Laboratório de Fisiopatologia Humana, IFF, FIOCRUZ, Rio de Janeiro, Brazil.
Am J Respir Crit Care Med. 2010 Mar 1;181(5):429-37. doi: 10.1164/rccm.200905-0800OC. Epub 2009 Dec 10.
The mechanism of action of diethylcarbamazine (DEC), an antifilarial drug effective against tropical pulmonary eosinophilia, remains controversial. DEC effects on microfilariae depend on inducible NO synthase (iNOS). In eosinophilic pulmonary inflammation, its therapeutic mechanism has not been established. We previously described the rapid up-regulation of bone marrow eosinophilopoiesis in ovalbumin (OVA)-sensitized mice by airway allergen challenge, and further evidenced the down-regulation of eosinophilopoiesis by iNOS- and CD95L-dependent mechanisms.
We investigated whether: (1) DEC can prevent the effects of airway challenge of sensitized mice on lungs and bone marrow, and (2) its effectiveness depends on iNOS/CD95L.
OVA-sensitized BALB/c mice were intranasally challenged for 3 consecutive days, with DEC administered over a 12-, 3-, or 2-day period, ending at the day of the last challenge. We evaluated: (1) airway resistance, cytokine (IFN-gamma, IL-4, IL-5, and eotaxin) production, and pulmonary eosinophil accumulation; and (2) bone marrow eosinophil numbers in vivo and eosinophil differentiation ex vivo.
DEC effectively prevented the effects of subsequent challenges on: (1) airway resistance, Th1/Th2 cytokine production, and pulmonary eosinophil accumulation; and (2) eosinophilopoiesis in vivo and ex vivo. Recovery from unprotected challenges included full responses to DEC during renewed challenges. DEC directly suppressed IL-5-dependent eosinophilopoiesis in naive bone marrow. DEC was ineffective in CD95L-deficient gld mice and in mice lacking iNOS activity because of gene targeting or pharmacological blockade.
DEC has a strong impact on pulmonary eosinophilic inflammation in allergic mice, as well as on the underlying hemopoietic response, suppressing the eosinophil lineage by an iNOS/CD95L-dependent mechanism.
作为一种对抗热带肺嗜酸性粒细胞增多症的抗丝虫药物，乙氨嗪的作用机制仍存在争议。乙氨嗪对微丝蚴的作用依赖于诱导型一氧化氮合酶（iNOS）。在嗜酸性粒细胞性肺部炎症中，其治疗机制尚未确定。我们之前描述了卵清蛋白（OVA）致敏小鼠通过气道变应原挑战引起骨髓嗜酸性粒细胞生成的快速上调，并进一步证明了 iNOS 和 CD95L 依赖性机制下调嗜酸性粒细胞生成。
我们研究了以下两个问题：（1）DEC 是否可以预防致敏小鼠气道挑战对肺和骨髓的影响；（2）其有效性是否依赖于 iNOS/CD95L。
对 OVA 致敏的 BALB/c 小鼠进行连续 3 天的鼻内挑战，DEC 给药时间为 12、3 或 2 天，持续至最后一次挑战当天。我们评估了：（1）气道阻力、细胞因子（IFN-γ、IL-4、IL-5 和 eotaxin）产生和肺部嗜酸性粒细胞聚集；（2）体内骨髓嗜酸性粒细胞数量和体外嗜酸性粒细胞分化。
DEC 有效预防了随后挑战对以下方面的影响：（1）气道阻力、Th1/Th2 细胞因子产生和肺部嗜酸性粒细胞聚集；（2）体内和体外嗜酸性粒细胞生成。在重新挑战时，未受保护的挑战的恢复包括 DEC 完全响应。DEC 直接抑制 IL-5 依赖性嗜酸性粒细胞生成。在缺乏 CD95L 的 gld 小鼠和缺乏 iNOS 活性的基因敲除或药物阻断小鼠中，DEC 无效。
DEC 对过敏性小鼠的肺部嗜酸性粒细胞炎症以及潜在的造血反应具有强烈影响，通过 iNOS/CD95L 依赖性机制抑制嗜酸性粒细胞谱系。
