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首页> 外文期刊>Cell and Tissue Research >Primary human coculture model of alveolo-capillary unit to study mechanisms of injury to peripheral lung
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Primary human coculture model of alveolo-capillary unit to study mechanisms of injury to peripheral lung

机译：肺泡-毛细血管单元的主要人类共培养模型，用于研究外周肺损伤的机制

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In order to delineate individual pathomechanisms in acute lung injury and pulmonary toxicology, we developed a primary coculture system to simulate the human alveolo-capillary barrier. Human pulmonary microvascular endothelial cells (HPMEC) were cocultivated with primary isolated human type II alveolar epithelial cells (HATII) on opposite sides of a permeable filter support, thereby constituting a bilayer. Within 7–11 days of coculture, the HATII cells partly transdifferentiated to type-I-like (HATI-like) cells, as demonstrated by morphological changes from a cuboidal to a flattened morphology, the loss of HATII-cell-specific organelles and the increase of HATI-cell-related markers (caveolin-1, aquaporin-5, receptor for advanced glycation end-products). Immunofluorescent analysis detected type-II-like and type-I-like alveolar epithelial cells mimicking the heterocellular composition of alveolar epithelium in vivo. The heterocellular epithelial monolayer showed a circumferential staining of tight-junctional (ZO-1, occludin) and adherens-junctional (E-cadherin, β-catenin) proteins. HPMEC on the opposite side also developed tight and adherens junctions (VE-cadherin, β-catenin). Under integral barrier properties, exposure to the proinflammatory cytokine tumour necrosis factor-α from either the endothelial (basolateral) or the epithelial (apical) side caused a largely compartmentalized release of the chemokines interleukin-8 and monocyte chemoattractant protein-1. Thus, the established coculture provides a suitable in vitro model to examine barrier function at the distal lung, including the interaction of microvascular endothelial cells with ATII-like and ATI-like epithelial cells. The compartmentalization of the barrier-forming bilayer also allows mechanisms of lung injury to be studied in both the epithelial (intra-alveolar) and the endothelial (intravascular) compartments.
机译：为了描述急性肺损伤和肺毒理学中的个体致病机理，我们开发了一种主要的共培养系统来模拟人肺泡-毛细血管屏障。将人肺微血管内皮细胞（HPMEC）与可分离的人眼II型肺泡上皮细胞（HATII）在可渗透滤膜支持器的相对侧共同培养，从而构成双层。共培养7-11天后，HATII细胞部分转分化为I型（HATI类）细胞，这表现为从长方体到扁平形的形态变化，HATII细胞特异性细胞器的丧失和增加HATI细胞相关标记（caveolin-1，aquaporin-5，晚期糖基化终产物的受体）。免疫荧光分析检测到II型和I型肺泡上皮细胞在体内模拟肺泡上皮的异细胞组成。异细胞上皮单层显示紧密连接蛋白（ZO-1，occludin）和粘附连接蛋白（E-cadherin，β-catenin）的圆周染色。另一侧的HPMEC也形成紧密连接的连接（VE-钙黏着蛋白，β-连环蛋白）。在整体屏障特性下，从内皮（基底外侧）或上皮（顶端）侧暴露于促炎细胞因子肿瘤坏死因子-α会导致趋化因子白介素8和单核细胞趋化蛋白1的大部分区域性释放。因此，建立的共培养物提供了合适的体外模型以检查远端肺的屏障功能，包括微血管内皮细胞与ATII样和ATI样上皮细胞的相互作用。形成屏障的双层的分隔也允许在上皮（肺泡内）和内皮（血管内）隔室中研究肺损伤的机制。

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