Abstract
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, p = 0.0037). In comparison, loss of PAI-1 at young age had negligible effects on sepsis survival (86% vs. 88% survival, p = 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.
Document Type
Article
Publication Date
1-2024
Digital Object Identifier (DOI)
https://doi.org/10.3389/fcell.2023.1330433
Funding Information
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the National Institute of General Medical Sciences within the National Institutes of Heath under award number R01 GM129532 awarded to MES. Additional support was provided by the Biospecimen Procurement and Translational Pathology Shared Resource of the University of Kentucky Markey Cancer Center under grant P30 CA177558, and by R01 AA028735-04S2.
Repository Citation
Bruno, Maria E. C.; Mukherjee, Sujata; Sturgill, Jamie L.; Cornea, Virgilius; Yeh, Peng; Hawk, Gregory S.; Saito, Hiroshi; and Starr, Marlene E., "PAI-1 as a critical factor in the resolution of sepsis and acute kidney injury in old age" (2024). Markey Cancer Center Faculty Publications. 375.
https://uknowledge.uky.edu/markey_facpub/375
Notes/Citation Information
© 2024 Bruno, Mukherjee, Sturgill, Cornea, Yeh, Hawk, Saito and Starr. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.