Instituto de Investigación Sanitaria del Principado de Asturias. Oviedo, Spain.
Instituto de Investigación Sanitaria del Principado de Asturias. Oviedo, Spain; Centro de Investigación Biomédica en Red (CIBER)-Enfermedades Respiratorias. Madrid, Spain.
Transl Res. 2021 Jul;233:104-116. doi: 10.1016/j.trsl.2021.01.008. Epub 2021 Jan 27.
The p53/p21 pathway is activated in response to cell stress. However, its role in acute lung injury has not been elucidated. Acute lung injury is associated with disruption of the alveolo-capillary barrier leading to acute respiratory distress syndrome (ARDS). Mechanical ventilation may be necessary to support gas exchange in patients with ARDS, however, high positive airway pressures can cause regional overdistension of alveolar units and aggravate lung injury. Here, we report that acute lung injury and alveolar overstretching activate the p53/p21 pathway to maintain homeostasis and avoid massive cell apoptosis. A systematic pooling of transcriptomic data from animal models of lung injury demonstrates the enrichment of specific p53- and p21-dependent gene signatures and a validated senescence profile. In a clinically relevant, murine model of acid aspiration and mechanical ventilation, we observed changes in the nuclear envelope and the underlying chromatin, DNA damage and activation of the Tp53/p21 pathway. Absence of Cdkn1a decreased the senescent response, but worsened lung injury due to increased cell apoptosis. Conversely, treatment with lopinavir and/or ritonavir led to Cdkn1a overexpression and ameliorated cell apoptosis and lung injury. The activation of these mechanisms was associated with early markers of senescence, including expression of senescence-related genes and increases in senescence-associated heterochromatin foci in alveolar cells. Autopsy samples from lungs of patients with ARDS revealed increased senescence-associated heterochromatin foci. Collectively, these results suggest that acute lung injury activates p53/p21 as an antiapoptotic mechanism to ameliorate damage, but with the side effect of induction of senescence.
p53/p21 通路在细胞应激时被激活。然而，其在急性肺损伤中的作用尚未阐明。急性肺损伤与肺泡毛细血管屏障的破坏有关，导致急性呼吸窘迫综合征（ARDS）。机械通气可能是 ARDS 患者支持气体交换所必需的，但是，高正压通气可能导致肺泡单位的局部过度扩张并加重肺损伤。在这里，我们报告急性肺损伤和肺泡过度拉伸激活 p53/p21 通路以维持内稳态并避免大量细胞凋亡。对肺损伤动物模型的转录组数据进行系统汇总表明，特定的 p53 和 p21 依赖性基因特征和经过验证的衰老特征丰富。在酸吸入和机械通气的临床相关鼠模型中，我们观察到核膜和基础染色质、DNA 损伤和 Tp53/p21 通路的激活发生变化。Cdkn1a 的缺失减少了衰老反应，但由于细胞凋亡增加，肺损伤恶化。相反，洛匹那韦和/或利托那韦的治疗导致 Cdkn1a 过表达，并改善细胞凋亡和肺损伤。这些机制的激活与衰老相关的早期标志物相关，包括衰老相关基因的表达和肺泡细胞中衰老相关异染色质焦点的增加。ARDS 患者肺的尸检样本显示出增加的衰老相关异染色质焦点。总之，这些结果表明，急性肺损伤激活 p53/p21 作为一种抗细胞凋亡机制来减轻损伤，但副作用是诱导衰老。
