哮喘中针对未折叠蛋白反应的机制
2022/02/28
摘要
肺细胞不断暴露于破坏蛋白质稳定的各种内部和外部应激物。为了应对这些刺激，细胞引发高度保守的适应性机制，称为未折叠蛋白反应（UPR）。UPR应激源可以对内质网ER施加更大的蛋白质分泌需求，导致这些细胞类型的发育、分化和存活，以满足这些日益增长的功能需求。UPR的失调导致疾病的发展。UPR和ER应激涉及几种人类病症，例如慢性炎症、神经变性代谢综合征和癌症。此外，靶向UPR途径的有效的和特定的化合物正在开发作为未来的疗法。这篇综述的重点是彻底描述内部和外部压力对哮喘ER的影响。此外，我们讨论了UPR信号通路如何在肺中被激活以克服细胞损伤。我们还概述了致病机制，并简要介绍了药物干预的潜在策略。
Mechanisms Targeting the Unfolded Protein Response in Asthma
Sanaz Dastghaib, P Sravan Kumar, Sajjad Aftabi, Gautam Damera, Azadeh Dalvand, Adel Sepanjnia, Mohammad Kiumarsi , Mohamad-Reza Aghanoori , Sukhwinder Singh Sohal, Sudharsana R Ande , Javad Alizadeh, Pooneh Mokarram, Saeid Ghavami , Pawan Sharma, Amir A Zeki
Abstract
Lung cells are constantly exposed to various internal and external stressors that disrupt protein homeostasis. To cope with these stimuli, cells evoke a highly conserved adaptive mechanism called the unfolded protein response (UPR). UPR stressors can impose greater protein secretory demands on the endoplasmic reticulum (ER), resulting in the development, differentiation, and survival of these cell types to meet these increasing functional needs. Dysregulation of the UPR leads to the development of the disease. The UPR and ER stress are involved in several human conditions, such as chronic inflammation, neurodegeneration, metabolic syndrome, and cancer. Furthermore, potent and specific compounds that target the UPR pathway are under development as future therapies. The focus of this review is to thoroughly describe the effects of both internal and external stressors on the ER in asthma. Furthermore, we discuss how the UPR signaling pathway is activated in the lungs to overcome cellular damage. We also present an overview of the pathogenic mechanisms, with a brief focus on potential strategies for pharmacological interventions.
肺细胞不断暴露于破坏蛋白质稳定的各种内部和外部应激物。为了应对这些刺激，细胞引发高度保守的适应性机制，称为未折叠蛋白反应（UPR）。UPR应激源可以对内质网ER施加更大的蛋白质分泌需求，导致这些细胞类型的发育、分化和存活，以满足这些日益增长的功能需求。UPR的失调导致疾病的发展。UPR和ER应激涉及几种人类病症，例如慢性炎症、神经变性代谢综合征和癌症。此外，靶向UPR途径的有效的和特定的化合物正在开发作为未来的疗法。这篇综述的重点是彻底描述内部和外部压力对哮喘ER的影响。此外，我们讨论了UPR信号通路如何在肺中被激活以克服细胞损伤。我们还概述了致病机制，并简要介绍了药物干预的潜在策略。
(中日友好医院呼吸与危重症医学科 张清 摘译 林江涛 审校)
(Am J Respir Cell Mol Biol. 2021 Jan;64(1):29-38. doi: 10.1165/rcmb.2019-0235TR.)
(Am J Respir Cell Mol Biol. 2021 Jan;64(1):29-38. doi: 10.1165/rcmb.2019-0235TR.)
Mechanisms Targeting the Unfolded Protein Response in Asthma
Sanaz Dastghaib, P Sravan Kumar, Sajjad Aftabi, Gautam Damera, Azadeh Dalvand, Adel Sepanjnia, Mohammad Kiumarsi , Mohamad-Reza Aghanoori , Sukhwinder Singh Sohal, Sudharsana R Ande , Javad Alizadeh, Pooneh Mokarram, Saeid Ghavami , Pawan Sharma, Amir A Zeki
Abstract
Lung cells are constantly exposed to various internal and external stressors that disrupt protein homeostasis. To cope with these stimuli, cells evoke a highly conserved adaptive mechanism called the unfolded protein response (UPR). UPR stressors can impose greater protein secretory demands on the endoplasmic reticulum (ER), resulting in the development, differentiation, and survival of these cell types to meet these increasing functional needs. Dysregulation of the UPR leads to the development of the disease. The UPR and ER stress are involved in several human conditions, such as chronic inflammation, neurodegeneration, metabolic syndrome, and cancer. Furthermore, potent and specific compounds that target the UPR pathway are under development as future therapies. The focus of this review is to thoroughly describe the effects of both internal and external stressors on the ER in asthma. Furthermore, we discuss how the UPR signaling pathway is activated in the lungs to overcome cellular damage. We also present an overview of the pathogenic mechanisms, with a brief focus on potential strategies for pharmacological interventions.
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