On the interdependence of pancreatic size, and tissue composition and cellularity, and growth : characterization of a caerulein-generated model of enhanced pancreatic growth in the adult male rat
The aim of this investigation was to characterize the mutual relevance of changes in pancreatic organ-level indeces of cellular size, and of differentiated functional capacity, in relation to an index of cell proliferation within the pancreatic acinar parenchyma. We have characterized pancreatic wet weight, two major cellular biochemical constituents with respect to their glandular levels and in vivo biosynthesis levels (RNA, protein), tissue levels of two hydrolases (amylase and chymotrypsinogen), together with organ DNA levels (reflective of cellularity) in the normoplastic eutrophie gland of adult male Sprague-Dawley rats (a) during the course of a normal 24-hour activity-rest cycle under standard laboratory conditions, (b) in a caerulein model of secretagogue-enhanced whole organ functional activity and trophism (Solomon et al., 1983), and (c) under conditions of depressed functional activity through the implementation of in vivo cycloheximide regimes. Characterization of the time-structure of the pancreas in terms of its size, tissue composition, digestive potential (tissue levels of two hydrolases) and cellularity describe this organ as a highly heterogeneous entity within the circadian-time domain. Circadian-stage dependent profiles of changes in measurments for each parameter present parameter-specific characteristics). Biochemical parameters reflective of cell number and cell size present maxima during the diurnal phase of the cycle, while the converse is true for tissue hydrolase levels. RNA and protein biosynthetic activity present both daytime and nighttime peak values. The phasing of changes in parameters reflective of tissue fonction (amylase and chymotrypsin activity levels, protein and RNA biosynthesis), and tissue size, and cellularity suggest (a) the occurrence of a growth /restoration phase during the resting (diurnal) phase of the activity cycle in the gland, classically considered as a kinetically stable entity, and (b) a reverse phasing between changes in tissue size and function. While classic sequelae of parameters reflective of cellular growth versus nuclear growth are upheld during the diurnal phase, the counterdirectional changes in tissue hydrolase and biosynthetic activity levels suggest the inadequacy of describing this organ's state in terms of a single or a limited number of tissue parameters, particularly in longitudinal studies. The suggested circadian-stage-dependent variation in tissue cellularity is of relevance (a) to the understanding of previously described variations in functional activity which may originate in part from variations in cellularityand (b) to the contradictory data pertaining to the trophic effects of agents such as secretin, glucocorticoids and EGF on this organ. Description of pancreatic size, tissue composition and glandular DNA levels during the initial times (0hrs-24hrs) following implementation (PRI) of secretagogue-models (caerulein, 1µg/kg BW/injection, TID and or secretin, 100µg/kg BW/injection, TID) of positive pancreaticotrophism suggest that classic sequelae of cellular growth versus nuclear growth events during putative instances of cellular proliferation are upheld in these models. Changes in tissue RNA levels constitute the most precocious indicators of ulterior enhancement of glandular DNA levels in these models (8hrs-12hrs PRI), with a chronology of onset and amplitude in change reflective of the secretagogue potential of each of the peptide boli used in these.models. Cell growth/cellular proliferation classic sequences of events are upheld only as of the 24hr PRI study time with respect to whole organ protein levels, developing over the 18hr-24hr PRI interval, with an amplitude reflective of secretagogue potential and ulterior levels of heightening of glandular DNA levels. Over the 12hr-18hr PRI study interval, secretagogues appear to induce a parallelism and a correspondence in amplitude between changes in parameters reflective of secretory fonction (depressed glandular amylase and chymotrypsinogen activity levels) relative to those glandular DNA levels. These data suggest that triggering of the pancreatic trophic response may have been have been initiated as an early response to exhaustion of the gland's functional capacity, rather than as a result of secretagogue-associated adaptive (hypertrophying) changes, such as enhancement of tissue RNA, protein and hydrolase levels. This postulate was in contradiction with the relative dynamics and levels of incremental changes in pancreatic organ size, tissue composition and heightening of glandular DNA levels observed throughout the course of more protracted (1 day to 5 day) protocols, wherein classic sequences of changes reflecting cellular growth versus nuclear growth are upheld. In these more protracted models, tissue amylase increments plateau prior to those for all other parameters, suggesting that mechanisms limiting the response of the pancreas in terms of its ability to enhance amylase levels in secreta may be of etiological relevance to this tissue's trophic (limited/biphasic) response in caerulein models. The time course of changes in size, enhanced tissue composition and glandular DNA levels observed at term of the protractedjoint or separate administration of caerulein and secretin reflects the nature of the cellular kinetics of major cell population edifying target organs, as suggested through the progressive incremental changes versus the episodic, transitory and recurrent trophic changes observed in the pancreas, and the duodenum, respectively, observations which uphold classic growth and proliferation sequelae of cells in tissues comprised primarily of an expanding versus a renewing cell populations.
Networked Digital Library of Theses and Dissertations