Related Experiment Video
Updated: Sep 26, 2026
Microfluidic Model of Necrotizing Enterocolitis Incorporating Human Neonatal Intestinal Enteroids and a Dysbiotic Microbiome
Published on: July 28, 2023
Matrix metalloproteinases in necrotising enterocolitis
Sylvia Lin Foon Pender1, Christian Braegger, Ute Gunther
1Division of Infection, Inflammation and Repair, Mailpoint 813, Level E, South Academic Block, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. s.pender@soton.ac.uk
Abstract:
Elevated cytokines, especially TNF-alpha, have been implicated in the pathogenesis of necrotising enterocolitis (NEC). We have previously shown that TNF-alpha drives the production of matrix degrading enzymes, the matrix metalloproteinases (MMPs), in the gut wall. In this study we have therefore investigated the role of MMPs in the pathogenesis of NEC in neonates. Nine newborn infant nonnecrotic resected bowels with confirmed NEC were studied and 8 newborn infants with neonatal bowel obstructions were used as controls. Immunostaining was used to identify the numbers of monocytes, macrophages, neutrophils, and T cells in the tissue. We used quantitative, competitive RT-PCR to analyze the number of TNF-alpha, IFN-gamma, MMP, and TIMP mRNA transcripts and western blotting to analyze MMP and TIMP protein production. Double labeling (immunostaining and in situ hybridization) was used to identify the phenotype of MMP mRNA expressing cells. We found increased numbers of monocytes, macrophages, and neutrophils in NEC tissue compared with controls. The number of T cells was unexpectedly low in NEC as was the number of IFN-gamma transcripts in comparison with the control samples. Increased numbers of transcripts for TNF-alpha were detected in NEC tissue, as was mRNA expression and protein production for stromelysin-1 and TIMP-1 but not collagenase, gelatinases, or TIMP-2. The cellular source of stromelysin-1 in NEC was alpha-smooth muscle actin positive cells. These results suggest that stromelysin-1, which has the ability to degrade the mucosal extra-cellular matrix, may be responsible for the extensive tissue injury in infants with NEC.
Insights
Necrotising enterocolitis (NEC) involves elevated TNF-alpha and matrix metalloproteinases (MMPs). Stromelysin-1, an MMP, may cause tissue injury in NEC by degrading the gut
Area of Science:
- Neonatal pathology
- Gastroenterology
- Immunology
Background:
- Necrotising enterocolitis (NEC) is a severe neonatal condition linked to inflammation and gut injury.
- Tumor necrosis factor-alpha (TNF-alpha) and matrix metalloproteinases (MMPs) are implicated in NEC pathogenesis.
- Previous research indicated TNF-alpha stimulates MMP production in the gut wall.
Purpose of the Study:
- To investigate the specific role of MMPs in the pathogenesis of NEC in neonates.
- To analyze the expression of various MMPs and their inhibitors (TIMPs) in NEC-affected infant bowels.
Main Methods:
- Studied resected bowel tissue from 9 NEC infants and 8 controls with neonatal bowel obstruction.
- Utilized immunostaining to quantify immune cell populations (monocytes, macrophages, neutrophils, T cells).
- Employed RT-PCR for mRNA analysis of TNF-alpha, IFN-gamma, MMPs, and TIMPs.
- Applied western blotting for protein analysis of MMPs and TIMPs.
- Used double labeling (immunostaining and in situ hybridization) to identify the cellular source of MMP mRNA.
Main Results:
- NEC tissue showed increased monocytes, macrophages, and neutrophils compared to controls.
- T cells and IFN-gamma transcripts were unexpectedly low in NEC samples.
- Elevated TNF-alpha transcripts were detected in NEC tissue.
- Stromelysin-1 (MMP-3) and TIMP-1 mRNA and protein were upregulated in NEC.
- Collagenase, gelatinases, and TIMP-2 showed no significant changes.
- Stromelysin-1 mRNA originated from alpha-smooth muscle actin-positive cells in NEC tissue.
Conclusions:
- Stromelysin-1, capable of degrading the mucosal extracellular matrix, is significantly upregulated in NEC.
- This suggests stromelysin-1 plays a key role in the extensive tissue damage observed in necrotising enterocolitis.
- The findings highlight stromelysin-1 as a potential therapeutic target for NEC.
Related Concept Videos
01:23Role of Matrix Metalloproteases in Degradation of ECM
A...
01:20Determinants of Bacterial Pathogenicity and Virulence