Humlicek Alicia L, Manzel Lori J, Chin Cecilia L, Shi Lei, Excoffon Katherine J D A, Winter Michael C, Shasby D Michael, Look Dwight C
Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
J Immunol. 2007 May 15;178(10):6395-403. doi: 10.4049/jimmunol.178.10.6395.
Respiratory pathogens and toxins often assault the lung from the airway lumen. Airway epithelia may initiate and amplify inflammation in response to these attacks, but under certain conditions confinement of inflammation to the airway lumen may be beneficial to the host. Accordingly, we hypothesized that airway epithelial polarity allows different responses to basolateral vs apical stimuli that may modulate inflammation. Using primary human airway epithelial cells differentiated at an air-liquid interface in culture, we found that responses to several cytokines required basolateral mediator application. In contrast, responses to Haemophilus influenzae occurred after either basolateral or apical interaction with airway epithelia. Experiments focused on IFN-gamma receptor polarity confirmed its predominant basolateral location in cultured airway epithelia as well as in normal human airway tissue. Furthermore, physical and pharmacologic disruption of barrier function in airway epithelia allowed responses to apical application of IFN-gamma and other cytokines. These in vitro studies directly correlated with experiments in mice in which an airway epithelial response to IFN-gamma injected into the airway lumen was seen only after disruption of barrier function. The results indicate that airway epithelia with intact barrier function restrict inflammatory responses by limitation of cell activation through requiring interaction of selected mediators with the basolateral surface. However, loss of barrier integrity allows epithelial responses to these mediators if located in the airway lumen to amplify airway defenses.
呼吸道病原体和毒素常常从气道管腔侵袭肺部。气道上皮细胞可能会对这些攻击引发并放大炎症反应，但在某些情况下，将炎症局限于气道管腔对宿主可能是有益的。因此，我们推测气道上皮极性使得对基底外侧刺激与顶端刺激产生不同反应，这可能会调节炎症。利用在气液界面培养分化的原代人气道上皮细胞，我们发现对几种细胞因子的反应需要施加基底外侧介质。相比之下，与气道上皮细胞进行基底外侧或顶端相互作用后，均可出现对流感嗜血杆菌的反应。聚焦于γ干扰素受体极性的实验证实，其在培养的气道上皮细胞以及正常人气道组织中主要位于基底外侧。此外，气道上皮屏障功能的物理和药理学破坏使得对顶端施加的γ干扰素和其他细胞因子产生反应。这些体外研究与小鼠实验直接相关，在小鼠实验中，只有在屏障功能破坏后，才能观察到对注入气道管腔的γ干扰素的气道上皮反应。结果表明，具有完整屏障功能的气道上皮细胞通过要求特定介质与基底外侧表面相互作用来限制细胞活化，从而限制炎症反应。然而，如果这些介质位于气道管腔中，屏障完整性的丧失会使上皮细胞对它们产生反应，从而增强气道防御。
