Necrotizing enterocolitis intestinal barrier function protection by antenatal dexamethasone and surfactant-D in a rat model

Lei Lu,Erika Claud,Jing Lu,Yueyue Yu

doi:10.1038/s41390-020-01334-0

Abstract

BackgroundNecrotizing enterocolitis (NEC) is the most common gastrointestinal disorder in premature neonates. Possible therapeutic approaches are centered on promoting maturation of the gastrointestinal mucosal barrier. Studies have demonstrated that antenatal administration of corticosteroids can decrease NEC incidence and mortality.MethodsPregnant rat dams were administered dexamethasone 48 h prior to delivery. The pups were subjected to an experimental NEC-like injury protocol. Ileal tissues and sera were collected and evaluated for inflammatory cytokines, gut permeability and expressions and localizations of tight junction proteins, and surfactant protein-D by immunohistochemistry/immunofluorescent staining. Intestinal epithelial cells (IEC-6) were pretreated with SP-D to examine the effect of SP-D on tight junction protein expressions when challenged with platelet-activating factor and lipopolysaccharide to model proinflammatory insults.ResultsAntenatal dexamethasone reduced systemic inflammation, preserved intestinal barrier integrity, and stimulated SP-D expression on the intestinal mucosal surface in pups exposed to NEC-like injury. Pretreatment of SP-D blocked platelet-activating factor/lipopolysaccharide-induced tight junction disruption in IEC-6 cells in vitro.ConclusionsAntenatal dexamethasone preserves the development of intestinal mucosal barrier integrity and reduces incidence and morbidity from an experimental NEC-like injury model. Dexamethasone upregulation of intestinal SP-D-protective effects on tight junction proteins.ImpactAntenatal administration of dexamethasone can function in concert with intestinal surfactant protein-D to decrease systemic inflammatory responses, and protect intestinal barrier integrity in a neonatal rat model of NEC.A novel role of intestinal SP-D in preserving tight junction protein structures under inflammatory conditions.We describe the intestinal SP-D—an overlooked role of antenatal dexamethasone in neonatal NEC?

Highlights

Necrotizing enterocolitis (NEC) is the most frequent gastrointestinal emergency of preterm infants, representing a major cause of morbidity and death in neonates.[1,2,3] This disease is characterized by massive epithelial necrosis, gut barrier dysfunction, and improper mucosal defense development.[4,5,6,7] Prematurity remains the most consistent risk factor for developing NEC.Glucocorticoids (GCs) are suggested to promote the maturation of many vital fetal organs, for example, have been used to induce maturation of fetal lungs, and are associated with subsequent improved postnatal survival.[8]
Since Surfactant protein-A (SP-A) and surfactant protein-D (SP-D) have been shown to protect against NEC in vivo and in vitro models,[17] we explored the possibility that antenatal dexamethasone may modulate SP-A and/or SP-D expression resulting in the protection of the mucosa barrier in the neonatal rat ileum
We focused our further investigation on intestinal SP-D and utilized an immature rat intestinal epithelial cell line (IEC-6) to elucidate the possible cellular mechanisms by which SP-D protects intestinal barrier function

Summary

BACKGROUND

Necrotizing enterocolitis (NEC) is the most common gastrointestinal disorder in premature neonates. CONCLUSIONS: Antenatal dexamethasone preserves the development of intestinal mucosal barrier integrity and reduces incidence and morbidity from an experimental NEC-like injury model. ● Antenatal administration of dexamethasone can function in concert with intestinal surfactant protein-D to decrease systemic inflammatory responses, and protect intestinal barrier integrity in a neonatal rat model of NEC. Animal studies have demonstrated that prenatal cortisone acetate administration reduces both incidence and morbidity in a rat model of NEC partially due to increased maturation of the intestinal mucosal barrier evidenced by decreased bacteria translocation, reduced uptake of macromolecules, and lower intestinal permeability.[13,14] In fetal lungs, GCs stimulate the production of surfactant-associated proteins.[15] Surfactant protein-A (SP-A) and surfactant protein-D (SP-D) are established as essential components of the innate immune system for protecting against pathogens.[16] In the gastrointestinal tract, SP-. Protecting offspring from NEC in part by regulating SP-D and APG2, which play important roles in TJ development and function

MATERIALS AND METHODS

Findings

DISCUSSION