Slide Set 6: Involution Flashcards
Define involution
- The regression of the mammary gland following the end of a lactation cycle
- The mammary gland returns to a non-lactating state
What are the characteristics of involution?
- Decrease in mammary cell number and activity
- Reduction in galctopoietic hormones (systemic factors)
- Accumulation of local factors (inhibition of lactation)
When does involution begin?
Around 4-5 months after parturition
What are the main features of involution?
Ø A decrease in cell number due to cell death
(apoptosis)
Ø A decrease in cell activities duo to tissue remodelling
What are the types of involution?
1-Gradual involution
2-Initiated involution
3-Senile involution
What is gradual involution and how does it occur?
Ø Occurs during normal lactation
Ø Results in gradual reduction in milk production
throughout lactation (i.e. less suckling)
Ø Decline in hormonal stimulus (galactopeiotic hormones)
Ø Accumulation of milk and local inhibitory factors in the mammary gland
What is initiated involution and how does it occur?
Ø Induced by humans on domestic animals
Ø sudden cessation of milk removal
Ø Changes in the mammary gland tissues more abrupt than changes observed during gradual involution
Ø Example: dry period in dairy cows
Ø Both gradual and initiated involution are reversible if
pregnancy occurs
What is senile involution and how does it occur?
- irreversible involution
Ø Occurs at the end of the reproductive cycle of the female (aging)
What is complete involution?
Ø Complete involution: rapid loss of secretory functions; complete loss of the epithelial secretory cells (virgin-like mammary gland)
Ø Epithelial cell components are degraded by lysosomal enzymes released into the cytoplasm
Ø Complete involution is common in some mammalian species such as rats and mice
What is incomplete involution?
Ø Incomplete involution: collapsing of the alveolar structure but the secretory cells are still intact (e.g. dairy cows)
What are the changes that occur during involution?
- Changes in mammary tissues
- Changes in mammary cell secretions
- Changes in mammary cell organelles
What are the changes in mammary gland during involution?
Ø Progressive regression from the peripheries towards the gland cisterns
Ø Entire lobes & lobules degenerate instead of single epithelial cells
What are the changes in mammary gland during involution (cow)?
Ø Decrease in alveolar size
Ø Decrease in # of alveoli per lobule
Ø Decrease in # of secretory cells per alveolus
Ø Reduction in luminal volume
Ø Connective tissue become more prominent
Ø Limited disengagement of epithelial cells from basement membrane (unlike rodents)
Despite the fact that the lobular structure is reduced, it is still recognizable (unlike virgin mammary gland)
What are the changes in milk volume during involution?
- Accumulation of milk in mammary cell
- Increased intra-mammary pressure
- Rupture & damage of the basement membrane
- Milk moves into interstitial space
- Milk components broken-down by phagocytosis
What are the local factors that are responsible for milk inhibition?
- milk accumulation
- FIL
- Serotonin
- Lactoferrin
What is the role role of plasminogen / plasmin in involution
Ø ensures normal functioning of the circulatory system
Ø maintains lumen fluidity in vascular system by cleaving excessive / unwanted clots (fibrin)
Ø Widely distributed in the body
Ø In mammary gland the concentration of plasominogen / plasmin increases as lactation progresses
What is the role of role of serotonin in involution?
- Potent inhibitor of lactation (rats, women, bovine)
- Immune response
- Junctional disruption (tight junctions)
- Cells death
- Inhibits milk protein synthesis
Explain the changes in milk volume during involution (cows)
Ø Milk volume increases during the first days of involution
Ø Milk volume declines substantially between day 3-7 following cessation of milk removal
Ø Further reduction occurs by day 30
What happens to the cell organelles during involution?
Ø Milk synthesis in the mammary secretory cell stops within 48 h after cessation of milk removal
Ø Appearance of large vacuoles after 48 h of milk cessation
Ø Vacuoles are formed by the fusion of secretory vesicles & fat droplets
Ø Organelles involved in milk biosynthesis (Golgi apparatus & RER): Almost disappear 48 hours following cassation of milk removal
Ø Mitochondria, ribosomes, nucleus: remain intact throughout involution
Which organelles remain intact during involution?
Mitochondria, ribosomes, nucleus: remain intact throughout involution
Explain the changes in milk constituents during involution
Ø Milk specific components decline
Ø Blood serum components increase
Ø Milk fat and lactose decrease
Ø concentration of total protein increases in early days of involution (high lactoferrin and high serum albumin)
Ø Milk export proteins (casein, α-lactalbumin, β- lactoglobulins) decreases
Ø Concentrations of other serum proteins (lactoferrin, immunoglobulins) increases
What happens to the lactoferrin during involution?
Ø iron-binding protein secreted by the mammary gland
Ø Synthesis of lactoferrin increases during milk stasis
and involution (~100 fold)
Ø Synthesis declines after ~14 d of involution
Ø Suppresses casein expression (inhibits secretion)
Ø Effect of lactoferrin on involution is reversible (based on duration of milk stasis)
Ø antibacterial properties
Ø Lactoferrin is higher in human milk than in cow milk
What happens to the leukocytes during involution?
