Petersen Jeffrey E, Hiran Tejindervir S, Goebel W Scott, Johnson Christopher, Murphy Robert C, Azmi Farrukh H, Hood Antoinette F, Travers Jeffrey B, Dinauer Mary C
Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
J Invest Dermatol. 2002 Mar;118(3):424-9. doi: 10.1046/j.0022-202x.2001.01691.x.
Chronic granulomatous disease is the manifestation of genetic defects of the leukocyte NADPH oxidase resulting in the absence of a respiratory burst. Patients with chronic granulomatous disease can develop chronic granulomas in many locations of the body, including the skin. Using an established murine model of X-linked chronic granulomatous disease (X-CGD) created by homologous recombinant disruption of the gene encoding the gp91phox component of the NADPH oxidase, in this study we examined cutaneous reactivity to sterile Aspergillus fumigatus hyphae. Injection of Aspergillus fumigatus into the dorsal ears of X-CGD mice resulted in an enhanced inflammatory response by 24 h, consisting of neutrophils, which developed into suppurative granulomas by 10 d. Intradermal injection of Aspergillus fumigatus into wild-type mice only resulted in a transient inflammatory response that resolved by 10 d. Injection of Aspergillus fumigatus into female carrier mice resulted in an acute inflammatory response that was similar to that of wild-type mice, but, at higher doses of Aspergillus fumigatus, many carriers subsequently developed granulomatous lesions that were qualitatively similar but smaller than those seen in X-CGD mice by 30 d. Consistent with the ability of X-CGD mice to mount an enhanced neutrophil-rich inflammatory response to Aspergillus fumigatus, significant levels of the potent neutrophil activator/chemoattractant leukotriene B4 were measured by mass spectrometry in skin biopsies at 24 and 72 h. In contrast to the exaggerated inflammatory response to intradermal Aspergillus fumigatus in X-CGD mice compared to their wild-type counterparts, similar levels of inflammation were seen in a model of delayed-type hypersensitivity using 2,4-dinitrofluorobenzene. This study represents the first report of a cutaneous granuloma model in mice with X-CGD, which may also prove useful as a functional test to evaluate the efficacy of gene therapy protocols being developed for chronic granulomatous disease.
慢性肉芽肿病是白细胞NADPH氧化酶基因缺陷的表现，导致呼吸爆发缺失。慢性肉芽肿病患者可在身体的许多部位形成慢性肉芽肿，包括皮肤。利用通过同源重组破坏编码NADPH氧化酶gp91phox成分的基因建立的X连锁慢性肉芽肿病（X-CGD）小鼠模型，在本研究中我们检测了皮肤对无菌烟曲霉菌丝的反应性。将烟曲霉菌注射到X-CGD小鼠的背部耳朵中，在24小时时导致炎症反应增强，由中性粒细胞组成，到10天时发展为化脓性肉芽肿。将烟曲霉菌皮内注射到野生型小鼠中仅导致短暂的炎症反应，在10天时消退。将烟曲霉菌注射到雌性携带者小鼠中导致急性炎症反应，与野生型小鼠相似，但在较高剂量的烟曲霉菌时，许多携带者随后在30天时出现肉芽肿性病变，其性质相似但比X-CGD小鼠中的病变小。与X-CGD小鼠对烟曲霉菌产生增强的富含中性粒细胞的炎症反应的能力一致，在24小时和72小时时通过质谱法在皮肤活检中检测到高水平的强效中性粒细胞激活剂/趋化因子白三烯B4。与X-CGD小鼠与其野生型对应物相比，对皮内烟曲霉菌的过度炎症反应相反，在使用2,4-二硝基氟苯的迟发型超敏反应模型中观察到相似水平的炎症。本研究代表了X-CGD小鼠皮肤肉芽肿模型的首次报道，这也可能被证明是一种有用的功能测试，以评估正在开发的用于慢性肉芽肿病的基因治疗方案的疗效。
