Details

Autor(en) / Beteiligte

• Bruno, Maria E C
• Mukherjee, Sujata
• Sturgill, Jamie L
• Cornea, Virgilius
• Yeh, Peng
• Hawk, Gregory S
• Saito, Hiroshi
• Starr, Marlene E

Titel

PAI-1 as a critical factor in the resolution of sepsis and acute kidney injury in old age

Ist Teil von

• Frontiers in cell and developmental biology, 2024-01, Vol.11, p.1330433

Ort / Verlag

Switzerland: Frontiers Media S.A

Erscheinungsjahr

2024

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Elevated plasma levels of plasminogen activator inhibitor type 1 (PAI-1) are documented in patients with sepsis and levels positively correlate with disease severity and mortality. Our prior work demonstrated that PAI-1 in plasma is positively associated with acute kidney injury (AKI) in septic patients and mice. The objective of this study was to determine if PAI-1 is causally related to AKI and worse sepsis outcomes using a clinically-relevant and age-appropriate murine model of sepsis. Sepsis was induced by cecal slurry (CS)-injection to wild-type (WT, C57BL/6) and PAI-1 knockout (KO) mice at young (5-9 months) and old (18-22 months) age. Survival was monitored for at least 10 days or mice were euthanized for tissue collection at 24 or 48 h post-insult. Contrary to our expectation, PAI-1 KO mice at old age were significantly more sensitive to CS-induced sepsis compared to WT mice (24% vs. 65% survival, = 0.0037). In comparison, loss of PAI-1 at young age had negligible effects on sepsis survival (86% vs. 88% survival, = 0.8106) highlighting the importance of age as a biological variable. Injury to the kidney was the most apparent pathological consequence and occurred earlier in aged PAI-1 KO mice. Coagulation markers were unaffected by loss of PAI-1, suggesting thrombosis-independent mechanisms for PAI-1-mediated protection. In summary, although high PAI-1 levels are clinically associated with worse sepsis outcomes, loss of PAI-1 rendered mice more susceptible to kidney injury and death in a CS-induced model of sepsis using aged mice. These results implicate PAI-1 as a critical factor in the resolution of sepsis in old age.