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 a 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/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 anti-apoptotic mechanism to ameliorate damage, but with the side effect of induction of senescence.

中文翻译：

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p21的激活可限制急性肺损伤并在酸吸入和机械通气后诱发早期衰老

p53 / p21途径响应细胞应激而被激活。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相关，从而导致急性呼吸窘迫综合征（ARDS）。机械通气对于支持ARDS患者的气体交换可能是必要的，但是，高的气道正压会导致肺泡单元区域性过度扩张并加重肺损伤。在这里，我们报道急性肺损伤和肺泡过度伸展激活了p53 / p21途径，以维持体内稳态并避免大量细胞凋亡。来自肺损伤动物模型的转录组数据的系统汇总证明了特定的p53和p21依赖基因签名的丰富性和经过验证的衰老特征。在临床上，在酸吸入和机械通气的小鼠模型中，我们观察到了核膜和潜在染色质的改变，DNA损伤和Tp53 / p21途径的激活。Cdkn1a的缺乏降低了衰老反应，但由于细胞凋亡增加而加重了肺损伤。相反，使用洛匹那韦/利托那韦治疗可导致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的早期标志物相关，包括衰老相关基因的表达以及肺泡细胞中衰老相关异染色质灶的增加。ARDS患者肺部的尸检样本显示，与衰老相关的异染色质病灶增加。总的来说，