The role of adenosine monophosphate-activated protein kinase and serum amyloid A proteins in the early diagnosis of neonatal sepsis
DOI:
https://doi.org/10.15574/SP.2024.5(141).4348Keywords:
neonatal sepsis, adenosine monophosphate-activated protein kinase, serum amyloid A, biomarkers, early diagnosis, C-reactive protein, procalcitoninAbstract
Neonatal sepsis is a leading cause of mortality among newborns globally, with an incidence of 1 per 1,000 live births. Current diagnostic markers such as C-reactive protein (CRP) and procalcitonin (PCT) lack specificity and sensitivity for early diagnosis, highlighting the need for more reliable biomarkers.
The aim of the study is to evaluate the role of adenosine monophosphate-activated protein kinase (AMPK) and serum amyloid A (SAA) proteins as potential biomarkers for the early diagnosis of sepsis in neonates suspected of having the condition.
Materials and methods. A cohort study was conducted involving 143 newborns suspected of sepsis, admitted to the intensive care units within the first 24 hours of life. Clinical evaluations included respiratory distress assessment, chest and abdominal imaging, and brain ultrasound. Blood samples were analyzed for CRP, PCT, AMPK, and SAA levels using enzyme-linked immunosorbent assay (ELISA) kits. Statistical analysis involved Mann-Whitney and independent samples t-tests, as well as receiver operating characteristic (ROC) analysis to determine diagnostic cutoff levels. The nonparametric Spearman rank correlation test (r - the Spearman rank-order correlation coefficient) was used. Differences at p˂0.05 were considered reliable.
Results. Inflammatory markers CRP and PCT were used to confirm sepsis diagnosis in conjunction with clinical assessment. However, 12.8% of infants with PCT >2 ng/mL and 17.5% with CRP >5 mg/mL did not have confirmed sepsis. Conversely, sepsis was confirmed in 63.6% of infants with PCT <2 ng/mL and 53.7% with CRP <5 mg/mL. A significant correlation between AMPK and SAA was observed in 111 infants (r=0.192, p=0.044). The ROC analysis indicated that AMPK and SAA levels below specific thresholds were significant for excluding sepsis.
Conclusion. AMPK and AA levels are promising diagnostic markers for neonatal sepsis, warranting further investigation in larger studies. These biomarkers can improve early diagnosis and reduce unnecessary antibiotic usage, thus improving neonatal outcomes.
The research was carried out in accordance with the principles of the Declaration of Helsinki. The research protocol was approved by the Local Ethics Committee of a participating institution. The informed consent of the patient was obtained for conducting the studies.
No conflict of interests was declared by the authors.
References
Angé M, Castanares-Zapatero D, Bertrand L, Horman S, Beauloye C. (2019, Apr 1). Role of AMP-activated protein kinase in sepsis-induced cardiovascular dysfunction. Am J Physiol Heart Circ Physiol. 316(4): H934-H935. PMID: 30946604. https://doi.org/10.1152/ajpheart.00015.2019
Bergheim I, Luyendyk JP, Steele C, Russell GK, Guo L, Roth RA, Arteel GE. (2006). Metformin prevents endotoxin-induced liver injury after partial hepatectomy. J. Pharmacol. Exp. Ther. 316: 1053-1061. https://doi.org/10.1124/jpet.105.092122
Eichberger J, Resch E, Resch B. (2022, Mar 8). Diagnosis of Neonatal Sepsis: The Role of Inflammatory Markers. Front Pediatr. 10: 840288. https://doi.org/10.3389/fped.2022.840288
