型小鼠会增加血管通透性。与C1INH缺陷但Bk2R充足的小鼠相比，同时缺乏C1INH和Bk2R的小鼠血管通透性降低。这些数据支持血管性水肿由缓激肽通过Bk2R介导的假说。
