Mitotic Asynchrony Induces Transforming Growth Factor-β1 Secretion from Airway Epithelium
Mitotic Asynchrony Induces Transforming Growth Factor-β1 Secretion from Airway Epithelium
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DOI：
10.1165/rcmb.2013-0396oc
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发表时间：
2014-09-01
影响因子：
6.4
通讯作者：
Freishtat, Robert J.
中科院分区：
文献类型：
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作者：
Alcala, Sarah E.;Benton, Angela S.;Freishtat, Robert J.
我们最近提出，修复组织中的有丝分裂不同步可能是慢性炎症和纤维化的基础，其中免疫细胞浸润是继发于不同步修复邻近组织中的促炎串扰。基于我们之前的发现，有丝分裂不同步与促炎/纤维化细胞因子（如转化生长因子[TGF]- β 1）的分泌有关，我们在此提供了支持因果关系的证据。在正常情况下，初级气道上皮基底细胞群同步进行有丝分裂，不分泌促炎或促纤维化细胞因子。然而，当对非哮喘培养物在12小时内有丝分裂同步，然后结合时，混合细胞群分泌的tgf - β 1水平升高。这表明有丝分裂不同步不仅与tgf - β 1分泌有关，而且也是其原因。哮喘细胞分泌的细胞因子和其他介质不是引起非同步再生的原因；同时有丝分裂的非哮喘上皮暴露于来自哮喘细胞的条件介质中，没有显示有丝分裂同步的变化。我们还测试了再生哮喘气道上皮的再同步是否会减少tgf - β 1的分泌，并发现脉冲剂量的地塞米松、辛伐他汀和阿菲迪克林都有效。因此，我们提出了一个新的模型慢性炎症和纤维化条件，其中一个潜在的因素是有丝分裂不同步。
We recently proposed that mitotic asynchrony in repairing tissue may underlie chronic inflammation and fibrosis, where immune cell infiltration is secondary to proinflammatory cross-talk among asynchronously repairing adjacent tissues. Building on our previous finding that mitotic asynchrony is associated with proinflammatory/fibrotic cytokine secretion (e.g., transforming growth factor [TGF]-beta 1), here we provide evidence supporting cause-and-effect. Under normal conditions, primary airway epithelial basal cell populations undergo mitosis synchronously and do not secrete proinflammatory or profibrotic cytokines. However, when pairs of nonasthmatic cultures were mitotically synchronized at 12 hours off-set and then combined, the mixed cell populations secreted elevated levels of TGF-beta 1. This shows that mitotic asynchrony is not only associated with but is also causative of TGF-beta 1 secretion. The secreted cytokines and other mediators from asthmatic cells were not the cause of asynchronous regeneration; synchronously mitotic nonasthmatic epithelia exposed to conditioned media from asthmatic cells did not show changes in mitotic synchrony. We also tested if resynchronization of regenerating asthmatic airway epithelia reduces TGF-beta 1 secretion and found that pulse-dosed dexamethasone, simvastatin, and aphidicolin were all effective. We therefore propose a new model for chronic inflammatory and fibrotic conditions where an underlying factor is mitotic asynchrony.