Escobar DA, Botero-Quintero AM, Kautza BC, Luciano J, Loughran P, Darwiche S et al. (2015). Adenosine monophosphate-activated protein kinase activation protects against sepsis-induced organ injury and inflammation. J. Surg. Res. 194: 262-272. https://doi.org/10.1016/j.jss.2014.10.009
Gulec GU, Turgut YB, Turgut M. (2022). Acute Phase Proteins. Encyclopedia of infection and İmmunity: 206-211. https://doi.org/10.1016/B978-0-12-818731-9.00089-6
Hattori Y, Suzuki K, Hattori S, Kasai K. (2006). Metformin inhibits cytokine-induced nuclear factor κB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension. 47: 1183-1188. https://doi.org/10.1161/01.HYP.0000221429.94591.72
Hayes R, Hartnett J, Semova G, Murray C, Murphy K, Carroll L et.al. (2023, Apr). Neonatal sepsis definitions from randomised clinical trials. Pediatr Res. 93(5): 1141-1148. Epub 2021 Nov 6. doi: 10.1038/s41390-021-01749-3. Erratum in: Pediatr Res. 2024 Jul 29. PMID: 34743180; PMCID: PMC10132965. https://doi.org/10.1038/s41390-024-03416-9
Hoogendijk AJ, Pinhancos SS, van der Poll T, Wieland CW. (2013). AMP-activated protein kinase activation by 5-aminoimidazole-4-carbox-amide-1-beta-D-ribofuranoside (AICAR) reduces lipoteichoic acid-induced lung inflammation. J. Biol. Chem. 288: 7047-7052. https://doi.org/10.1074/jbc.M112.413138
Jeong HW, Hsu KC, Lee JW, Ham M, Huh JY, Shin HJ et al. (2009). Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Am. J. Physiol. Endocrinol. Metab. 296: E955-E964. https://doi.org/10.1152/ajpendo.90599.2008
Jin K, Ma Y, Manrique-Caballero CL, Li H, Emlet DR, Li S et al. (2020, May). Activation of AMP-activated protein kinase during sepsis/inflammation improves survival by preserving cellular metabolic fitness. FASEB J. 34(5): 7036-7057. Epub 2020 Apr 4. PMID: 32246808.
https://doi.org/10.1096/fj.201901900R
Kim J, Kwak HJ, Cha JY, Jeong YS, Rhee SD, Kim KR, Cheon HG. (2014). Metformin suppresses lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages via activating transcription factor-3 (ATF-3) induction. J. Biol. Chem. 289: 23246-23255. https://doi.org/10.1074/jbc.M114.577908
Liu Z, Bone N, Jiang S, Park DW, Tadie JM, Deshane J et al. (2016). AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3beta Modulate the Severity of Sepsis-Induced Lung Injury. Mol. Med. 21: 937-950. https://doi.org/10.2119/molmed.2015.00198
Mulchandani N, Yang WL, Khan MM, Zhang F, Marambaud P, Nicastro J, Coppa GF, Wang P. (2015) Stimulation of Brain AMP-Activated Protein Kinase Attenuates Inflammation and Acute Lung Injury in Sepsis. Mol Med. 30;21(1):637-44. https://doi.org/10.2119/molmed.2015.00179
Mukhopadhyay S, Puopolo KM, Hansen NI, Lorch SA, DeMauro SB, Greenberg RG, et al. NICHD Neonatal Research Network. Neurodevelopmental outcomes following neonatal late-onset sepsis and blood culture-negative conditions. Arch Dis Child Fetal Neonatal Ed. 2021 Sep;106(5):467-473. https://doi.org/10.1136/archdischild-2020-320664
Park DW, Jiang S, Tadie JM, Stigler WS, Gao Y, Deshane J et al. (2013). Activation of AMPK enhances neutrophil chemotaxis and bacterial killing. Mol. Med. 19: 387-398. https://doi.org/10.2119/molmed.2013.00065
Sag D, Carling D, Stout RD, Suttles J. (2008). Adenosine 50 -monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J. Immunol. 181: 8633-8641. https://doi.org/10.4049/jimmunol.181.12.8633
