Age, as well as cell turnover kinetics, regulates brain/gut repair.
The prototypical brain/gut peptide cholecystokinin (CCK) has been used to assess brain and gut repair kinetics following cytotoxic injury in the rat. Studies addressed the effect of repetitive injury as well as aging. Injury was induced by one of the two alkylating agents, one active in the brain, the other systematically. Consistently the responses differ between brain and intestine. Total RNA falls (as predicted) in the intestine (control 1.5 +/- 1.4 versus cytotoxic 0.21 +/- 0.06 tRNA mg/organ, P < or = 0.0001), but rises (unexpectedly) in the brain (control 0.79 +/- 0.04 versus cytotoxic 1.02 +/- 0.03 tRNA mg/organ, P < or = 0.001). CCK mRNA concentration falls in the brain (predicted) (control 27 +/- 1 versus cytotoxic 11 +/- 1 pg CCK mRNA/micrograms tRNA, P < or = 0.001), but rises in the intestine (unexpectedly) (control 0.18 +/- 0.02 versus cytotoxic 0.3 +/- 0.04 pg CCK mRNA/micrograms tRNA, P < or = 0.001). CCK peptides do not change in the brain (control 39 +/- 4 versus cytotoxic 34 +/- 4 nmol/g, P < or = NS), but rise (unexpectedly) in the intestine (control 43 +/- 4 versus cytotoxic 250 +/- 27 nmol/g, P < or = 0.001). We ascribe these observations to differing brain/gut cell turnover kinetics. These data indicate that a rebound phenomenon occurs during gut recovery from cytotoxic injury. We additionally show a differential age-related response to cytotoxic injury. Younger animals tolerated the injury better than old ones (mortality: young 27% (3/11) versus old 66% (8/12), P < or = 0.001). Additionally, intestinal recovery is more rapid in younger animals. These data suggest that with increasing age, chemotherapeutic dosages may need to be modulated. It is additionally possible that clinically applicable algorithms may be developed using our animal model.
Greenstein
R J
RJ
Department of Surgery, Mount Sinai School of Medicine CUNY New York 10468.
D000375:Aging / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D002330:Carmustine / Q000494:pharmacology; D002453:Cell Cycle; D002766:Cholecystokinin / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000502:physiology*; D008466:Mechlorethamine / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley
D012333:RNA, Messenger; D008466:Mechlorethamine; D004247:DNA; D002766:Cholecystokinin; D002330:Carmustine