Spleen Tyrosine Kinase Modulates Fibrous Airway Obliteration and Associated Lymphoid Neogenesis After Transplantation
Spleen Tyrosine Kinase Modulates Fibrous Airway Obliteration and Associated Lymphoid Neogenesis After Transplantation
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脾酪氨酸激酶调节移植后纤维气道闭塞和相关淋巴新生
DOI：
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发表时间：
2016
影响因子：
8.8
通讯作者：
C. Chow
中科院分区：
文献类型：
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作者：
Y. Matsuda;X. Wang;H. Oishi;Z. Guan;M. Saito;M. Liu;S. Keshavjee;C. Chow
慢性同种异体肺移植功能障碍是肺移植术后死亡的主要原因，通常表现为不可逆的气流阻塞，并伴有闭塞性细支气管炎（OB），这是一种以慢性炎症、淋巴样细胞新生、纤维增生和小气道闭塞为特征的病变。脾酪氨酸激酶（Syk）是一种调节B细胞功能和先天免疫的酪氨酸激酶，与慢性炎症和组织修复的发病机制有关。本研究利用Syk基因敲除Sykflox/flox//rosa26‐CreERT2小鼠和Syk选择性抑制剂GSK2230413的OB肺内气管移植模型，评估了Syk在OB发展中的作用。BALB/c气管同种异体移植物被移植到Syk基因敲除（Sykdel/del）小鼠或GSK2230413处理的野生型C57BL/6受体中。在第28天，组织学分析显示，在Sykdel/del和GSK2230413‐处理的C57BL/6受体中，与移植到Syk‐表达（Sykflox/flox）和安慰剂对照处理的C57BL/6受体中的同种异体移植物相比，移植物管腔保持开放。免疫荧光显示对照小鼠淋巴细胞新生，具有明显的B细胞区和T细胞区。相比之下，Sykdel/del和GSK2230413‐处理的小鼠没有淋巴细胞新生，并且很少发现B或T细胞。这些观察结果表明，抑制Syk可能是肺移植后OB治疗的潜在治疗策略。
Chronic lung allograft dysfunction, the major cause of death following lung transplantation, usually manifests as irreversible airflow obstruction associated with obliterative bronchiolitis (OB), a lesion characterized by chronic inflammation, lymphoid neogenesis, fibroproliferation and small airway obliteration. Spleen tyrosine kinase (Syk), a tyrosine kinase that regulates B cell function and innate immunity, has been implicated in the pathogenesis of chronic inflammation and tissue repair. This study evaluated the role of Syk in development of OB, using an intrapulmonary tracheal transplant model of OB with the conditional Syk‐knockout Sykflox/flox//rosa26‐CreERT2 mice and a Syk‐selective inhibitor, GSK2230413. BALB/c trachea allografts were transplanted into Syk‐knockout (Sykdel/del) mice or wild‐type C57BL/6 recipients treated with GSK2230413. At day 28, histological analysis revealed that in the Sykdel/del and GSK2230413‐treated C57BL/6 recipients, the graft lumen remained open compared with allografts transplanted into Syk‐expressing (Sykflox/flox) and placebo control–treated C57BL/6 recipients. Immunofluorescence showed lymphoid neogenesis with distinct B and T cell zones in control mice. In contrast, lymphoid neogenesis was absent and few B or T cells were found in Sykdel/del and GSK2230413‐treated mice. These observations suggest that inhibition of Syk may be a potential therapeutic strategy for the management of OB following lung transplantation.
影响因子：
13.8
作者：
Geahlen, Robert L.
通讯作者：
Geahlen, Robert L.
影响因子：
7.2
作者：
Lowell CA
通讯作者：
Lowell CA