Inhibition of the Src and Jak kinases protects against lipopolysaccharide-induced acute lung injury
Inhibition of the Src and Jak kinases protects against lipopolysaccharide-induced acute lung injury
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DOI：
10.1164/rccm.200407-981oc
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发表时间：
2005-04-15
影响因子：
24.7
通讯作者：
Simon, AR
中科院分区：
文献类型：
--
作者：
Severgnini, M;Takahashi, S;Simon, AR
介导急性肺损伤的细胞和分子通路级联反应是复杂的，并且不完全确定。虽然Src和Jak激酶家族在LPS诱导的小鼠肺损伤中上调，但它们在肺损伤发展中的作用尚不清楚。在这里，我们报告说，这些激酶的系统抑制使用特定的小分子抑制剂（PP 2，SU 6656，酪氨酸磷酸化抑制剂）显着衰减LPS诱导的肺损伤，通过组织学和毛细血管通透性测定。这些抑制剂阻断肺和血清中LPS依赖性细胞因子和趋化因子的产生。相反，通过腺病毒介导的显性阴性Src或细胞因子信号转导抑制因子（SOCS-1）的基因转移，肺靶向抑制气道上皮中的这些激酶，破坏肺细胞因子的产生，但对全身细胞因子的产生或肺血管通透性没有影响。Jak和Src激酶的小分子抑制剂显著保护小鼠免受致死性LIPS攻击。重要的是，即使在LPS攻击后6小时施用抑制剂，这种保护仍然是明显的。总之，这些观察结果表明，Jak和Src激酶参与急性肺损伤，并验证了这类选择性酪氨酸激酶抑制剂作为这种疾病的新型治疗药物的潜力。
The cascade of cellular and molecular pathways mediating acute lung injury is complex and incompletely defined. Although the Src and Jak family of kinases is upregulated in LPS-induced murine lung injury, their role in the development of lung injury is unknown. Here we report that systemic inhibition of these kinases using specific small molecule inhibitors (PP2, SU6656, tyrphostin All) significantly attenuated LPS-induced lung injury, as determined by histologic and capillary permeability assays. These inhibitors blocked LPS-dependent cytokine and chemokine production in the lung and in the serum. In contrast, lung-targeted inhibition of these kinases in the airway epithelium via adenoviral-mediated gene transfer of dominant negative Src or of suppressor of cytokine signaling (SOCS-1) disrupted lung cytokine production but had no effect on systemic cytokine production or lung vascular permeability. Mice were significantly protected from lethal LIPS challenge by the small molecule inhibitors of Jak and Src kinase. Importantly, this protection was still evident even when the inhibitors were administered 6 hours after LPS challenge. Taken together, these observations suggest that Jak and Src kinases participate in acute lung injury and verify the potential of this class of selective tyrosine kinase inhibitors to serve as novel therapeutic agents for this disease.