Shintani Y, Kapoor A, Kaneko M, Smolenski RT, D'Acquisto F, Coppen SR et al. (2013). TLR9 mediates cellular protection by modulating energy metabolism in cardiomyocytes and neurons. Proc. Natl. Acad. Sci. USA. 110: 5109-5114. https://doi.org/10.1073/pnas.1219243110
Su M, Zhang L. (2022, Jun 29). Research status of serum amyloid A in infection: a bibliometric analysis. Annals of Palliative Medicine. 11(6). https://doi.org/10.21037/apm-22-487
Vaez H, Rameshrad M, Najafi M, Barar J, Barzegari A, Garjani A. (2016). Cardioprotective effect of metformin in lipopolysaccharide-induced sepsis via suppression of toll-like receptor 4 (TLR4) in heart. Eur. J. Pharmacol. 772: 115-123. https://doi.org/10.1016/j.ejphar.2015.12.030
Wasyluk W, Zwolak A. (2021, May 29). Metabolic Alterations in Sepsis. J Clin Med. 10 (11): 2412. PMID: 34072402; PMCID: PMC8197843. https://doi.org/10.3390/jcm10112412
Webb NR. (2021, Jan 15). High-Density Lipoproteins and Serum Amyloid A (SAA). Curr Atheroscler Rep. 23(2): 7. doi: 10.1007/s11883-020-00901-4. Erratum in: Curr Atheroscler Rep. 2022 Jan; 24(1): 73. PMID: 33447953; PMCID: PMC7808882. https://doi.org/10.1007/s11883-022-01005-x
WHO. (2020).Target product profile for therapy of neonatal sepsis in high resistance settings. Geneva: World Health Organization. URL: https://www.who.int/publications/i/item/9789240003859.
Wilkinson ThS. (2022). İmmunity to Bacterial infections. Encyclopedia of infection and Immunity. https://doi.org/10.1016/B978-0-12-818731-9.00208-1
Xing J, Wang Q, Coughlan K, Viollet B, Moriasi C, Zou MH. (2013). Inhibition of AMP-activated protein kinase accentuates lipopolysaccharide-induced lung endothelial barrier dysfunction and lung injury in vivo. Am. J. Pathol. 182: 1021-1030. https://doi.org/10.1016/j.ajpath.2012.11.022
Yahia Sohiera, El-Assmy Mohamed M, Eldars Waleedb, Mahmoud Marwaa et al. (2019, Oct-Dec). Serum amyloid A versus C-reactive protein in sepsis: new insights in an Egyptian ICU. Research and Opinion in Anesthesia and Intensive Care. 6(4): 429-432. https://doi.org/10.4103/roaic.roaic_58_19
Yu H, Liu Q, Chen G, Huang L, Luo M, Lv D, Luo S. (2022, May). SIRT3-AMPK signaling pathway as a protective target in endothelial dysfunction of early sepsis. Int Immunopharmacol. 106: 108600. https://doi.org/10.1016/j.intimp.2022.108600
Yuan H, Huang J, Lv B, Yan W, Hu G, Wang J, Shen B. (2013). Diagnosis value of the serum amyloid A test in neonatal sepsis: a meta-analysis. Biomed Res Int. 2013: 520294. Epub 2013 Aug 5. PMID: 23984377; PMCID: PMC3747616. https://doi.org/10.1155/2013/520294
Zhang H, Feng YW, Yao YM. (2018, Nov 26). Potential therapy strategy: targeting mitochondrial dysfunction in sepsis. Mil Med Res. 5(1): 41. PMID: 30474573; PMCID: PMC6260865. https://doi.org/10.1186/s40779-018-0187-0
Zhao X, Zmijewski JW, Lorne E, Liu G, Park YJ, Tsuruta Y, Abraham E. (2008). Activation of AMPK attenuates neutrophil proinflammatory activity and decreases the severity of acute lung injury. Am. J. Physiol. Lung Cell Mol. Physiol. 295: L497-L504. https://doi.org/10.1152/ajplung.90210.2008
Zmijewski JW, Lorne E, Zhao X, Tsuruta Y, Sha Y, Liu G et al. (2008). Mitochondrial respiratory complex I regulates neutrophil activation and severity of lung injury. Am. J. Respir. Crit. Care Med. 178: 168-179. https://doi.org/10.1164/rccm.200710-1602OC
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