Remote ischaemic conditioning as a novel therapy for necrotising enterocolitis

Abstract

Necrotising enterocolitis (NEC) is a devastating disease that afflicts neonates leading to high mortality and morbidity. The majority of infants affected are born prematurely but the disease is also seen in other groups of babies – pre-eminently those born with congenital cardiac conditions. There is a broad range of clinical manifestations of the disease; in some cases babies recover completely with only conservative management. In more severe cases, babies require surgery and bowel resection. These infants also develop systemic disease and multi-organ failure.
A systematic review I conducted showed that in the 21st century, whilst the overall outcomes for babies born prematurely continue to improve, NEC still confers significant mortality and morbidity. Even the most premature babies born today have an expected survival of around 90%. Conversely, NEC carries an average mortality of one in four and for the smallest babies (< 1000g) who require surgery for NEC, the mortality is over 50%. Similarly, in the most severely ill babies, the majority will have life-long disability due to the injury to the developing brain resulting in neurodevelopmental delay.
The pathophysiology of NEC is complicated and involves multiple pathways leading to bowel necrosis. The cumulative evidence shows that key risk factors including enteral feeds, prematurity, and colonisation by potentially pathogenic bacteria are all critical to the development of NEC. In recent years, much interest has focused on the immunological pathways involved but ultimately, NEC is a disease characterised by ischaemia-reperfusion injury (IRI) to the bowel. Ischaemic conditioning is a phenomenon whereby brief episodes of non-injurious ischaemia and reperfusion ‘condition’ tissue and organs to be resistant to IRI. Remote ischaemic conditioning (RIC) refers to the fact that the conditioning can be done to one organ or tissue and provide a protective effect
on a different organ. The fact that the conditioning can be done on skeletal muscle with a simple blood pressure cuff inflated to above systolic pressure for short periods of time means that this has the potential to be easily translated to clinical practice.
In this work, I used a rat model of NEC based on creating an ischaemia-reperfusion injury to the bowel that produces a similar injury pattern and systemic effects to human NEC.
Animals that underwent RIC immediately prior to injury had significant decreases in both the extent and severity of the bowel injury. Similarly, animals that underwent RIC following the ischaemic insult demonstrated reduced injury although the effect was not as pronounced as those who had the RIC prior to injury. Furthermore, a protective effect was demonstrated in animals that had the RIC upto 48 hours prior to injury. An additive effect was seen if the animals underwent two separate cycles of RIC 48 hours apart.
Analysis of serum cytokine levels across the various protocols supports a role for IFN-γ, IL-1β and IL-4 in the transmission of RIC: All three may be important in the pathway of delivering a protective effect in a distant organ.
Whole transcriptome analysis performed on the intestine showed that multiple pathways are involved in this process including the down-regulation of NF-ĸβ which is known to be a central regulator of multiple pro-inflammatory pathways. This is particularly appealing as NF-ĸβ is important for the pathogenesis of NEC at several stages in the process.
NEC remains a devastating disease, very much in need of novel therapeutic options. These results collectively show the potential for using RIC as that novel therapeutic option. The potential protective effect of RIC even 48 hours later as well as the additive effect of more than one application provides a good starting point for designing a protocol for a clinical study. The data on the mechanisms of RIC also deserve further study.

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Identifiers

ORCID for Ian Howard Jones: orcid.org/0000-0002-5161-2096

ORCID for Nigel Hall: orcid.org/0000-0001-8570-9374

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