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1.
Transl Res ; 233: 104-116, 2021 07.
Article in English | MEDLINE | ID: covidwho-1051128

ABSTRACT

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.


Subject(s)
Acute Lung Injury/metabolism , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Acids/administration & dosage , Acids/toxicity , Acute Lung Injury/etiology , Acute Lung Injury/pathology , Animals , Apoptosis , Cellular Senescence , Cyclin-Dependent Kinase Inhibitor p21/deficiency , Cyclin-Dependent Kinase Inhibitor p21/genetics , DNA Damage , Disease Models, Animal , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Respiration, Artificial/adverse effects , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/pathology , Signal Transduction , Stress, Mechanical , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
2.
Biochem Biophys Res Commun ; 553: 25-29, 2021 05 14.
Article in English | MEDLINE | ID: covidwho-1147359

ABSTRACT

The current COVID-19 pandemic is caused by infections with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A sex-bias has been observed, with increased susceptibility and mortality in male compared to female patients. The gene for the SARS-CoV-2 receptor ACE2 is located on the X chromosome. We previously generated TP53 mutant pigs that exhibit a sex-specific patho-phenotype due to altered regulation of numerous X chromosome genes. In this study, we explored the effect of p53 deficiency on ACE2 expression in pigs. First, we identified the p53 binding site in the ACE2 promoter and could show its regulatory effect on ACE2 expression by luciferase assay in porcine primary kidney fibroblast cells. Later, quantitative PCR and western blot showed tissue- and gender-specific expression changes of ACE2 and its truncated isoform in p53-deficient pigs. We believe these findings will broaden the knowledge on ACE2 regulation and COVID-19 susceptibility.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Gene Expression Regulation , Organ Specificity , Sex Characteristics , Sus scrofa/metabolism , Tumor Suppressor Protein p53/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Animals , Base Sequence , Binding Sites , COVID-19/metabolism , COVID-19/virology , Disease Models, Animal , Female , Fibroblasts , Gene Deletion , Male , Promoter Regions, Genetic/genetics , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Protein p53/genetics , X Chromosome/genetics
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