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- W2195767240 abstract "A study has been made of the progress of involution of the mouse and rat mammary gland using histologic, electron microscopic, histochemical and autoradiographic methods. Particular emphasis has been placed on the morphology, metabolic alte-rations and activities of histochemically identifiable enzymes, and on the pharmacologic effects of lactation inhibiting agents and cytostatic drugs on lactation and involution. In order to allow a systematic investi-gation, involution was initiated in rats and mice by ligation of individual gland ducts at various time intervals. Both lactating glands and glands in different phases of involution were thus available in a given animal. The most important observation was that involution, which altogether takes approximately 2 weeks to be complete, involves a three-phase process, each phase being clearly distinguishable by morphologic and histochemical criteria. The first phase comprises approximately 4 days during which production of milk may be reinitiated. The second phase starts on day 5 of involution and constitutes the period of involution per se characterized by appreciable parenchymal cell degradation. The third phase, which starts around day 10, is the period of reorganization to the resting mammary gland. Early in the first phase of involution, substantial alveolar enlargement due to engorgement with milk, together with epithelial flattening, are prominent features. By day 3, the glandular contents decrease again in volume, the number of glandular cells and the constituent cytoplasmic organelles remaining unchanged during this period, except for the diminished appearance of fat droplets. In addition to normal appearing vacuoles with only occasional or sparse protein granules, giant vacuoles containing, in part, several hundred casein granules are found. Their formation appears to be due to increased stacking of granules in distended vacuoles prior to dissociation from the Golgi apparatus. In addition, however, the enhanced reactions of a1P (alkaline phosphatase) and ATPase, which are found in the apical plasmalemma, are suggestive of resorptive activities. Protein particles absorbed from the glandular lumen equally appear to have a capacity for fusing into large vacuoles. The large protein granule-containing vacuoles regularly exhibit intense (3-Glu activity. This enzyme would appear to contribute actively to the degradation of excess milk during the first phase of involution. Autoradiographic studies reveal that the synthesis and release of proteins into the secretion is maintained for 3 days. While 3H-tyrosine uptake by the alveolar cells continues unchanged, the incorporation of 3H-palmitic acid into glandular lipoids, and of 3H-fucose into glandular polysaccharides is virtually blocked completely. An immediate reaction of the lipoid metabolism is also indicated by the decrease in 3HBDH activity on the first day of involution. The activities of the histochemically detected oxidoreductases (LDH, MDH, SDH, G6PDH, 3HBDH) show a sharp fall on day 1 of involution, reaching levels approximately one half of the activity observed during lactation, as shown on micro densitometry. The activities remain unchanged during the following 4 days. No degradation of glandular parenchyma is noted during the-first phase of involution. The glandular cells rather take a -wait-and-see- attitude which enables them to participate again in the secretion of milk, as need arises. At this time the activities of the enzymes implicated in energy metabolism have reached approximately the resting mammary gland level. Only protein synthesis is maintained virtually unrestricted and this results in the production of excess milk constituents that are degraded as soon as they are being formed. In the second phase of involution, large seg-ments of the glandular epithelium undergo invo-lution, a process which involves the destruction of glandular epithelial cells and the removal of the resulting cellular debris from the mammary gland. The glandular cells remaining are transformed into resting cells. The lysosomes of the glandular epithelial cells, with maximum numbers being attained between days 7 to 9, contribute decisively to this degradative process. Ultra-structurally, this stage is initially characterized by the appearance in the alveolar cell cytoplasm of segregated cytoplasmic areas which stain negatively for acP (acid phosphatase) and are rich in organelles. These cytoplasmic areas change to membrane-bordered lysosomes which possess intense acP activity. The lysosomes are obviously required for the autophagic degradation of cytoplasmic segments. At the same time the activities of other lysosomal enzymes, involving acP, N-A-Gase, AMPase and AS, show a sharp increase. ATPase and TPPase likewise exhibit considerably increased activity during the second phase of involution. It is seen on microdensitometry that during this phase the acP attains approximately three times the lactation activity. In contrast, the activity of (3-Glu, after having shown a very high increase during the first phase, reverts again to the resting mammary gland level. During the second phase of involution, the oxidoreductases are subject to a further drastic decline of their activities. This process, which consistently affects all segments of the mammary gland,,comes to completion within a few hours. The reaction is found to be minimal around day 5 of involution, at a time when the enzyme activities are approximately one quarter of the lactation levels. At this time, many alveolar cells are destroyed and released into the glandular lumen, the acP retaining its activity in the lysosomes of sloughed cells or cell debris. The resulting gaps in the alveolar epithelium are either bridged immediately or remain detectable on histology. Yet the glandular contents do not pass into the interstitial tissue. The adherence of the glandular tree and the glandular epithelium is ensured by myoepithelial cells. The basement membrane effects the complete segregation of the parenchyma from the interstitial tissue: Macrophages which at this stage occur increa-singly near the alveoli, in the alveolar epithelium and in regional lymph nodes, and which are conspicuous due to numerous acP-laden lysosomes participate essentially in glandular regression. The third phase of involution, which takes place approximately 10 to 14 days following the onset of milk stasis, is the period of reorganization to the resting mammary gland, a period during which glandular cells containing little cytoplasm and sparse organelle lining make their appearance. However, the activities of acP and other lysosomal enzymes remain elevated compared to the pregestational level. Histochemically, the reaction of the oxidoreductases is more intense than during the second involutionary phase, corresponding roughly to the level of the mammary gland in the resting state. The formation of the glandular epithelial cells of the resting mammary gland is not due to renewed mitotic activity, but results from the reduction of actively secreting epithelial cells. Throughout the period of involution the myo-epithelium consistently changes its shape. How-ever, cytoplasmic alterations are not discernible on electron microscopy, nor do these cells undergo degradation during glandular involution. The alP reaction is of particular value for the identification of the myoepithelial cells. No alteration in enzyme activities is demonstrable at the histochemical level throughout the process of involution. Alterations in the interstitial tissue affect particularly the adipose tissue. During lactation, the interalveolar space exhibits only a narrow connective tissue layer which changes insignificantly during the first phase of involution, whereas the subsequent incorporation of lipids results in the formation of plurilocular lipid cells and the reappearance of unilocular adipose tissue as involution advances. During this period the vessels move away from the alveoli. The response of the mammary gland to lactation inhibiting and cytostatic drugs varies, depending on the agent administered. Estrogencontaining drugs lead to an involutionary process which in its initial phase differs from that observed during normal glandular regression. Due to the fact that the milk continues to be suckled by the young, milk production however ceasing very rapidly, the (3-Glu activity is not found to increase greatly during the first phase of involution. The behavior of the lysosomal enzymes during the second phase resembles that seen during normal involution. After administration of the ergot alkaloid 2-Br-a-ergokryptine methane sulfonate (CB 154), the process of involution is initiated only in individual mammary gland cells if the young are left with the mother. In these areas involution takes a normal course. Altogether, milk production changes only insignificantly. The cytostatic drug 5-fluorouracil does not induce direct involution. Milk production apparently is not arrested. However, the pups, when left with the mother, die after 5 to 6 days. Death would appear to be due to the cytotoxic action of 5-fluorouracil." @default.
- W2195767240 created "2016-06-24" @default.
- W2195767240 creator A5009085216 @default.
- W2195767240 date "1976-01-01" @default.
- W2195767240 modified "2023-09-25" @default.
- W2195767240 title "Die Mammainvolution" @default.
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