ANS 124: Involution

In a mouse MG, what are the changes in Alveolar Volume upon weaning?

Alveolar Volume goes up, then down.

In a mouse MG, what are the changes in Adipose Volume upon weaning? What process is happening?

Adipose Volume increases gradually with time as the adipocytes refill with triglycerides.

In a mouse MG, what are the changes in number of Epithelial Cells upon weaning? Via what process?

Epithelial cells start to disappear (via apoptosis).

What area of the body goes through the highest rate of apoptosis?

mammary gland

What are the 2 phases/stages of Mammary Involution?

Apoptotic Phase

Tissue Remodeling Phase

What triggers the Apoptotic Phase of mammary involution?

Occurs with milk accumulation.

The Apoptotic Phase takes about ____ hours to occur.

48 hours

Once the Apoptotic Phase starts, can it be stopped in the middle? If so, how?

Yes, it can be halted by suckling if pups are returned.

what genetically?In order to start the Apoptotic Phase, cells must first alter what genetically?

cells must first alter gene expression for proteins that control cell function (by activating cell death pathways)

What are 3 transcription factors that would activate cell death pathways (apoptosis) at the gene promoters?

CEBP-Delta

STAT3

NF-KappaB

What are 3 ways to induce involution?

Weaning of offspring

Drying a cow off

Teat Sealing

What is Teat Sealing?

it is a 'model' for mimicking milk stasis

With how many hours after teat sealing do transcription factors start activating cell death pathways (apoptosis)?

within 12 hours

During Apoptosis, what 5 things are happening inside the cell?

Nuclear Condensation

Mitochondrial Breakdown

Cytoskeletal Breakdown

Membrane Blebbing

DNA Fragmentation

Mitochondrial breakdown during apoptosis leads to the activation of what enzymes?

Caspases

What do Caspases do?

they are enzymes involved in cell death and trigger the cell to fall apart

What does Membrane Blebbing mean?

the membrane has holes and is now permeable

What are the 2 main reasons why epithelial cells do apoptosis so quickly? Explain each reason.

To prevent mastitis (risk of mastitis is very high for milk just stored there).

The MG becomes a viral target for viruses, so the gland is getting rid of any cells that are not necessary so that there is no DNA that can be hosts for the viral genome.

What is an example of a virus that targets the MG?

HPAI

What are the 2 places where apoptotic epithelial cells "die" or end up at?

Either apoptotic cells are shed into the alveolar lumen.

OR

Apoptotic cells die in their bed (within the alveolus)

How long does apoptosis of epithelial cells take after the start of involution? (estimate # of days)

2-4 days after involution starts

What do epithelial cells detach from during apoptosis?

detach from the basement membrane

During involution, what cells come through the lymphatics to help?

Immune cells

What is an example of an immune cell that is involved in involution of the MG?

macrophages

What do immune cells do in the MG during involution?

they help clean up cellular debris

What can the remaining epithelial cells, that are still there after the immune cells come, do?

Epithelial cells are able to phagocytose (eat) their neighbors.

What happens to the milk in the lumen during involution? (where does it go)

Milk in alveoli lumen goes through Tight Junctions to go to the Extracellular Space. The liquid and nutrients of the milk are absorbed back to circulation through the lymphatics.

What are the 4 purposes of cells in the MG phagocytosing Epithelial Cells during involution?

Remove Excess Cells

Remove Potential Toxins being Released from Dying Cells

Possibly Help to Plug Holes in Alveoli (remodeling)

Reduce Possible Risks of Mastitis?

During involution, as the epithelial cells go through apoptosis, what process are they undergoing?

Necrosis

Is it only epithelial cells that can phagocytose other epithelial cells?

No, other cells can eat them too.

What are 3 other cells in the MG that can phagocytose epithelial cells?

Macrophages

There's a hypothesis that Fibroblasts and Adipocytes can also phagocytose them.

Does phagocytosis of apoptotic cells induce an inflammatory response in the tissue?

No, it does not induce an inflammatory response.

During involution, there is an induction of what type of activity in the epithelial cells remaining in the alveoli?

induction of antimicrobial activity

During days 3-5 after involution starts, what molecules are present for antimicrobial activity?

Ferrous Molecules

2-3 days after stasis, the synthesis of what 3 proteins in mice stops?

Whey Acidic Protein (WAP)

Caseins

α-Lactalbumin

During lactation, what transcription factor was binding to the promoters of Whey Acidic Protein (WAP), Caseins, and α-Lactalbumin?

STAT5

During involution, what transcription factor is binding to the promoters of Whey Acidic Protein (WAP), Caseins, and α-Lactalbumin now?

STAT3 binds to the promoter to stop synthesis.

2-3 days after stasis, the remaining cells are now turning on gene expression of what 2 specific Ferrous Molecules?

Lactoferrin (LF)

Ferritin Heavy Chain (FHC)

Why are the remaining cells turning on gene expression for Ferrous Molecules during involution?

to prevent mastitis

Around how many days into involution does the "second phase" of tissue remodeling happen?

5-7 days after involution starts

During tissue remodeling, what is produced? By what cells?

various enzymes produced by the stromal cells

The various enzymes produced by the stromal cells during tissue remodeling do what 2 specific things?

Help to remodel the basement membrane

Digest milk proteins, epithelial cell components, etc.

After involution and tissue remodeling is finished, what does the MG ducts look like?

ducts go back to the pregnancy-associated ducts with no alveoli.

