ArticleJournal of immunology (Baltimore, Md. : 1950)2016
Pulmonary Epithelial TLR4 Activation Leads to Lung Injury in Neonatal Necrotizing Enterocolitis.
Article in Journal of immunology (Baltimore, Md. : 1950), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 58 citations in OpenAlex.
- NEC-Associated Bronchopulmonary Dysplasia and the Gut-Lung Axis in Preterm Infants.American journal of perinatology · 2026Review
- The gut-brain ConNECtion: exploring the developmental impact of necrotizing enterocolitis on the neonatal brain.Pediatric research · 2026Review
- Necrotizing enterocolitis.Nature reviews. Disease primers · 2026Review
- Role of the gut‑lung axis in bronchopulmonary dysplasia: Physiological basis, pathogenesis and immunological modulation (Review).Molecular medicine reports · 2025Review
- Digging deeper into necrotizing enterocolitis: bridging clinical, microbial, and molecular perspectives.Gut microbes · 2025Review
- Necrotizing Enterocolitis: A Comprehensive Review on Toll-like Receptor 4-Mediated Pathophysiology, Clinical, and Therapeutic Insights.Biomedicines · 2025Review
- Overview of extracellular vesicles as biomarkers and therapeutic tools in pediatric diseases: focus on the gut-lung axis.Extracellular vesicles and circulating nucleic acids · 2025Review
- Article
- Effect of prenatal heparin-binding epidermal growth factor (HB-EGF) administration on necrotizing enterocolitis-induced lung injury in a murine model.World journal of pediatric surgery · 2025Article
- An anti-eCIRP strategy for necrotizing enterocolitis.Molecular medicine (Cambridge, Mass.) · 2024Article
- Clinical Correlates of Moderate-to-Severe Bronchopulmonary Dysplasia in Preterm Infants following Surgical Necrotizing Enterocolitis.American journal of perinatology · 2024Article
- Necrotizing enterocolitis: current understanding of the prevention and management.Pediatric surgery international · 2024Review
- Chromatin as alarmins in necrotizing enterocolitis.Frontiers in immunology · 2024Review
- Changes in inflammatory proteins following platelet transfusion in a neonatal population.Pediatric research · 2023Observational
- Bovine milk-derived exosomes attenuate NLRP3 inflammasome and NF-κB signaling in the lung during neonatal necrotizing enterocolitis.Pediatric surgery international · 2023Article
- A Paternal Fish Oil Diet Preconception Reduces Lung Inflammation in a Toxicant-Driven Murine Model of New Bronchopulmonary Dysplasia.Marine drugs · 2023Article
- β-glucan protects against necrotizing enterocolitis in mice by inhibiting intestinal inflammation, improving the gut barrier, and modulating gut microbiota.Journal of translational medicine · 2023Article
- Pneumonia, lymphocytes and C-reactive protein are valuable tests for predicting surgical intervention in necrotizing enterocolitis.Frontiers in pediatrics · 2023Article
- Tumor-intrinsic NLRP3-HSP70-TLR4 axis drives premetastatic niche development and hyperprogression during anti-PD-1 immunotherapy.Science translational medicine · 2022Article
- A hydrogen-sulfide derivative of mesalamine reduces the severity of intestinal and lung injury in necrotizing enterocolitis through endothelial nitric oxide synthase.American journal of physiology. Regulatory, integrative and comparative physiology · 2022Article
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 1 country.
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Abstract
We seek to define the mechanisms leading to the development of lung disease in the setting of neonatal necrotizing enterocolitis (NEC), a life-threatening gastrointestinal disease of premature infants characterized by the sudden onset of intestinal necrosis. NEC development in mice requires activation of the LPS receptor TLR4 on the intestinal epithelium, through its effects on modulating epithelial injury and repair. Although NEC-associated lung injury is more severe than the lung injury that occurs in premature infants without NEC, the mechanisms leading to its development remain unknown. In this study, we now show that TLR4 expression in the lung gradually increases during postnatal development, and that mice and humans with NEC-associated lung inflammation express higher levels of pulmonary TLR4 than do age-matched controls. NEC in wild-type newborn mice resulted in significant pulmonary injury that was prevented by deletion of TLR4 from the pulmonary epithelium, indicating a role for pulmonary TLR4 in lung injury development. Mechanistically, intestinal epithelial TLR4 activation induced high-mobility group box 1 release from the intestine, which activated pulmonary epithelial TLR4, leading to the induction of the neutrophil recruiting CXCL5 and the influx of proinflammatory neutrophils to the lung. Strikingly, the aerosolized administration of a novel carbohydrate TLR4 inhibitor prevented CXCL5 upregulation and blocked NEC-induced lung injury in mice. These findings illustrate the critical role of pulmonary TLR4 in the development of NEC-associated lung injury, and they suggest that inhibition of this innate immune receptor in the neonatal lung may prevent this devastating complication of NEC.
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