Antisecretory factor suppresses intestinal inflammation and hypersecretion

Abstract

Background: Antisecretory factor (AF) is a recently identified regulatory protein which inhibits the intestinal fluid secretion induced by cholera toxin.

Aims: To test the effect of AF on: (a) inflammation and hypersecretion induced by toxin A from Clostridium difficile; and (b) morphological changes and hypersecretion induced by okadaic acid (the blue mussel toxin) in rat intestinal mucosa.

Methods: Morphological changes and fluid accumulation were observed in intestinal loops challenged with 1 microgram of toxin A or 3 micrograms of okadaic acid administered before or after injection of 0.1 microgram of recombinant AF (rAF).

Results: The cytotoxic and inflammatory reaction caused by toxin A was abolished after treatment with rAF given either intraveneously or intraluminally prior to the toxin or one hour after the toxin. The intestinal fluid response induced by toxin A and okadaic acid was reduced 55-80% by rAF. However, the characteristic increase in goblet cells at the tips of villi in the okadaic acid treated mucosa was not inhibited by rAF.

Conclusion: Results suggest that AF might be involved in protection against inflammation and in counteracting dehydration caused by enterotoxins. Both effects are probably mediated via the enteric nervous system.

Figure 1

: (A) Control morphology in ligated jejunal loop challenged with PBS. The apical parts of the villi (open arrows) are distinctly lineated against the intestinal lumen (L). The lamina propria (lp) is intact, as are the crypt cells (cr) and muscularis mucosae (mm). The black arrow points to the black stained goblet cell. (B) Morphology in the ligated loop five hours after challenge with C difficile toxin A. The upper half of the villi is totally disintegrated, and the intestinal morphology in this part of the villi cannot be reconstructed. The intestinal lumen is full of cell debris. The basal part of the villi shows a more intact morphology, along with the crypt cells and muscularis mucosae. (C) The intact and preserved morphology in the ligated loop despite five hours of challenge with C difficile toxin A. Systemic injection of recombinant antisecretory factor inhibited substantially the cytotoxic action of toxin A. The upper half of the villi is morphologically intact; however, in the intestinal lumen some shed goblet and epithelial cells can be seen. The morphology further down the basal part of the villi and in the crypts and muscularis mucosae is identical to that of the control. Bars are 100 µm.