Mechanical Ventilation induced DNA Damage and P21 in an Acute Aging Model of Lung Injury
Abstract Acute respiratory distress syndrome (ARDS) is a form of acute lung injury which leads to a paucity of oxygen. To remedy ARDS, patients are put on mechanical ventilators; however, the stretch resulting from the mechanical ventilator can lead to ventilator-induced lung injury or VILI. VILI is exacerbated by age. The combined effects of ARDS and mechanical ventilation can result in a hostile environment which may lead to senescence (stable cell cycle arrest). The role of senescence in VILI is poorly understood. Senescence is characterized by increased cyclin-dependent kinase inhibitors P16 and P21; however, P21 has been shown to occur in early senescence. We hypothesized that mechanical ventilation would lead to DNA damage and senescence-like phenotype. Both in vivo and in vitro models of VILI were used to investigate senescence and its mechanism in VILI. Mechanical ventilation increased senescence-associated markers such as DNA damage marker characterized by ɣH2AX, P21, senescence-associated secretory phenotype IL6, and decreased proliferation. Moreover, mechanical ventilation led to increased apoptosis. Lung sections were stained for KRT8 proteins, markers of transiently differentiated alveolar type 2 (AT2) cells which were reported to be more prone to DNA damage. Age and mechanical ventilation increased KRT8 positive cells. Finally, we probed a potential mediator of the stretch induced senescence in vitro by inhibiting P38-MAPK, which can be activated by DNA damage response, leading to increased P21. Inhibiting P38 decreased in P21 but did not decrease ɣH2AXThese findings suggest that mechanical ventilation may lead to a senescence-like phenotype involving the P38-MAPK pathway..
Medienart: |
Preprint |
---|
Erscheinungsjahr: |
2022 |
---|---|
Erschienen: |
2022 |
Enthalten in: |
bioRxiv.org - (2022) vom: 10. März Zur Gesamtaufnahme - year:2022 |
---|
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Kamga Gninzeko, Franck J. [VerfasserIn] |
---|
Links: |
Volltext [kostenfrei] |
---|
doi: |
10.1101/2022.03.08.483505 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
XBI035439033 |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | XBI035439033 | ||
003 | DE-627 | ||
005 | 20230429082817.0 | ||
007 | cr uuu---uuuuu | ||
008 | 220310s2022 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1101/2022.03.08.483505 |2 doi | |
035 | |a (DE-627)XBI035439033 | ||
035 | |a (biorXiv)10.1101/2022.03.08.483505 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
082 | 0 | |a 570 |q DE-84 | |
100 | 1 | |a Kamga Gninzeko, Franck J. |e verfasserin |4 aut | |
245 | 1 | 0 | |a Mechanical Ventilation induced DNA Damage and P21 in an Acute Aging Model of Lung Injury |
264 | 1 | |c 2022 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a Computermedien |b c |2 rdamedia | ||
338 | |a Online-Ressource |b cr |2 rdacarrier | ||
520 | |a Abstract Acute respiratory distress syndrome (ARDS) is a form of acute lung injury which leads to a paucity of oxygen. To remedy ARDS, patients are put on mechanical ventilators; however, the stretch resulting from the mechanical ventilator can lead to ventilator-induced lung injury or VILI. VILI is exacerbated by age. The combined effects of ARDS and mechanical ventilation can result in a hostile environment which may lead to senescence (stable cell cycle arrest). The role of senescence in VILI is poorly understood. Senescence is characterized by increased cyclin-dependent kinase inhibitors P16 and P21; however, P21 has been shown to occur in early senescence. We hypothesized that mechanical ventilation would lead to DNA damage and senescence-like phenotype. Both in vivo and in vitro models of VILI were used to investigate senescence and its mechanism in VILI. Mechanical ventilation increased senescence-associated markers such as DNA damage marker characterized by ɣH2AX, P21, senescence-associated secretory phenotype IL6, and decreased proliferation. Moreover, mechanical ventilation led to increased apoptosis. Lung sections were stained for KRT8 proteins, markers of transiently differentiated alveolar type 2 (AT2) cells which were reported to be more prone to DNA damage. Age and mechanical ventilation increased KRT8 positive cells. Finally, we probed a potential mediator of the stretch induced senescence in vitro by inhibiting P38-MAPK, which can be activated by DNA damage response, leading to increased P21. Inhibiting P38 decreased in P21 but did not decrease ɣH2AXThese findings suggest that mechanical ventilation may lead to a senescence-like phenotype involving the P38-MAPK pathway. | ||
700 | 1 | |a Tho, Cindy K. |e verfasserin |4 aut | |
700 | 1 | |a Valentine, Michael S. |e verfasserin |4 aut | |
700 | 1 | |a Wandling, Emily N. |e verfasserin |4 aut | |
700 | 1 | |a Heise, Rebecca L. |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2022) vom: 10. März |
773 | 1 | 8 | |g year:2022 |g day:10 |g month:03 |
856 | 4 | 0 | |u http://dx.doi.org/10.1101/2022.03.08.483505 |z kostenfrei |3 Volltext |
912 | |a GBV_XBI | ||
912 | |a SSG-OLC-PHA | ||
951 | |a AR | ||
952 | |j 2022 |b 10 |c 03 | ||
953 | |2 045F |a 570 |