University of British Columbia James Hogg Research Centre, St. Paul's Hospital, 1081 Burrard St., Vancouver, BC, Canada.
Am J Respir Cell Mol Biol. 2013 Sep;49(3):453-62. doi: 10.1165/rcmb.2012-0512OC.
Granzyme B (GzmB) is a serine protease with intracellular and extracellular activities capable of regulating inflammation through cytokine processing and the apoptosis of effector cells. We tested the hypothesis that GzmB expression in T regulatory cells (Tregs) is required for the control of inflammatory responses and pathology during acute lung injury. To substantiate the clinical relevance of GzmB during lung injury, we performed GzmB immunohistochemistry on lung tissue from patients with acute respiratory distress syndrome (ARDS) and healthy control subjects. We also performed in vivo experiments with wild-type (WT) C57BL/6 and GzmB(-/-) mice exposed to a single intranasal instillation of bleomycin to model lung injury. Our results demonstrate that the expression of GzmB was elevated in ARDS lung sections, relative to healthy control samples. Bleomycin-exposed GzmB(-/-) mice exhibited greater morbidity and mortality, which was associated with increased numbers of lung lymphocytes. Bleomycin induced an equal increase in CD4(+)/CD25(+)/FoxP3(+) Treg populations in WT and GzmB(-/-) mice. GzmB expression was not significant in Tregs, with the majority of the expression localized to natural killer (NK)-1.1(+) cells. The expression of GzmB in NK cells of bleomycin-exposed WT mice was associated with greater lymphocyte apoptosis, reduced total lymphocyte numbers, and reduced pathology relative to GzmB(-/-) mice. Our data demonstrate that GzmB deficiency results in the exacerbation of lymphocytic inflammation during bleomycin-induced acute lung injury, which is associated with pathology, morbidity, and mortality.
颗粒酶 B（GzmB）是一种具有细胞内和细胞外活性的丝氨酸蛋白酶，能够通过细胞因子处理和效应细胞凋亡来调节炎症。我们检验了这样一个假设，即 T 调节细胞（Tregs）中的 GzmB 表达对于控制急性肺损伤中的炎症反应和病理是必需的。为了证实 GzmB 在肺损伤中的临床相关性，我们对急性呼吸窘迫综合征（ARDS）患者和健康对照者的肺组织进行了 GzmB 免疫组织化学染色。我们还对接受单次鼻腔内滴注博来霉素以模拟肺损伤的野生型（WT）C57BL/6 和 GzmB（-/-）小鼠进行了体内实验。我们的结果表明，与健康对照样本相比，ARDS 肺组织中 GzmB 的表达升高。博来霉素暴露的 GzmB（-/-）小鼠表现出更高的发病率和死亡率，这与肺淋巴细胞数量增加有关。博来霉素诱导 WT 和 GzmB（-/-）小鼠中 CD4（+）/CD25（+）/FoxP3（+）Treg 群体的同等增加。GzmB 在 Tregs 中的表达不显著，其大部分表达定位于自然杀伤（NK）-1.1（+）细胞。博来霉素暴露的 WT 小鼠中 NK 细胞中的 GzmB 表达与淋巴细胞凋亡增加、总淋巴细胞数量减少以及与 GzmB（-/-）小鼠相比病理学减少相关。我们的数据表明，GzmB 缺乏导致博来霉素诱导的急性肺损伤中淋巴细胞炎症的加剧，这与病理学、发病率和死亡率相关。
