Acute lung injury fibroblast migration and invasion of a fibrin matrix is mediated by CD44.
Acute lung injury fibroblast migration and invasion of a fibrin matrix is mediated by CD44.
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DOI：
10.1172/jci118970
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发表时间：
1996-10
期刊：
影响因子：
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通讯作者：
Kent Svee;J. White;P. Vaillant;J. Jessurun;U. Roongta;Marci Krumwiede;Debra D. Johnson;C. Henke
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文献类型：
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作者：
Kent Svee;J. White;P. Vaillant;J. Jessurun;U. Roongta;Marci Krumwiede;Debra D. Johnson;C. Henke
当肌成纤维细胞侵入伤口纤维蛋白临时基质时，导致纤维化。细胞表面的细胞外基质受体介导细胞粘附、迁移和侵袭。最近对转化细胞的研究表明，这些细胞利用细胞表面基质受体CD 44进行迁移和侵袭。在这项研究中，我们检查是否肺成纤维细胞，从急性肺泡纤维化死亡的患者分离，使用CD 44侵入纤维蛋白基质。与CD 44在介导成纤维细胞侵袭和随后的组织纤维化中的作用一致，对肺损伤后死于急性肺泡纤维化的患者的肺组织的免疫组织化学分析显示，在整个新形成的纤维化组织中表达CD 44的间充质细胞。PCR、Western和免疫沉淀分析表明，急性肺损伤成纤维细胞表达85-kD CD 44亚型。与介导基质粘附和迁移超微结构中的作用一致，CD 44均匀地分布在细胞表面，并被发现密集标记丝状伪足和片状伪足，高度能动的结构参与细胞迁移。为了确定肺损伤成纤维细胞是否使用CD 44侵入纤维蛋白，使用纤维蛋白凝胶纤维化模型。通过用单克隆抗体阻断CD 44的功能，成纤维细胞侵入纤维蛋白基质被抑制。为了研究CD 44介导成纤维细胞侵袭的机制，评价了CD 44在成纤维细胞迁移和粘附中的作用。抗CD 44抗体阻断成纤维细胞在临时基质蛋白纤连蛋白、纤维蛋白原和透明质酸上的迁移。此外，成纤维细胞CD 44介导粘附到临时基质蛋白纤连蛋白，纤维蛋白和透明质酸，但不层粘连蛋白，基底膜的一个组成部分。这些发现支持了成纤维细胞CD 44作为临时基质蛋白粘附受体的假设，并且能够介导成纤维细胞迁移和伤口临时基质的入侵，从而导致纤维化组织的形成。
Fibrosis results when myofibroblasts invade the wound fibrin provisional matrix. Extracellular matrix receptors on the cell surface mediate cell adhesion, migration, and invasion. Recent work with transformed cells indicates that these cells use the cell surface matrix receptor CD44 for migration and invasion. In this study, we examine whether lung fibroblasts, isolated from patients dying with acute alveolar fibrosis, use CD44 to invade a fibrin matrix. Consistent with a role for CD44 in mediating fibroblast invasion and subsequent tissue fibrosis, immunohistochemical analysis of lung tissue from patients who died from acute alveolar fibrosis after lung injury reveals CD44-expressing mesenchymal cells throughout newly formed fibrotic tissue. PCR, Western, and immunoprecipitation analysis demonstrate that the 85-kD CD44 isoform is expressed by acute lung injury fibroblasts. Consistent with a role in mediating matrix adhesion and migration ultrastructurally, CD44 was found uniformly over the cell surface and was found densely labeling filopodia and lamellipodia, highly motile structures involved in cell migration. To determine if lung injury fibroblasts use CD44 to invade fibrin, a fibrin gel model of fibrosis was used. By blocking the function of CD44 with monoclonal antibodies, fibroblast invasion into a fibrin matrix was inhibited. To examine the mechanism by which CD44 mediates fibroblast invasion, the role of CD44 in fibroblast migration and adhesion was evaluated. Anti-CD44 antibody blocked fibroblast migration on the provisional matrix proteins fibronectin, fibrinogen, and hyaluronic acid. Additionally, fibroblast CD44 mediated adhesion to the provisional matrix proteins fibronectin, fibrin, and hyaluronic acid, but not to laminin, a component of the basement membrane. These findings support the hypothesis that fibroblast CD44 functions as an adhesion receptor for provisional matrix proteins and is capable of mediating fibroblast migration and invasion of the wound provisional matrix resulting in the formation of fibrotic tissue.