Department of Pediatrics Respiratory Sciences, Johns Hopkins University, Baltimore, MD, USA.
Curr Mol Med. 2012 Aug;12(7):807-14. doi: 10.2174/156652412801318809.
Proteostasis is a critical cellular homeostasis mechanism that regulates the concentration of all cellular proteins by controlling protein- synthesis, processing and degradation. This includes protein-conformation, binding interactions and sub-cellular localization. Environmental, genetic or age-related pathogenetic factors can modulate the proteostasis (proteostasis-imbalance) through transcriptional, translational and post-translational changes that trigger the development of several complex diseases. Although these factors are known to be involved in pathogenesis of chronic obstructive pulmonary disease (COPD), the role of proteostasis mechanisms in COPD is scarcely investigated. As a proof of concept, our recent data reveals a novel role of proteostasis-imbalance in COPD pathogenesis. Briefly, cigarette- and biomass- smoke induced proteostasis-imbalance may aggravate chronic inflammatory-oxidative stress and/or protease-anti-protease imbalance resulting in pathogenesis of severe emphysema. In contrast, pathogenesis of other chronic lung diseases like ΔF508-cystic fibrosis (CF), α1-anti-trypsin-deficiency (α-1 ATD) and pulmonary fibrosis (PF) is regulated by other proteostatic mechanisms, involving the degradation of misfolded proteins (ΔF508-CFTR/α1-AT- Z variant) or regulating the concentration of signaling proteins (such as TGF-β1) by the ubiquitin-proteasome system (UPS). The therapeutic strategies to correct proteostasis-imbalance in misfolded protein disorders such as ΔF508-CF have been relatively well studied and involve strategies that rescue functional CFTR protein to treat the underlying cause of the disease. While in the case of COPD-emphysema and/or PF, identification of novel proteostasis-regulators that can control inflammatory-oxidative stress and/or protease-anti-protease balance is warranted.
蛋白质稳态是一种关键的细胞内稳态机制，通过控制蛋白质合成、加工和降解来调节所有细胞蛋白质的浓度。这包括蛋白质构象、结合相互作用和亚细胞定位。环境、遗传或与年龄相关的致病因素可以通过转录、翻译和翻译后变化来调节蛋白质稳态（蛋白质稳态失衡），从而引发几种复杂疾病的发展。尽管这些因素已知与慢性阻塞性肺疾病（COPD）的发病机制有关，但蛋白质稳态机制在 COPD 中的作用尚未得到充分研究。作为概念验证，我们最近的数据揭示了蛋白质稳态失衡在 COPD 发病机制中的新作用。简而言之，香烟和生物质烟雾引起的蛋白质稳态失衡可能会加重慢性炎症氧化应激和/或蛋白酶-抗蛋白酶失衡，从而导致严重肺气肿的发病。相比之下，其他慢性肺部疾病（如 ΔF508 囊性纤维化（CF）、α1-抗胰蛋白酶缺乏症（α-1 ATD）和肺纤维化（PF））的发病机制则由其他蛋白质稳态机制调节，包括错误折叠蛋白（ΔF508-CFTR/α1-AT-Z 变体）的降解或通过泛素-蛋白酶体系统（UPS）调节信号蛋白（如 TGF-β1）的浓度。纠正错误折叠蛋白紊乱中的蛋白质稳态失衡的治疗策略，如 ΔF508-CF，已经得到了相对较好的研究，涉及挽救功能性 CFTR 蛋白的策略，以治疗疾病的根本原因。然而，在 COPD-肺气肿和/或 PF 的情况下，需要确定新的蛋白质稳态调节剂，以控制炎症氧化应激和/或蛋白酶-抗蛋白酶平衡。
