Necrotizing enterocolitis (NEC), or necrotic cell death of the intestinal mucosa, is a neonatal critical illness that is most common in prematurity. In severe cases, which can require surgery and are associated with a high mortality rate, NEC causes systemic inflammation and multiple organ dysfunction, the pathogenesis of which is incompletely understood. Focusing on acute lung injury associated with this disease, Jia et al. used an established model of NEC, in which neonatal mice are exposed to four days of intermittent hypoxia and formula feeding supplemented with enteric bacteria isolated from an infant with NEC. Lung necropsy samples from neonatal mice exposed to this procedure and humans who died of NEC were notable for airspace destruction, neutrophilia, and increased expression of the innate immune receptor TLR4 (Toll-like receptor 4). The procedure itself did not directly cause lung injury independent of NEC, as mice lacking TLR4 in only the gut epithelium were protected from NEC and did not develop lung injury. Conversely, mice lacking TLR4 specifically in the lung epithelium developed NEC but not the associated lung injury.
Having established that lung injury in NEC is dependent on lung epithelial TLR4 expression, the authors searched for potential TLR4 ligands produced in the gut in the setting of NEC. High-mobility group box 1 (HMGB1) is an endogenous TLR4 agonist, and it was increased in the serum of NEC patients and NEC model mice. Furthermore, recombinant HMGB1 instilled into the airway of wild-type mice caused acute lung injury, and mice lacking HMGB1 in the intestinal epithelium or treated with anti-HMGB1 antibody were protected from acute lung injury in the NEC model. Mechanistically, the authors showed that the lung injury in the NEC model was caused by neutrophilia, which in turn was dependent on CXCL5 expression induced by activation of TLR4 by circulating HMGB1. As a proof-of-concept, administration of an aerosolized small-molecule inhibitor of TLR4 during the development of NEC in mouse models decreased lung airspace obliteration, inflammatory cytokine expression, and neutrophilia.
This study by Jia et al. yields several potential targets in a neutrophilic pathway of NEC-associated acute lung injury, including HMGB1, TLR4, and CXCL5, which could also be relevant to other sites of systemic dysfunction in NEC. The findings provide rationale for future studies to establish the efficacy and safety of inhibition of this pathway, with the goal of eventual translation to patients with NEC.
H. Jia et al., Pulmonary epithelial TLR4 activation leads to lung injury in neonatal necrotizing enterocolitis. J. Immunol. 10.4049/jimmunol.1600618 (2016). [Abstract]
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