Morphological effects of a large single dose of cycloheximide on the intestinal epithelium of the rat

Abstract

Adult male rats received 15 mg/kg cycloheximide and the subsequent morphological effects at three and six hours after injection were evaluated using histometry, light and electron microscopy, histological demonstration of terminal web and acid phosphatase, and radioautography with tritiated thymidine. Rapid atrophy of the villi took place, progressing from the villus tip by premature exfoliation of epithelial cells. The crypts also diminished by random exfoliation of many crypt cells and by partial or complete disintegration. Mitosis and epithelial cell migration were absent. By six hours, the area occupied by the villi and the crypts per unit length of histological section was decreased by about 70-90% in most of the small intestine but only by about 40-60% in the duodenum and the terminal ileum. In the upper half of the villi, the epithelium was strongly positive for acid phosphatase and contained large numbers of round bodies resembling primary lysosomes. In the lower half, the microvillous border and terminal web were found to be disrupted. Animals receiving only 5 mg/kg cycloheximide also showed the atrophy of villi and crypts, and the round bodies resembling lysosomes. Evidence from several sources has indicated that protein synthesis in normal villus epithelial cells subsides toward the villus tip and becomes minimal at exfoliation. At exfoliation, proteins responsible for epithelial cohesion probably fail because they are no longer replenished. Cycloheximide appears to accelerate this process.

Response of intestinal cells of differing topographical and hierarchical status to ten cytotoxic drugs and five sources of radiation

“…Hence with time after CH, or decreased whereas for most agents it normally increased. In rats, Altmann (1975) has reported somewhat similar effects, namely nectrotic cells on the villus (particularly the villus tip) within a few hours of treatment and extrusion of dead or dying cells (condensed cytoplasm and chromatin) into the lumen of the crypt. These cell migration studies will all be presented in greater detail elsewhere.…”

Extrusion of colonic epithelial cells in vitro

“…In keeping with the notion of "ailing" cells prior to extrusion (Leblond, 1981) and the decline of enzymatic activity (Nordstrom et al, 19681, a general hypothesis has been forwarded that the synthesis and turnover of proteins responsible for cell-to-cell adhesion are altered in enterocytes destined to be lost (Altmann, 1975;Leblond, 1981). Alternatively, a mechanical signal mediated by the cytoskeleton or structural proteins in the junctional complex has been proposed to initiate the extrusion process (Hudspeth, 1982).…”

“…One signal posited for the extrusion of senescent cells is the decreased synthesis or degradation of cell adhesion proteins (Altmann, 1975) in concert with a generalized decrease in enzyme synthesis and nuclear atrophy (Leblond, 1981). These changes occur in "predesquamating" cells concentrated in an extrusion zone defined anatomically by intestinal region (Nordstrom et al, 1968).…”

Renewal of the intestinal epithelium: New aspects as indicated by recent ultrastructural observations

“…These included vesiculation of the Golgi apparatus and the rough endoplasmic reticulum to the point that near extrusion, these organelles appeared to be of minimal use so that protein synthesis had to be also minimal. Cycloheximide, an inhibitor of protein synthesis at the translational level, has indeed brought about such vesiculation prematurely as well as a premature extrusion (Falconer, 1982) so that within hours all villus epithelial cells extruded apparently by the normal extrusion mechanism which however was now accelerated (Altmann, 1975). Falconer's study included compacted nucleolus is shown, usually seen in the villus tip columnar cells.…”