UCD Clinical Research Centre, Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland.
Int J Mol Sci. 2023 Apr 4;24(7):6737. doi: 10.3390/ijms24076737.
Organ fibrosis represents a dysregulated, maladaptive wound repair response that results in progressive disruption of normal tissue architecture leading to detrimental deterioration in physiological function, and significant morbidity/mortality. Fibrosis is thought to contribute to nearly 50% of all deaths in the Western world with current treatment modalities effective in slowing disease progression but not effective in restoring organ function or reversing fibrotic changes. When physiological wound repair is complete, myofibroblasts are programmed to undergo cell death and self-clearance, however, in fibrosis there is a characteristic absence of myofibroblast apoptosis. It has been shown that in fibrosis, myofibroblasts adopt an apoptotic-resistant, highly proliferative phenotype leading to persistent myofibroblast activation and perpetuation of the fibrotic disease process. Recently, this pathological adaptation has been linked to dysregulated expression of tumour suppressor gene p53. In this review, we discuss p53 dysregulation and apoptotic failure in myofibroblasts and demonstrate its consistent link to fibrotic disease development in all types of organ fibrosis. An enhanced understanding of the role of p53 dysregulation and myofibroblast apoptosis may aid in future novel therapeutic and/or diagnostic strategies in organ fibrosis.
器官纤维化代表一种失调的、适应性不良的创伤修复反应，导致正常组织结构的进行性破坏，从而导致生理功能的严重恶化和显著的发病率/死亡率。纤维化被认为导致了西方世界近 50%的死亡，目前的治疗方法虽然能有效减缓疾病的进展，但不能有效恢复器官功能或逆转纤维化的变化。当生理创伤修复完成后，肌成纤维细胞被编程进行细胞死亡和自我清除，然而，在纤维化中，肌成纤维细胞的凋亡明显缺失。研究表明，在纤维化中，肌成纤维细胞采用一种抗凋亡、高增殖的表型，导致持续的肌成纤维细胞激活和纤维化疾病过程的持续。最近，这种病理适应性与肿瘤抑制基因 p53 的失调表达有关。在这篇综述中，我们讨论了肌成纤维细胞中 p53 的失调和凋亡失败，并证明了它与所有类型的器官纤维化的纤维化疾病发展之间的一致联系。对 p53 失调和肌成纤维细胞凋亡的作用的深入了解可能有助于未来在器官纤维化方面的新型治疗和/或诊断策略。
