Nho Richard Seonghun, Hergert Polla
Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America.
PLoS One. 2014 Apr 11;9(4):e94616. doi: 10.1371/journal.pone.0094616. eCollection 2014.
Idiopathic pulmonary fibrosis (IPF) is a chronic, lethal interstitial lung disease in which the aberrant PTEN/Akt axis plays a major role in conferring a survival phenotype in response to the cell death inducing properties of type I collagen matrix. The underlying mechanism by which IPF fibroblasts become desensitized to polymerized collagen, thereby eluding collagen matrix-induced cell death has not been fully elucidated. We hypothesized that the pathologically altered PTEN/Akt axis suppresses autophagy via high mTOR kinase activity, which subsequently desensitizes IPF fibroblasts to collagen matrix induced cell death. We found that the autophagosome marker LC3-2 expression is suppressed, while mTOR activity remains high when IPF fibroblasts are cultured on collagen. However, LC3-2 expression increased in response to IPF fibroblast attachment to collagen in the presence of rapamycin. In addition, PTEN over-expression or Akt inhibition suppressed mTOR activity, thereby increasing LC3-2 expression in IPF fibroblasts. Furthermore, the treatment of IPF fibroblasts over-expressing PTEN or dominant negative Akt with autophagy inhibitors increased IPF fibroblast cell death. Enhanced p-mTOR expression along with low LC3-2 expression was also found in myofibroblasts within the fibroblastic foci from IPF patients. Our data show that the aberrant PTEN/Akt/mTOR axis desensitizes IPF fibroblasts from polymerized collagen driven stress by suppressing autophagic activity, which produces a viable IPF fibroblast phenotype on collagen. This suggests that the aberrantly regulated autophagic pathway may play an important role in maintaining a pathological IPF fibroblast phenotype in response to collagen rich environment.
特发性肺纤维化（IPF）是一种慢性致死性间质性肺疾病，其中异常的PTEN/Akt轴在赋予细胞对I型胶原基质诱导细胞死亡特性的存活表型中起主要作用。IPF成纤维细胞对聚合胶原脱敏从而逃避胶原基质诱导的细胞死亡的潜在机制尚未完全阐明。我们假设病理改变的PTEN/Akt轴通过高mTOR激酶活性抑制自噬，这随后使IPF成纤维细胞对胶原基质诱导的细胞死亡脱敏。我们发现，当IPF成纤维细胞在胶原上培养时，自噬体标志物LC3-II的表达受到抑制，而mTOR活性仍然很高。然而，在雷帕霉素存在的情况下，IPF成纤维细胞附着于胶原时LC3-II表达增加。此外，PTEN过表达或Akt抑制可抑制mTOR活性，从而增加IPF成纤维细胞中LC3-II的表达。此外，用自噬抑制剂处理过表达PTEN或显性负性Akt的IPF成纤维细胞会增加IPF成纤维细胞的死亡。在IPF患者的成纤维细胞灶内的肌成纤维细胞中也发现p-mTOR表达增强以及LC3-II表达降低。我们的数据表明，异常的PTEN/Akt/mTOR轴通过抑制自噬活性使IPF成纤维细胞对聚合胶原驱动的应激脱敏，这在胶原上产生了存活的IPF成纤维细胞表型。这表明异常调节的自噬途径可能在维持对富含胶原环境的病理性IPF成纤维细胞表型中起重要作用。
