Directed Transport of CRP Across In Vitro Models of the Blood-Saliva Barrier Strengthens the Feasibility of Salivary CRP as Biomarker for Neonatal Sepsis.

Grace C Lin,Angelika Berger,Lynne Bingle,Erik Küng,Lukas Wisgrill,Sandra Domazet,Johannes R Peham,Winfried Neuhaus,Heinz P Friedl,Joachim Angerer,Merima Smajlhodzic

doi:10.3390/pharmaceutics13020256

Grace C Lin, Angelika Berger + Show 9 more

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https://doi.org/10.3390/pharmaceutics13020256

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Abstract

C-reactive protein (CRP) is a commonly used serum biomarker for detecting sepsis in neonates. After the onset of sepsis, serial measurements are necessary to monitor disease progression; therefore, a non-invasive detection method is beneficial for neonatal well-being. While some studies have shown a correlation between serum and salivary CRP levels in septic neonates, the causal link behind this correlation remains unclear. To investigate this relationship, CRP was examined in serum and saliva samples from 18 septic neonates and compared with saliva samples from 22 healthy neonates. While the measured blood and saliva concentrations of the septic neonates varied individually, a correlation of CRP levels between serum and saliva samples was observed over time. To clarify the presence of active transport of CRP across the blood–salivary barrier (BSB), transport studies were performed with CRP using in vitro models of oral mucosa and submandibular salivary gland epithelium. The results showed enhanced transport toward saliva in both models, supporting the clinical relevance for salivary CRP as a biomarker. Furthermore, CRP regulated the expression of the receptor for advanced glycation end products (RAGE) and the addition of soluble RAGE during the transport studies indicated a RAGE-dependent transport process for CRP from blood to saliva.

Highlights

First clinical studies using C-reactive protein (CRP) as biomarker to detect bacterial infections were performed in the late 1980s, and CRP was used in the 1990s for detection of septic neonates showing promising clinical usage of CRP for diagnosis of neonatal sepsis [36,37,38,39]
Patients with samples drawn at several time points (Figure 1B) in this study showed a median ratio between salivary and serum concentration of 1600 (5300 ± 10,100, mean ± SD) similar to the ratio found in a clinical study with 61 healthy volunteers by Ouellet-Morin et al [23] reporting a ratio of 1633
In this study on measurement of serum and salivary CRP levels, clinical data suggest that studying individual ratios and progression is more useful than relying on the measurement of a single time-point

Summary

Introduction

Licensee MDPI, Basel, Switzerland.Attribution (CC BY) license (https://creativecommons.org/licenses/by/ 4.0/).Neonatal sepsis and other neonatal infections account for 0.88% of all disability adjusted life years worldwide, demonstrating similar percentages compared with motor vehicle road injuries (0.98%) and asthma (0.91%) [1]. Neonatal infections are associated with a high mortality [2], brain injury [3], and poor neurodevelopmental outcome in early childhood [4]. Preterm infants are particularly vulnerable to infections and sepsis due to multiple factors such as prematurity, immature host defense mechanisms, frequently used antibiotics combined with invasive interventions, and prolonged stay in the neonatal intensive care unit. Furthermore, clinical signs and symptoms of neonatal sepsis are Pharmaceutics 2021, 13, 256. https://doi.org/10.3390/pharmaceutics13020256 https://www.mdpi.com/journal/pharmaceutics

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