Functional analysis of tetraspanins(CD9, CD151) in lung fibrosis

肺纤维化（PF）是过量纤维结缔组织形成的过程，其特征是纤维胶原蛋白的积累。四联蛋白是整合素的重要伙伴，促进多种分子复合物的形成并调节细胞功能。我们之前报道了小鼠自发发生copd样表型的四跨蛋白CD9和CD81双缺失。来自DNA微阵列的基因功能分析意外地显示，“结缔组织发育和功能”在CD151 KO肺中排名较高。值得注意的是，随着年龄的增长，CD151 KO小鼠自发发生肺纤维化。在CD151 KO小鼠中，p-Smad2水平在全肺和上皮中一致升高。事实上，肺泡上皮细胞中CD151的缺失会导致基质细胞上p-Smad2活性的增加和间质样改变。有趣的是，与健康对照相比，IPF患者上皮细胞中CD151的表达下调。鉴于CD151通过维持上皮完整性在预防纤维化中起关键作用，CD151可能是PF的新靶点。

Pulmonary fibrosis(PF) is the process whereby excess fibrous connective tissue forms and characterized by the accumulation of fibrillar collagen. Tetraspanins, key partners of integrins, facilitate the formation of multiple molecular complexes and regulate cell function. We previously reported double deletion of tetraspanin CD9 and CD81 in mice spontaneously developed COPD-like phenotype. The gene functions analyses from DNA Microarray unexpectedly revealed that' connective tissue development and function' were ranked high in CD151 KO lungs. Notably, CD151 KO mice spontaneously developed lung fibrosis with age. Consistently, the level of p-Smad2 in the CD151 KO mice was augmented in the whole lung and in the epithelium. Indeed, deletion of CD151 in alveolar epithelial cells leads to increased p-Smad2 activity on Matrigel, and mesenchymal-like changes. Of interest, expression of CD151 in epithelial cells from IPF patients was downregulated compared with that of healthy controls. Given that CD151 plays a pivotal role to prevent fibrosis through maintaining epithelial integrity, CD151 could be a novel target for PF.