Journal of Environmental Pathology, Toxicology and Oncology

ISSN for PRINT: 0731-8898

For Online Access

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2004, Volume23

Issue 2

90 pages

DOI: 10.1615/JEnvPathToxOncol.v23.i2

Issue price - $160.00

Richard Naftalin
King's College London, Physiology Division, Guys Campus, London, UK

This article reviews how cytokines and radiation-induced apoptosis affect the barrier function of the colonic pericryptal sheath and thereby colonic crypt fluid absorption. A layer of myofibroblasts forming a pericryptal sheath surrounds the colonic crypt epithelial cells. The colonic pericryptal hypertonicity (250—350 mM NaCl) resulting from Na⁺ pumping into the space between the crypt epithelial cells and the myofibroblasts provides the driving force required to produce the suction tension (5—10 atmospheres) that dehydrates feces. [Na⁺] in the pericryptal space and crypt lumen is monitored in vivo with a Na⁺ ion-sensitive fluorescent dye, Sodium Red. Dietary Na⁺ restriction increases this hypertonicity. The rate of dextran—labeled with fluorescein isothiocyanate (FITC)—accumulation in the crypt lumen monitors fluid absorption by the crypt lumen. The rate of leakage of FITC dextran (10 kDa) across the crypt wall reflects its permeability. With low Na⁺ intake, there is decreased crypt luminal dextran permeability. This decrease in crypt permeability is due to increased systemic and local release of angiotensin II and TGF-β and is accompanied by pericryptal growth stimulation with consequent increased expression of myofibroblast proteins, smooth muscle actin, collagen 4, and OB cadherin. Inhibition of cytokine formation by the angiotensin-converting enzyme inhibitor (ACEI) captopril prevents these trophic effects. Colonic fluid absorption is inhibited 4 days after whole-body exposure to ionizing radiation of >8 Gy. Concurrently, there is loss of the pericryptal myofibroblasts resulting from apoptosis, with consequent loss of the barrier function of the pericryptal sheath. These effects cause increased rates of dextran leakage across the crypt wall and loss of myofibroblast markers. Normal colonic function returns after 10 days accompanied by repair of the pericryptal sheath. The caspase inhibitor, Z-VAD Fmk, reduces sheath apoptosis. Longer term irradiation of >8 Gy produces overgrowth of the myofibroblasts and fibrosis, which is inhibited by captopril.

DOI: 10.1615/JEnvPathToxOncol.v23.i2.10 Download article, 20 pages

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