After involution, what happens if pregnancy happens again?

the MG starts the rebuilding process all over again

For a dairy cow, what is their involution called?

The Dry Period

For a dairy cow, the optimal dry period relates to what in their lactation?

relates to maximum milk yield

In an optimal dry period, the cow is pregnant for about ___% of lactation.

70%

A cow lactates for around ________ days.

300 days

After a cow calves, do they keep cycling during lactation?

Yes

After a cow calves, when do they get pregnant again?

at day 60 of lactation after they calve

How long is gestation for a dairy cow?

9 months

During what timeframe is a cow's dry period?

The time after lactation stops and the cow hasn't given birth yet.

The optimal dry period should be ___-___ days for a dairy cow. What is the ideal number of days?

45-60 days

ideal is 45 days

What happens if a cow's dry period is <45 days? How does that affect milk yield?

MG does not have enough time to involute properly, so the next lactation will not give maximum milk yield.

In Dairy Cows, when milking is stopped, do the alveoli undergo massive apoptosis (like in the mice)?

No, the alveoli don't undergo massive apoptosis as much as mice.

In Dairy Cows, what happens immediately after milking is stopped?

the cessation of milk synthesis following milk accumulation

During the involution/dry period of Dairy Cows, what is the cow getting ready for at the same time? What process is that called?

getting ready for next lactation (ex. starting colostrogenesis)

What are 3 benefits of Breastfeeding in humans?

Less Disease (ex. allergies)

Increase IQ

Increase Maternal Infant Bonding

The benefit of breastfeeding leading to less disease is particularly important in what babies? Why?

premature babies, because it increases their chances of survival.

Why is the rate of Breastfeeding Rates in the US low? What are they using instead?

Because moms were using formula. Historically, there was a push by formula companies to use baby formula instead of breastfeeding.

Over the years, what is the trendline of Breastfeeding Rates in the US?

It is increasing as more and more women choose to breastfeed now.

Human babies should be breastfed at minimum to what age?

~6 months old

Are there variations of % of mothers that breastfeed their babies between the US and different parts of the world? Why?

Yes, there are differences. One reason is the difference in social acceptance/stigma of breastfeeding in public.

The majority (95%) of mothers choose the decision to breastfeed because of what reason?

choose due to health benefits for baby

5% of mothers choose the decision to breastfeed because of what reason?

convenience

As the child gets older, what happens to the % that are breastfed?

It decreases

List a few other reasons/benefits to breastfeeding.

Nutrient Balance

Antibody Transfer & Composition

Sterile & Warm Milk

Cheap

No Mess, No Fuss vs. Bottle Prep

etc.

What is the major #1 (30-40% of women) reason why women stop breastfeeding?

Not producing any milk, or inadequate amount.

What are 4 potential reasons why women would be not producing any milk, or an inadequate amount to have to stop breastfeeding?

Stress

Nutritional reasons

Disease

Mom's own perception that they're not making enough, when in reality they are.

What are a few other major reasons why women stop breastfeeding?

Felt it was time to stop

Resumed Work

Teething

Pregnant (again)

etc.

In the first week of lactation for humans, many women will complain of what?

engorged breasts (pain)

In the first week of lactation for humans, many women will complain of engorged breasts, which is caused by what 2 reasons?

Baby can't latch on

Lack of milk release

What are 4 ways to provide relief for women that complain of engorged breasts (pain) in the first week of lactation?

Breast Pumping

Warm/Cold Compress

Cabbage Compress

Milk Expression

What does the American Academy of Family Physicians recommend to adoptive mothers?

encourage them to breast feed if possible

For humans, they may require assistance to stimulate lactation. List a few ways they can do that.

Contraceptive Pill short term to induce mammary growth?

Dopamine Antagonists (to induce PRL)

Breast Pumping (to remove milk and stimulate cells to make more)

etc..

Is Oxytocin still used to assist humans in stimulating lactation?

it's no longer used

List a few factors that can negatively impact milk production in humans.

Polycystic Ovary

Medium/Heavy Smoker

Hypothyroidism

Retained Placenta

Anemia

Obesity

Stress

etc.

In humans, what is a tool that is used for milk collection?

Breast Pumps

Breast Pumps can be used for what 2 reasons?

Engorgement Relief

Milk Collection for Working Mothers

etc.

Breast Pumps typically cycle up to ____ pulses/second with a vacuum of ____-____ mmHg.

50 pulses/second with a vacuum of 200-250 mmHg.

Typically ___-___ mL of milk is expressed when a Breast Pump is used.

50-100 mL milk

What are 2 physical devices that assist in breast milk acceptance during adoptive lactation?

Lact-Aid Nursing Trainer

Supplemental Nursing System (SNS)

Breast Cancer affects what part of the world more?

North America (western part of the world)

In the US, what is a woman's chance of getting Breast Cancer?

1 in 8

Do white or black people have more incidences of Breast Cancer?

White people

Why do black people have a higher mortality of Breast Cancer compared to white people that have higher incidences of Breast Cancer?

Due to differences in access to health care.

How does a woman's chance of getting breast cancer relate to age?

Risk increases with age.

A lot of breast cancer cases usually start at what age?

At a younger age of 20-30s years old. (but doesn't appear until later)

What is one risk factor of Breast Cancer?

Radiation Exposure

Explain how radiation exposure increased risk of Breast Cancer in the post WWII atomic bomb survivors.

Younger women had an increased incidence of breast cancer compared to older women because the mammary gland was still growing when exposed to large amounts of radiation (causing mutations in the DNA).