Modifications intracellulaires radio-induites conduisant à la diminution de la capacité absorptive et sécrétoire de l'épithélium colique de rat

Eric Morel, Thèse de doctorat de l'Université Paris VII, spécialité : métabolisme énergétique et régulation nutritionnelle, 289 p., soutenue le 18 décembre 2002.

Exposure of the abdominal sphere to ionizing radiation leads to gastrointestinal dysfunction, notably of the small intestine and colon. The aim of this work was to determine functional modifications of tha rat distal colon after abdominal irradiation. A decrease of both absorptive and secretory capacities of this segment was observed four days after irradiation. We have shown decreased responses to the secretagogue Vasoactive Intestinal Peptide (VIP) were associated with reduced cAMP production in isolated crypts, adenyl cyclase (AC) activity and VIP receptor number in mucosal membranes. Alteration of cAMP production was not due to a marked decrease in crypt cell number. However other intracellular pathways may influence cAMP production. Thus, the effect of ionizing radiation on the cGMP and [Ca2+]i pathway was studied in order to investigate their putative implication in the hyporesponsiveness to VIP. The secretory response to carbachol via [Ca2+]i pathway was unchanged althought muscarinic receptor numbers were decreased. The lack of interaction between the [Ca2+]i pathway and cAMP pathway in both the secretory response and cAMP production suggests this pathway was not implicated in the altered VIP response. The secretory responses to guanylin and sodium nitroprusside (NO donor) were not altered by irradiation. In contrast the NO donor amplified both the decreased secretory response and cAMP production elicited by VIP. Interestingly, this hyporesponsiveness to VIP was not modified following addition of an inhibitor of the inducible form of NO synthase suggesting that this enzyme may not have a major role. An immunological localization of various AC isoforms (II-IX) showed a marked decrease of ACII, II, IV and V/VI in colonic crypts in agreement with reduced AC activity. This may be associated with changes in epithelial cell differentiation and maturation state in agreement with the observed increase in the crypt cell proliferative zone.