Transdisciplinary Institute for Research and Innovation in Health Sciences/Institute for Research in Chronic-Degenerative Diseases, Department of Molecular Biology and Genomics, University Campus for Health Sciences, University of Guadalajara, Guadalajara, Jalisco, Mexico.
Histol Histopathol. 2024 Jul;39(7):805-816. doi: 10.14670/HH-18-699. Epub 2023 Dec 28.
The aim of this review is to update and synthesize the molecular mechanisms that lead to the heterogeneous effect on tissue remodeling observed in the two most important clinical phenotypes of chronic obstructive pulmonary disease (COPD), pulmonary emphysema (PE) and chronic bronchitis (CB). Clinical and experimental evidence suggests that this heterogeneous response to promote PE, CB, or both, is related to differentiated genetic, epigenetic, and molecular conditions. Specifically, a tendency toward PE could be related to a variant in the gene, SIRT1 downregulation, macrophage polarization to M1, as well as the involvement of the noncanonical Wnt5A signaling pathway, among other alterations. Additionally, in advanced stages of COPD, PE development is potentiated by dysregulations in autophagy, which promotes senescence and subsequently cell apoptosis, through exacerbated inflammasome activation and release of caspases. On the other hand, CB or the pro-fibrotic phenotype could be potentiated by the downregulated activity of HDAC2, the activation of the TGF-β/Smad or Wnt/β-catenin signaling pathways, macrophage polarization to M2, upregulation of TIMP-1, and/or the presence of the epithelial-mesenchymal transition (EMT) mechanism. Interestingly, the upregulated activity of MMPs, especially MMP-9, is widely involved in the development of both phenotypes. Furthermore, MMP-9 and MMP-12 enhance the severity, perpetuation, and exacerbation of COPD, as well as the development of autoimmunity in this disease.
这篇综述的目的是更新和综合导致慢性阻塞性肺疾病（COPD）两种最重要的临床表型（肺气肿[PE]和慢性支气管炎[CB]）中观察到的组织重塑异质性效应的分子机制。临床和实验证据表明，这种促进 PE、CB 或两者的异质性反应与分化的遗传、表观遗传和分子条件有关。具体来说，PE 的倾向可能与基因中的变体、SIRT1 下调、巨噬细胞向 M1 极化以及非经典 Wnt5A 信号通路的参与等改变有关。此外，在 COPD 的晚期，自噬失调会增强 PE 的发展，通过炎症小体的过度激活和半胱天冬酶的释放，促进衰老和随后的细胞凋亡。另一方面，CB 或促纤维化表型可能会因 HDAC2 活性下调、TGF-β/Smad 或 Wnt/β-catenin 信号通路激活、巨噬细胞向 M2 极化、TIMP-1 上调以及/或上皮-间充质转化（EMT）机制的存在而增强。有趣的是，MMPs 的上调活性，特别是 MMP-9，广泛参与两种表型的发展。此外，MMP-9 和 MMP-12 增强了 COPD 的严重程度、持续性和恶化，以及该疾病中自身免疫的发展。
