Back to Search
Start Over
Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2008 Jan; Vol. 118 (1), pp. 229-38. - Publication Year :
- 2008
-
Abstract
- Patients with protein-losing enteropathy (PLE) fail to maintain intestinal epithelial barrier function and develop an excessive and potentially fatal efflux of plasma proteins. PLE occurs in ostensibly unrelated diseases, but emerging commonalities in clinical observations recently led us to identify key players in PLE pathogenesis. These include elevated IFN-gamma, TNF-alpha, venous hypertension, and the specific loss of heparan sulfate proteoglycans from the basolateral surface of intestinal epithelial cells during PLE episodes. Here we show that heparan sulfate and syndecan-1, the predominant intestinal epithelial heparan sulfate proteoglycan, are essential in maintaining intestinal epithelial barrier function. Heparan sulfate- or syndecan-1-deficient mice and mice with intestinal-specific loss of heparan sulfate had increased basal protein leakage and were far more susceptible to protein loss induced by combinations of IFN-gamma, TNF-alpha, and increased venous pressure. Similarly, knockdown of syndecan-1 in human epithelial cells resulted in increased basal and cytokine-induced protein leakage. Clinical application of heparin has been known to alleviate PLE in some patients but its unknown mechanism and severe side effects due to its anticoagulant activity limit its usefulness. We demonstrate here that non-anticoagulant 2,3-de-O-sulfated heparin could prevent intestinal protein leakage in syndecan-deficient mice, suggesting that this may be a safe and effective therapy for PLE patients.
- Subjects :
- Animals
Anticoagulants adverse effects
Anticoagulants therapeutic use
Cell Line
Heparin adverse effects
Heparin pharmacology
Heparin therapeutic use
Heparitin Sulfate genetics
Humans
Hypertension drug therapy
Hypertension genetics
Hypertension metabolism
Hypertension pathology
Interferon-gamma genetics
Interferon-gamma metabolism
Intestinal Mucosa ultrastructure
Mice
Mice, Knockout
Protein-Losing Enteropathies drug therapy
Protein-Losing Enteropathies genetics
Protein-Losing Enteropathies pathology
Syndecan-1 genetics
Tumor Necrosis Factor-alpha genetics
Tumor Necrosis Factor-alpha metabolism
Heparin analogs & derivatives
Heparitin Sulfate metabolism
Intestinal Mucosa metabolism
Protein-Losing Enteropathies metabolism
Syndecan-1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9738
- Volume :
- 118
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 18064305
- Full Text :
- https://doi.org/10.1172/JCI32335