CFTR-regulated MAPK/NF-κB signaling in pulmonary inflammation in thermal inhalation injury.
CFTR-regulated MAPK/NF-κB signaling in pulmonary inflammation in thermal inhalation injury.
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DOI：
10.1038/srep15946
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发表时间：
2015-10-30
影响因子：
4.6
通讯作者：
Peng YZ
中科院分区：
文献类型：
--
作者：
Dong ZW;Chen J;Ruan YC;Zhou T;Chen Y;Chen Y;Tsang LL;Chan HC;Peng YZ
热吸入性损伤引起肺部炎症的机制仍不清楚。囊性纤维化，也是以肺部炎症为特征的，是由CFTR突变引起的，其表达对温度敏感。我们调查了CFTR是否参与了热诱导的肺部炎症。我们在体内对cftr基因表达下调或过表达的16HBE14o-细胞进行了热处理，并进行了热吸入。在体外和体内的早期阶段，热处理导致CFTR显著减少，而COX-2则相反地增加。在热处理的细胞中检测到ERK/jnk、NF-κB和COX-2/PGE_2的激活，并被cftr或已报道的cftr突变校正因子Vx-809的过表达逆转。抑制jnk/erk可逆转热/cftr基因敲除诱导的NF-κB活化，而抑制nf-κB对jnk/erk无明显影响。IL-8可通过热处理或cftr基因敲除而增强，而通过抑制NF-κB、jnk/erk或COX-2而被取消。此外，姜黄素(一种天然酚类化合物)在体外或体内处理后，显著增强了CFTR的表达，并逆转了热诱导的COX-2/PGE2/IL-8增加、中性粒细胞浸润和呼吸道组织损伤。这些结果揭示了cftr调控的MAPK/NF-κB通路导致热吸入性损伤中COX-2/PGE_2/IL-8的激活，并证实了姜黄素对热致肺部炎症的治疗作用。
The mechanism underlying pulmonary inflammation in thermal inhalation injury remains elusive. Cystic fibrosis, also hallmarked with pulmonary inflammation, is caused by mutations in CFTR, the expression of which is temperature-sensitive. We investigated whether CFTR is involved in heat-induced pulmonary inflammation. We applied heat-treatment in 16HBE14o- cells with CFTR knockdown or overexpression and heat-inhalation in rats in vivo. Heat-treatment caused significant reduction in CFTR and, reciprocally, increase in COX-2 at early stages both in vitro and in vivo. Activation of ERK/JNK, NF-κB and COX-2/PGE2 were detected in heat-treated cells, which were mimicked by knockdown, and reversed by overexpression of CFTR or VX-809, a reported CFTR mutation corrector. JNK/ERK inhibition reversed heat-/CFTR-knockdown-induced NF-κB activation, whereas NF-κB inhibitor showed no effect on JNK/ERK. IL-8 was augmented by heat-treatment or CFTR-knockdown, which was abolished by inhibition of NF-κB, JNK/ERK or COX-2. Moreover, in vitro or in vivo treatment with curcumin, a natural phenolic compound, significantly enhanced CFTR expression and reversed the heat-induced increases in COX-2/PGE2/IL-8, neutrophil infiltration and tissue damage in the airway. These results have revealed a CFTR-regulated MAPK/NF-κB pathway leading to COX-2/PGE2/IL-8 activation in thermal inhalation injury, and demonstrated therapeutic potential of curcumin for alleviating heat-induced pulmonary inflammation.