Ø Leukocytes # in secretion increase during early involution and remain elevated (non-inflammatory reaction
Ø Involve in phagocytosis of residual milk constituent
Ø Involve in protecting the mammary gland from bacterial invasion
What happens to the leukocytes (phagocytes) during involution?
Ø Play a major rule in removing fat droplets, cellular debris
ØTwo types
1-Neutrophils (polymorphonuclear)
ØDominant during the initial few days of involution
2-Macrophages & lymphocytes (mononuclear)
ØDominate after neutrophils
What are the two types of phagocytes that are found in milk contituents? What are their functions?
1-Neutrophils (polymorphonuclear)
ØDominant during the initial few days of involution
2-Macrophages & lymphocytes (mononuclear)
ØDominate after neutrophils
What happens to the lysosomal enzymes during involution? Give examples
Ø Activities of several lysosomal enzymes increases during involution
Example:
Ø Lactoperoxidase
Ø Proteases
Ø Plasminogen activators
Involution in rodents (complete involution) is characterized by:
Ø Rapid loss of tissue function
Ø Degeneration of alveolar structure
Ø Massive loss of epithelial cells (>50%) Involution remains reversible for 30-36 h
Ø The cell loss is due to programmed cell death (apoptosis)
What is apoptosis?
- Programmed (active) cell death
- Cell shrinks, losses contact with neighboring cells and displays intracellular protein on its surface
- Chromatin condenses and DNA cleaved into small fragments
- Small membrane bodies break off containing intracellular materials (apoptotic bodies)
- Secondary necrosis (breakdown) will follow
What is necrosis?
- Uncontrolled (passive) cell death
- Cell swells and mitochondria is damaged (rapid energy depletion)
- Breakdown of homoestatic control
- Cell membrane lysis and release of cellular contents
- Inflammatory response and damages to surrounding cells
Explain the involution in rodents
- A rapid process (8-10 days) where the epithelial cells of the lactating gland is returned to a rudimentary state (virgin-state)
- Can be divided into 2 stages (based on reversibility):
1- Reversible stage (2 days): Gland can return to lactating state if suckling is re-introduced
2- Irreversible stage(3-10days): Gland is unable to return to lactation without being re-stimulated by pregnancy
What are the 2 stages of involution in rodents? What is it based on?
- Can be divided into 2 stages (based on reversibility):
1- Reversible stage (2 days): Gland can return to lactating state if suckling is re-introduced
2- Irreversible stage(3-10days): Gland is unable to return to lactation without being re-stimulated by pregnancy
What are the detailed categories of involution in rodents?
1- Milk stasis (inhibition)
2- Epithelial regression (via cell death)
3- Immune response and clearance of debris
4- tight junction and barrier disruption
5- Extra cellular matrix (ECM) remodeling
6- Adipose tissue remodeling
7- Vascular remodeling
Define dry period
Period between the end of one lactation and the start of the next (2 month prior to parturition or calving)
What does life of a cow look like
Calf –> Bred (14-18 months) –> 1st calving (23-25 months) –> dried off (305-320 days in milk) –> calf for 2nd time –> calf or culled re-bred
Explain the lifecycle of cottontail rabbit
- Becomes pregnant immediately after parturition
- Pregnant and lactate for 18 days
- Dry period of 8-10 days after weaning
- Cycle is repeated 4-6 times a year
- Rarely repeated for more than 2 seasons
What is the importance of dry period?
Ø Allow mammary gland to go through a period of Involution
Ø Ensures maximum number of secretory cells in Early lactation
Ø Minimize metabolic disorder
What are the characteristics of unique involution?
- Involution during the dry period in markedly less than in other species
- Few epithelial cells are lost, no detachment of cells from basement membrane
- Area occupied by epithelium does not change and alveolar structures remain intact
What are the justifications for the dry period?
1- Old cells produce less milk than new cells
2- Life span of old cells is shorter than new cells
3- # of proliferative cells will increase during the dry period
What are the stage of drying-off?
Ø Build-up of intra-mammary pressure
Ø Rapid decline of lactose biosynthesis (within few
hours)
Ø Water transportation to the epithelial cells stops
Ø Aveolar and lumenal areas decline (within 7 days)
Ø Aveolar system considerably collapses by day 28 but does not disappear
Physiology of the mammary gland during the dry period can be divided into three phases:
1- Active involution
2- Steady state involution
3- Redevelopment and colostrogenesis
Explain active involution
Ø Transition phase from lactating to non-lactating stage
Ø Duration: 21-30 days
Ø Changes in milk constituents, cell organelles and cell Secretions (discussed earlier)
Explain steady state involution
Ø Transition between active involution &re- development Ø Little fluid in the gland Ø High concentrations of leukocytes Ø Little milk fat or casein debris left Ø Immunoglobulin concentrations are high
Explain redevelopment and colostrogenesis
Ø Transition between non-lactating to lactating phase
Ø Begins 3-4 weeks prepartum
Ø Selective increase in uptake of immunoglobulins
Ø Increased concentrations of milk components (~2 weeks pre-partum, increased markedly 3-5 pre- calving)
