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ORIGINAL RESEARCH article

Front. Cell. Infect. Microbiol.
Sec. Molecular Bacterial Pathogenesis
Volume 14 - 2024 | doi: 10.3389/fcimb.2024.1507914
This article is part of the Research Topic Advancing Understanding of Neonatal Bacterial Infections View all articles

Journal: Frontiers in Cellular & Infection Microbiology Frontiers Research Topic: Neonatal Bacterial Infections Article Type: Original Research Title: Attenuation of acute kidney injury in a murine model of neonatal Escherichia coli sepsis

Provisionally accepted
Esther M Speer Esther M Speer 1*Atilade A Adedeji Atilade A Adedeji 1Joyce Lin Joyce Lin 1Alexandra Khorasanchi Alexandra Khorasanchi 1Asma Rasheed Asma Rasheed 1Maya Bhat Maya Bhat 1Kelly Mackenzie Kelly Mackenzie 2Kimberly Jean Reidy Kimberly Jean Reidy 3Robert P Woroniecki Robert P Woroniecki 1
  • 1 Pediatrics, Stony Brook University, Stony Brook, United States
  • 2 Chemistry, Stony Brook University, Stony Brook, United States
  • 3 Pediatrics, Children's Hospital at Montefiore, New York, New York, United States

The final, formatted version of the article will be published soon.

    Introduction: Sepsis is a risk factor for acute kidney injury (AKI) in neonates, for which no effective treatment exists. The phosphodiesterase inhibitor pentoxifylline (PTX) has demonstrated renal protection from ischemia and inflammation in adult rodents. We hypothesized that addition of PTX to antibiotics may attenuate immune and histological AKI in a murine neonatal sepsis model. Methods: Postnatal (PN) day 1 C57BL/6J mice were injected with E. coli K1 strain at 10 5 colony forming units per gram weight or saline control. After 1.5 hours, septic pups randomly received saline, gentamicin or cefotaxime, with/without PTX. 5.5h after sepsis initiation, kidneys and blood were harvested for measurements of biomarkers of inflammation and kidney injury. Renal sections from PN7 mice were used for histology and immunofluorescence. Linear mixed effect models were employed to fit the outcomes including interaction between treatment group and sex. Results: Septic mice demonstrated robust expression of pro-inflammatory cytokines, chemokines and biomarkers of tubular injury in renal tissue, which were attenuated in response to combined PTX and antibiotics (gentamicin or cefotaxime): chemokines (p<0.001), plasma (p<0.01) and tissue IL-6 (p<0.05), plasma TNF (p<0.001), NGAL (p<0.01), CXCL10 (p<0.01), osteopontin (p<0.05), and VEGF (p<0.05), with a trend for KIM-1 (tissue concentration: p=0.21, fluorescence area: p=0.12). Interactions between treatment and sex were present for several cytokines and kidney injury biomarkers. Immunofluorescence findings for the tubular injury markers (NGAL and KIM-1) were consistent with biomarker expression in tissue lysates. Conclusion: Neonatal E. coli sepsis leads to increased expression of renal tissue inflammation and injury biomarkers consistent with AKI, which may be attenuated with PTX combined with antibiotic treatment.

    Keywords: Neonatal sepsis, acute kidney injury (AKI), Inflammatory Response, kidney injury markers, Antiinflammatory agents, Pentoxifylline, Escherichia coli sepsis

    Received: 08 Oct 2024; Accepted: 23 Dec 2024.

    Copyright: © 2024 Speer, Adedeji, Lin, Khorasanchi, Rasheed, Bhat, Mackenzie, Reidy and Woroniecki. 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) or licensor 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.

    * Correspondence: Esther M Speer, Pediatrics, Stony Brook University, Stony Brook, United States

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