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FULL TEXT PAPER
Role of Cell Loss in Mammary Gland Function
by Jane M. Bryson and Walter L. Hurley


TAKE HOME MESSAGE

  • The early dry period is a time of rapid functional and structural change in the cow's mammary gland. The initial stage of the dry period is when the gland undergoes a process of involution.
  • Loss of mammary cells by programmed cell death, or apoptosis, occurs in the cow's mammary gland during involution.
  • Despite this loss of cells, the cow seems to maintain partial integrity of the mammary tissue structure throughout most of the involution period.

DRY PERIOD AND MAMMARY GLAND INVOLUTIO

The significance of giving a dairy cow a 50-60 day dry period to maximize subsequent milk production is firmly established in dairy management practices. The early stage of the dry period marks the phase in the lactation cycle where resistance to mastitis is lowest. Understanding the biochemical and cellular changes which occur in the gland during the dry period will ultimately lead to means of manipulating mammary function to enhance subsequent milk production and minimize mastitis. Shortly after drying off a cow, the mammary gland begins a process of involution. Changes in composition of mammary secretions during the early phases of involution indicate rapid changes in the normal mechanisms involved in milk synthesis and secretion. A substantial reduction in fluid volume in the gland occurs between day 3 and 7 of involution. Ultrastructural changes in bovine mammary cells begin within 48 hours of cessation of milk removal. Alveolar lumenal area declines during the subsequent 2-3 weeks, while interalveolar stromal area increases. By day 28, the remaining collapsed alveolar structures are considerably smaller than during lactation, with a very small lumen. However, general alveolar structure is maintained throughout involution.

Our previous work on the bovine mammary gland during involution provided no evidence for the extensive tissue degeneration observed in other species. A detachment of epithelial cells from the basement membrane and their loss from the tissue has been reported in rodents and other species. This leaves characteristic bare spaces on the basement membrane and myoepithelial cells are thought to fill the space. No such situations are observed in the involuting bovine gland. More recently, involution in the mouse has been characterized by examining the role of apoptosis in this process.

APOPTOSIS AND MAMMARY GLAND INVOLUTION

Mammary involution in the mouse is characterized by a rapid loss of tissue function and degeneration of the alveolar structure and massive loss of epithelial cells. This cell loss is due to programmed cell death or apoptosis. Apoptosis is a natural and systematic method of cell suicide which takes place during normal morphogenesis, during tissue remodelling and in response to infection or irreparable cell damage. There are two distinct types of cell death, apoptosis and necrosis, which may be distinguished by morphological, biochemical and molecular changes in dying cells. Apoptosis may be identified by a characteristic pattern of morphological changes: nuclear and cytoplasmic condensation, nuclear fragmentation and formation of apoptotic bodies. These changes are associated with cleavage of chromatin into discrete fragments of DNA by an endonuclease. Appearance of this oligonucleosomal DNA laddering in stained gels typically has been used to detect apoptosis. Enzymatic labelling of DNA strand breaks also allows for histological detection of apoptosis in situ in the tissue.

A morphology consistent with apoptotic cell death can be observed in the mouse mammary gland within two days of milk stasis. The nucleus and cytoplasm condense, the chromatin becomes fragmented and marginated, and apoptotic bodies are formed. This cell loss results in extensive disintegration of alveolar structure during the early period of involution in the mouse. Apoptosis also has been detected in goat mammary tissue during early and late lactation and during late lactation in the cow. This would suggest that removal of secretory epithelial cells by apoptosis is a normal physiological event in the ruminant mammary gland, even during lactation. In addition, cessation of milk removal has been demonstrated to stimulate apoptosis in both goat and cow mammary tissue. These observations suggest that mammary epithelial cells are indeed lost during involution in the bovine mammary gland. However, this process of cell loss does not seem to be as dramatic as that observed in the mouse. Despite the loss of cells, bovine mammary alveoli retain general structural integrity throughout involution. While the role of cell loss in the mouse mammary gland during involution is clear, the impact of mammary apoptosis in the bovine is not fully understood.

We have been developing techniques for detection of apoptosis in mammary tissue. Preliminary work has confirmed observations of apoptosis during involution of the mouse mammary gland. Litter removal at peak lactation induces morphological changes within mouse mammary tissue. Two days after pup removal, the alveoli appeared swollen with accumulated milk and there was some loss of alveolar integrity. Cells were visible in the alveolar lumen. Following 4 days of milk stasis, the alveolar structure was extensively disrupted. In some cases the alveoli collapsed or appeared stripped of epithelial cells. Apoptotic cells in situ were detected using the histological technique. Little evidence of apoptosis was observed in lactating tissue. However, increased positive staining was observed 48 h after litter removal, particularly in the lumen of the alveoli. Extensive labelling was seen throughout the mammary tissue following 4 days of milk stasis. Additionally, DNA laddering which is indicative of apoptosis, was detected in mouse mammary tissue following removal of the litter. Peak DNA laddering was apparent 4 days after pup removal.

This work has been extended to examine bovine mammary involution. The histological method was used to identify apoptotic bodies in bovine mammary tissues representing lactating tissue, d3 involuting tissue, and d14 involuting tissue. Lactating tissue had little evidence of apoptosis. Apoptotic bodies were observed in d3 and d14 involuting tissues. Subjectively, apoptotic bodies seemed to be less conspicuous in the bovine tissue than in the mouse tissue. Our preliminary results, combined with those of others demonstrate that apoptosis is occurring in the bovine mammary gland during involution.

CONCLUSIONS

Mammary gland involution in the cow is of particular interest because of its relationship to the loss of tissue function during the declining phase of lactation and because of the impact of involution on the subsequent lactation. Understanding the factors which control milk stasis-induced involution will help us to understand the factors which control mammary function during declining lactation. Furthermore, redevelopment of the gland prior to a subsequent lactation is in part dependent upon the cell population present when redevelopment begins. Understanding the factors which control cell and functional loss during involution will provide clues on how to maximize cell carry-over between lactations.







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