Attenuation of acute kidney injury in a murine model of neonatal Escherichia coli sepsis
IntroductionSepsis 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 anti...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcimb.2024.1507914/full |
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| author | Esther M. Speer Atilade A. Adedeji Joyce Lin Alexandra Khorasanchi Asma Rasheed Maya Bhat Kelly Mackenzie Randolph Hennigar Kimberly J. Reidy Robert P. Woroniecki |
| author_facet | Esther M. Speer Atilade A. Adedeji Joyce Lin Alexandra Khorasanchi Asma Rasheed Maya Bhat Kelly Mackenzie Randolph Hennigar Kimberly J. Reidy Robert P. Woroniecki |
| author_sort | Esther M. Speer |
| collection | DOAJ |
| description | IntroductionSepsis 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.MethodsPostnatal (PN) day 1 C57BL/6J mice were injected with E. coli K1 strain at 105 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.ResultsSeptic 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.ConclusionNeonatal 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. |
| format | Article |
| id | doaj-art-895589d7f1dd4cbc8a494307b46479f4 |
| institution | Kabale University |
| issn | 2235-2988 |
| language | English |
| publishDate | 2025-02-01 |
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| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj-art-895589d7f1dd4cbc8a494307b46479f42025-02-03T06:33:38ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882025-02-011410.3389/fcimb.2024.15079141507914Attenuation of acute kidney injury in a murine model of neonatal Escherichia coli sepsisEsther M. Speer0Atilade A. Adedeji1Joyce Lin2Alexandra Khorasanchi3Asma Rasheed4Maya Bhat5Kelly Mackenzie6Randolph Hennigar7Kimberly J. Reidy8Robert P. Woroniecki9Department of Pediatrics, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, United StatesDepartment of Pediatrics, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, United StatesDepartment of Pediatrics, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, United StatesDepartment of Pediatrics, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, United StatesDepartment of Pediatrics, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, United StatesDepartment of Pediatrics, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, United StatesDepartment of Chemistry, Stony Brook University, Stony Brook, NY, United StatesDepartment of Pathology, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, United StatesDivision of Pediatric Nephrology, Department of Pediatrics, Children’s Hospital at Montefiore, Bronx, NY, United StatesDepartment of Pediatrics, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, United StatesIntroductionSepsis 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.MethodsPostnatal (PN) day 1 C57BL/6J mice were injected with E. coli K1 strain at 105 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.ResultsSeptic 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.ConclusionNeonatal 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.https://www.frontiersin.org/articles/10.3389/fcimb.2024.1507914/fullneonatal sepsisacute kidney injury (AKI)inflammatory responsekidney injury markersanti-inflammatory agentspentoxifylline |
| spellingShingle | Esther M. Speer Atilade A. Adedeji Joyce Lin Alexandra Khorasanchi Asma Rasheed Maya Bhat Kelly Mackenzie Randolph Hennigar Kimberly J. Reidy Robert P. Woroniecki Attenuation of acute kidney injury in a murine model of neonatal Escherichia coli sepsis Frontiers in Cellular and Infection Microbiology neonatal sepsis acute kidney injury (AKI) inflammatory response kidney injury markers anti-inflammatory agents pentoxifylline |
| title | Attenuation of acute kidney injury in a murine model of neonatal Escherichia coli sepsis |
| title_full | Attenuation of acute kidney injury in a murine model of neonatal Escherichia coli sepsis |
| title_fullStr | Attenuation of acute kidney injury in a murine model of neonatal Escherichia coli sepsis |
| title_full_unstemmed | Attenuation of acute kidney injury in a murine model of neonatal Escherichia coli sepsis |
| title_short | Attenuation of acute kidney injury in a murine model of neonatal Escherichia coli sepsis |
| title_sort | attenuation of acute kidney injury in a murine model of neonatal escherichia coli sepsis |
| topic | neonatal sepsis acute kidney injury (AKI) inflammatory response kidney injury markers anti-inflammatory agents pentoxifylline |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2024.1507914/full |
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