When wheeze leads to squeeze: growth under pressure.
When wheeze leads to squeeze: growth under pressure.
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当喘息导致挤压时：压力下的增长。
DOI：
10.1165/rcmb.f297
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发表时间：
2005
影响因子：
6.4
通讯作者：
Deshmukh,HiteshS
中科院分区：
文献类型：
--
作者：
Leikauf,GeorgeD;Deshmukh,HiteshS
在这个问题上的杂志（pp。373-380），Chu和同事研究了压缩应力对气道上皮的影响，很像哮喘中支气管收缩期间产生的压力（1）。压缩和拉伸应力已在肌肉和骨组织培养中得到广泛研究（2），并且已经提出了关于它如何控制干细胞命运的令人兴奋的理论（3）。关于压力在气道疾病中的作用还很不确定。此前，这些研究者报道，压缩应力导致表皮生长因子受体（EGFR）磷酸化，随后增加肝素结合表皮生长因子样生长因子（HBEGF）转录物和免疫染色蛋白（4）。由细胞增殖的刺激触发，膜结合的EGF家族配体被基质金属蛋白酶（MMP）切割，从而脱落以与EGFR结合，导致磷酸化。因此，EGFR激活→配体转录→ MMP激活→配体脱落→ EGFR激活的过程构成了一个自分泌反馈回路，这被认为是粘液细胞增生（5）和可能的气道纤维化（6）中的主要问题。压缩应力导致EGFR活化的机制尚不清楚。然而，这些研究人员提出，这是由于上皮细胞周围的侧向细胞间隙（LIS）的压缩（7）。假设进入塌陷体积的恒定脱落速率，局部配体浓度理论上可以增加到足以解释所观察到的受体信号传导。他们还表明，这种作用不是由于渗透应激反应，激活额外的丝裂原活化蛋白激酶。虽然这种“LIS挤压”理论有其优点，但人们可以想象其他可能的解释，即触发机械转导的其他机制的作用。例如，专门的机械感觉细胞通过拉伸激活的门控离子通道在许多组织中发挥作用（8，9）。细胞间隙-整联蛋白相互作用可能通过粘着斑复合物或细胞-细胞粘附连接激活生长因子，这已被讨论为导致转录编程改变的机械传感器（10）。在这项新的研究中，研究结果扩展到其他EGF家族成员，包括epiregulin（作为转录本和蛋白质检测）和双调蛋白（单独转录本）。几分钟的短暂压力会引发持续数小时的反应，这表明支气管痉挛发作的长期后果。然而，这一过程似乎减弱时，持续压缩延长超过4小时，这表明存在一个“关”的机制尚未被发现。终止信号的调节显然在许多生物过程中是关键的，包括器官发生、增生和肿瘤发生。在所有
In this issue of the Journal (pp. 373–380), Chu and colleagues examine the consequences to the airway epithelium of compressive stress, much like that generated during bronchoconstriction in asthma (1). Compressive and tensile stress have been studied extensively in muscle and bone tissue culture (2), and exciting theories have been advanced as to how it may control the fate of stem cells (3). Much less is certain about the role of the stresses in airway diseases. Previously, these investigators reported that compressive stress led to phosphorylation of epidermal growth factor receptor (EGFR), with a subsequent increase in of heparin-binding epidermal growth factor-like growth factor (HBEGF) transcripts and immunostaining protein (4). Triggered by stimuli of cell proliferation, membrane-bound EGF family ligands are cleaved by matrix metalloproteinases (MMP) and thus shed to bind to EGFR, leading to phosphorylation. Thus, this process of EGFR-activation→ ligand transcription→ MMP activation→ ligand shedding→ EGFR-activation constitutes an autocrine feedback loop, which is thought to be of major concern in mucus cell hyperplasis (5) and possibly airway fibrosis (6). The mechanisms by which compressive stress leads to EGFR activation are unknown. However, these investigators have proposed that it is due to compression of the lateral intercellular space (LIS) surrounding epithelial cells (7). Assuming a constant shedding rate into a collapsing volume, local ligand concentrations could theoretically increase sufficiently to account for the observed receptor signaling. They also suggest that this effect is not due to osmotic stress response, which activated additional mitogen-activated protein kinases. Although this “LIS squeeze” theory has merits, one could image other possible explanations for the role of other mechanisms triggering mechanotransduction. For example, specialized mechanosensory cells function in many tissues through stretch-activated gated ion channels (8, 9). Cytoskeletal–integrin interactions can activate growth factors possibly through focal adhesion complexes or cell–cell adherens junctions, which have been discussed as mechnosensors leading to altered transcriptional programming (10). In this new study, findings are broadened to other EGF family members, including epiregulin (which is detected as transcript and protein) and amphiregulin (transcript alone). Transient stress of only a few minutes triggers a response lasting several hours, suggesting long-term consequences of bouts of bronchospasm. However, this process seems to wane when continuous compression is extended past 4 h, suggesting that the existence of an “off” mechanism yet to be discovered. Regulation of the stop signal obviously may be critical in many biological processes, including organogenesis, hyperplasia, and tumorigenesis. In all
分子和细胞生物学的细胞培养方法
影响因子：
17.3
作者：
M. C. Berenbaum
通讯作者：
M. C. Berenbaum