LPS-binding protein enables intestinal epithelial restitution despite LPS exposure
Open accessAbstract
OBJECTIVES: Intestinal epithelial restitution is the first part in the process of mucosal repair after injury in the intestine. Integrity of the intestinal mucosal barrier is important as a first line of defense against bacteria and endotoxin. Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in extremely-low-birth-weight infants, but its mechanisms are not well defined. Abnormal bacterial colonization, immature barrier function, innate immunity activation, and inflammation likely play a role. Lipopolysaccharide (LPS)-binding protein (LBP) is secreted by enterocytes in response to inflammatory stimuli and has concentration-dependent effects. At basal concentrations, LBP stimulates the inflammatory response by presenting LPS to its receptor; however, at high concentrations, LBP is able to neutralize LPS and prevent an exaggerated inflammatory response. We sought to determine how LBP would affect wound healing in an in vitro model of intestinal cell restitution and protect against intestinal injury in a rodent model of NEC. METHODS: Immature intestinal epithelial cells (IEC-6) were seeded in poly-L-lysine-coated 8-chamber slides and grown to confluence. A 500-μm wound was created using a cell scraper mounted on the microscope to achieve uniform wounding. Media was replaced with media containing LPS ± LBP. Slide wells were imaged after 0, 8, and 24 hours and then fixed. Cellular restitution was evaluated via digital images captured on an inverted microscope and wound closure was determined by automated analysis. Toll-like receptor 4 (TLR4) was determined by reverse transcriptase-polymerase chain reaction after RNA isolation from wounded cells 24 hours after treatment. RESULTS: LPS alone attenuated wound healing in immature intestinal epithelium. This attenuation is reversed by 24 hours with increasing concentrations of LBP so that wound healing is equivalent to control (P < 0.001). TLR4 was increased with LPS alone but levels returned to that of control after addition of LBP in the higher concentrations. LBP had no effect on the development of intestinal injury when given during our rodent model of NEC. Abnormal bacterial colonization and activation of innate immunity by LPS are likely involved in the pathogenesis of NEC.The attenuation of wound healing was reversed when LBP was added to LPS but only in the higher concentrations. At these same concentrations of LBP, TLR4 was decreased to that of control. CONCLUSIONS: These results indicate that LBP may be a novel therapeutic strategy to facilitate wound healing after the acute phase of NEC and other forms of intestinal injury.
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Age-related changes in the microbiota toward gram-negative and endotoxigenic bacteria are known to induce cellular senescence and apoptosis in endothelial cells and damage to intestinal epithelial cells and gut-associated lymphoid tissues, thereby disrupting intestinal epithelial barrier integrity.
“Furthermore, age-related changes in the microbiota toward gram-negative and endotoxigenic bacteria are known to induce cellular senescence and apoptosis in endothelial cells and damage to intestinal epithelial cells and gut-associated lymphoid tissues thereby disrupting the intestinal epithelial barrier integrity (50–54).”
From Senolytic Combination of Dasatinib and Quercetin Alleviates Intestinal Senescence and Inflammation and Modulates the Gut Microbiome in Aged Mice (2021) · cites this paper as [50]
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- Authors
- Richter, J. M., Schanbacher, B. L., Huang, H., Xue, J., Bauer, J. A., & Giannone, P. J.
- Affiliations
- Nationwide Children's Hospital (US)
- Corresponding author
- Giannone, Peter J.
- Venue
- Journal of Pediatric Gastroenterology and Nutrition
- Publisher
- Wiley
- Published
- 2012-05
- Volume
- 54
- Issue
- 5
- Pages
- 639-644
- ISSN
- 0277-2116 (ISSN-L)
- 1536-4801
- PMC
- PMC3288261
- OpenAlex
- W2059442923
- Cited by
- 36
- References
- 26
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 1 · 2015: 4 · 2014: 4 · 2013: 4 · 2012: 2
- FWCI
- 1.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Pediatric Gastroenterology and Nutrition (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1K23DK078909)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Nursing › Nutrition and Dietetics › Infant Nutrition and Health
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Keywords
- lipopolysaccharide-binding protein, intestinal epithelial restitution, intestinal wound healing, necrotizing enterocolitis, lipopolysaccharide, TLR4, intestinal barrier, intestinal injury, bacterial colonization, innate immunity, extremely low birth weight infants, IEC-6 cells, therapeutic target, endotoxin neutralization, inflammation reduction, intestinal epithelium
- MeSH terms
- Lipopolysaccharide-Binding Protein, Acute Disease, Acute-Phase Proteins, Administration, Oral, Animals, Carrier Proteins, Cell Line, Disease Models, Animal, Epithelial Cells, Immunity, Innate, Inflammation, Intestinal Mucosa, Intestines, Lipopolysaccharides, Membrane Glycoproteins, Wound Healing, Signal Transduction, Reverse Transcriptase Polymerase Chain Reaction, Enterocolitis, Necrotizing, Enterocytes, Toll-Like Receptor 4, Rats
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