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Exploring Clinically-Relevant Experimental Models of Neonatal Shock and Necrotizing Enterocolitis.

ABSTRACT: Neonatal shock and necrotizing enterocolitis (NEC) are leading causes of morbidity and mortality in premature infants. NEC is a life-threatening gastrointestinal illness, the precise etiology of which is not well understood, but is characterized by an immaturity of the intestinal barrier, altered function of the adaptive immune system, and intestinal dysbiosis. The complexities of NEC and shock in the neonatal population necessitate relevant clinical modeling using newborn animals that mimic the disease in human neonates to better elucidate the pathogenesis and provide an opportunity for the discovery of potential therapeutics. A wide variety of animal species-including rats, mice, piglets, and primates-have been used in developing experimental models of neonatal diseases such as NEC and shock. This review aims to highlight the immunologic differences in neonates compared with adults and provide an assessment of the advantages and drawbacks of established animal models of both NEC and shock using enteral or intraperitoneal induction of bacterial pathogens. The selection of a model has benefits unique to each type of animal species and provides individual opportunities for the development of targeted therapies. This review discusses the clinical and physiologic relevance of animal models and the insight they contribute to the complexities of the specific neonatal diseases: NEC and shock.

SUBMITTER: Nolan LS

PROVIDER: S-EPMC7376956 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNecrotizing enterocolitis (NEC) is an inflammatory gastrointestinal disease primarily affecting preterm neonates. Neonates with NEC suffer from a degree of neurodevelopmental delay that is not explained by prematurity alone. There is a need to understand the pathogenesis of neurodevelopmental delay in NEC. In this study, we assessed the macroscopic and microscopic changes that occur to brain cell populations in specific brain regions in a neonatal mouse model of NEC. Moreover, we investigated the role of intestinal inflammation as part of the mechanism responsible for the changes observed in the brain of pups with NEC.MethodsBrains of mice were assessed for gross morphology and cerebral cortex thickness (using histology). Markers for mature neurons, oligodendrocytes, neural progenitor cells, microglia, and astrocytes were used to quantify their cell populations in different regions of the brain. Levels of cell apoptosis in the brain were measured by Western blotting and immunohistochemistry. Endoplasmic reticulum (ER) stress markers and levels of pro-inflammatory cytokines (in the ileum and brain) were measured by RT-qPCR and Western blotting. A Pearson test was used to correlate the levels of cytokines (ELISA) in the brain and ileum and to correlate activated microglia and astrocyte populations to the severity of NEC.ResultsNEC pups had smaller brain weights, higher brain-to-body weight ratios, and thinner cortices compared to control pups. NEC pups had increased levels of apoptosis and ER stress. In addition, NEC was associated with a reduction in the number of neurons, oligodendrocytes, and neural progenitors in specific regions of the brain. Levels of pro-inflammatory cytokines and the density of activated microglia and astrocytes were increased in the brain and positively correlated with the increase in the levels pro-inflammatory cytokines in the gut and the severity of NEC damage respectively.ConclusionsNEC is associated with severe changes in brain morphology, a pro-inflammatory response in the brain that alters cell homeostasis and density of brain cell populations in specific cerebral regions. We show that the severity of neuroinflammation is associated with the severity of NEC. Our findings suggest that early intervention during NEC may reduce the chance of acute neuroinflammation and cerebral damage.

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Exploring Clinically-Relevant Experimental Models of Neonatal Shock and Necrotizing Enterocolitis.

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