Abstract
The etiology of necrotizing enterocolitis (NEC) is not known. Alterations in gut microbiome, mucosal barrier function, immune cell activation, and blood flow are characterized events in its development, with stress as a contributing factor. The hormone corticotropin-releasing factor (CRF) is a key mediator of stress responses and influences these aforementioned processes. CRF signaling is modulated by NEC's main risk factors of prematurity and formula feeding. Using an established neonatal rat model of NEC, we tested hypotheses that: (i) increased CRF levels-as seen during stress-promote NEC in formula-fed (FF) newborn rats, and (ii) antagonism of CRF action ameliorates NEC. Newborn pups were formula-fed to initiate gut inflammation and randomized to: no stress, no stress with subcutaneous CRF administration, stress (acute hypoxia followed by cold exposure-NEC model), or stress after pretreatment with the CRF peptide antagonist Astressin. Dam-fed unstressed and stressed littermates served as controls. NEC incidence and severity in the terminal ileum were determined using a histologic scoring system. Changes in CRF, CRF receptor (CRFRs), and toll-like receptor 4 (TLR4) expression levels were determined by immunofluorescence and immunoblotting, respectively. Stress exposure in FF neonates resulted in 40.0% NEC incidence, whereas exogenous CRF administration resulted in 51.7% NEC incidence compared to 8.7% in FF non-stressed neonates (p<0.001). Astressin prevented development of NEC in FF-stressed neonates (7.7% vs. 40.0%; p = 0.003). CRF and CRFR immunoreactivity increased in the ileum of neonates with NEC compared to dam-fed controls or FF unstressed pups. Immunoblotting confirmed increased TLR4 protein levels in FF stressed (NEC model) animals vs. controls, and Astressin treatment restored TLR4 to control levels. Peripheral CRF may serve as specific pharmacologic target for the prevention and treatment of NEC.
Highlights
Necrotizing enterocolitis (NEC) is the most common fatal gastrointestinal (GI) disease affecting premature infants in the developed world [1]
Necrotizing enterocolitis is a major cause of morbidity and mortality in premature neonates
Little is known about the role of key mediators of the stress axis—such as corticotropin-releasing factor (CRF) and CRF receptors (CRFRs)—in necrotizing enterocolitis (NEC)
Summary
Necrotizing enterocolitis (NEC) is the most common fatal gastrointestinal (GI) disease affecting premature infants in the developed world [1]. The incidence is 0.3–2.4 cases of NEC for every 1,000 live births [2], corresponding to annual costs ranging between $500 million to $1 billion in the United States [3]. No specific therapy is available to treat NEC. One half of patients afflicted with NEC develop complications requiring surgical intervention; of these, approximately 50% die [1]. Overall mortality has remained unchanged over the past 30 years [3]. Survivors face ongoing morbidity due to malnutrition, recurrent small bowel obstructions, liver failure, and neurocognitive deficits [1, 4]
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