milk synthesis and lactation

Milk synthesis and lactation

Mammary gland:

                               Milk production   units  of  the mammals are known as mammary gland ex: cattle have four mammary glands.

Number of mammary glands in different species

Anatomy  and Physiology of Mammary gland:

                                                                                   The mammary gland of the dairy cow is composed of millions of milk-producing alveoli, which convert blood components into protein, fat, and lactose. The gland is attached to the body by the median and lateral suspensory ligaments. Milk exits each mammary gland via a teat equipped with a teat canal. Nutrients are brought to mammary tissue by the mammary artery, which passes through the inguinal canal to the dorsal surface of the udder, ending in capillaries that supply milk precursors to alveoli. After the interchange between blood and tissue, blood reaches the small veins, which run dorsally and unite to form the mammary veins at the base of the udder. Interstitial fluids originating from capillaries that nourish milk-producing cells recirculate via the lymphatic system, which carries waste products away from the udder. The major nerves are the sensory nerves that carry impulses from the four quarters and teats to the brain. The nervous system has no direct involvement in the production of milk or removal from the udder, but it is essential to the milking process by triggering mechanisms of hormone release from the brain to the mammary tissue.

Lactogenic:

                   is the term meaning the initiation of lactation? This is the process of functional differentiation which mammary tissue undergoes when changing from a nonlactating to a lactating state. This process is normally associated with the end of pregnancy and around the time of parturition. Because lactogenesis is particularly dependent upon a specific set of hormones (called the Lactogenic Complex of hormones), mammary tissue from most states of the nonlactating mammary gland also can be made to undergo some degree of lactogenesis by the administration of high amounts of those hormones, even in nonpregnant animals.

Defining Principles of Lactogenesis:

Lactogenesis is a series of cellular changes whereby mammary epithelial cells are converted from a nonsecretory state to a secretory state.

Lactogenesis is a two-stage process :

1. Cytologic and enzymatic differentiation of alveolar epithelial cells. This coincides with very limited milk synthesis and secretion before parturition. Cytological changes associated with stage 1 of lactogenesis are described below. Enzymatic changes include increased synthesis of acetyl CoA carboxylase, fatty acid synthetase, and other enzymes associated with lactation, and increases in uptake transport systems for amino acids, glucose, and other substrates for milk synthesis. Note that synthesis of a-lactalbumin, and therefore, lactose synthesis does not begin until stage 2 of lactogenesis. Stage 1 of lactogenesis coincides with the formation of colostrum and immunoglobulin uptake (see The Neonate and Colostrum sections).

2. Copies secretion of all milk components. In the cow, this begins about 0-4 days before parturition and extends through a few days postpartum. It is not until the release of the inhibitory effects of progesterone on lactogenesis (about 2 days prepartum in many mammals) and the stimulation by the very high blood concentrations of prolactin and glucocorticoids associated with parturition, that copious milk secretion begins (stage 2 of lactogenesis).

Milk synthesis process:                          

The precursors of milk components leave the blood and enter the extracellular fluid between the capillaries and the epithelial cells. Precursors then are taken up from the extracellular fluid through the basolateral membrane of the epithelial cell. Once inside the cell the precursors enter the appropriate synthetic pathway. Also, some pre-formed proteins, such as immunoglobulins, are transported intact through the cell. There are 5 routes by which milk precursors or components enter milk in the alveolar lumen, including uptake of amino acids, uptake of sugars and salts, uptake of milk fat precursors, uptake of preformed proteins (immunoglobulins, and the paracellular pathway. The diagram below indicates the mechanisms of uptake and utilization of amino acids for protein synthesis, glucose for lactose synthesis, fatty acids, and glycerol for milk fat synthesis, immunoglobulins for transport across the cells, and the paracellular pathway.
Amino acids to proteins: Amino acids are absorbed through the basal membrane of the cell by several specific amino acid transport systems. Once inside the cell, amino acids are covalently bound together to form proteins at the polysomes (poly-ribosomes) on the rough endoplasmic reticulum (RER). Proteins that are synthesized at the RER include the proteins to be secreted (such as the milk proteins casein, ß-lactoglobulin, and a-lactalbumin) and membrane bound proteins (such as proteins involved in cell-cell contacts and membrane bound enzymes). Newly synthesized proteins are transferred from the RER to the Golgi apparatus where they are processed for transport out of the cell. Remember that casein is secreted as a micelle; the micelle is formed in the Golgi from the casein molecules, calcium, and phosphorous. Caseins and other proteins undergo post-translational processing in the Golgi. Proteins that remain in the cell are synthesized by the ribosomes in the cytoplasm; these would include all the cellular enzymes, structural proteins in the cells such as keratin, and all other cellular proteins. Milk proteins and lactose are transported to the apical membrane of the cell via secretory vesicles that bud off of the Golgi; these secretory vesicles are bounded by a lipid bilayer membrane. These secretory vesicles make their way to the apical membrane by a mechanism involving microtubules (made of polymerized tubulin). Tubulin is one of several cytoskeletal proteins which form the cellular scaffolding, providing the cell with structure; keratin is another cytoskeletal protein. The secretory vesicles do not transfer to the basolateral membrane. At the apical membrane, the membrane of the secretory vesicle fuses with the inner surface of the apical membrane, resulting in an opening through which the vesicle contents are discharged into the alveolar lumen. Glucose to lactose: Glucose enters the cell via the basolateral membrane via a specific transport mechanism. Some glucose is converted to galactose. Both glucose and galactose enter the Golgi and enter into a reaction resulting in the formation of lactose (see Lactose Lesson). The formation of lactose in the Golgi results in drawing water into the cell, into the Golgi, and ultimately becoming part of milk. Note that the Golgi apparatus is involved in the processing of milk proteins, synthesis of lactose, and the osmotic draw for water. The Golgi apparatus is very important to the synthesis of skim milk components. Note that lactose (and therefore much of the water of milk) is secreted via the secretory vesicles along with the milk proteins. Milk fat precursors to milk fat: Precursors of milk fat synthesis are also taken up by the epithelial cells at the basolateral membrane. Acetate and ß-hydroxybutyrate are important precursors of fatty acid synthesis in mammary cells in some species (ruminants, especially). These precursors are absorbed through the basolateral membrane. Besides, preformed fatty acids, glycerol, and monoacylglycerides are absorbed in the basolateral membrane. All these components enter into the synthesis of triglycerides of milk (see milk Fat Lesson). Milk fat triglycerides are synthesized on the smooth endoplasmic reticulum (SER) and form small droplets. Numerous small lipid droplets will fuse together as the growing lipid droplet moves toward the apical membrane. At the apical membrane the large lipid droplet forces out the apical membrane of the cell, the apical membrane surrounds the lipid droplet until it pinches off and enters the lumen. [Imagine standing inside a balloon and trying to punch your hand through the balloon's wall. The balloon's wall would wrap around your hand.] So, in the lumen of the alveolus, the milk fat globule (or milk lipid globule as it is now called) is surrounded by a membrane. This membrane originally was part of the epithelial cell's apical membrane. Note that INSIDE the cell the lipid is NOT membrane-bound and is called a lipid droplet, while after secretion in the LUMEN, the milk lipid globules are surrounded by a membrane. Transport of Milk Components Not Synthesized in the Epithelial Cells :  Several other components pass across the epithelial cell barrier essentially unchanged from their form in the blood. These include immunoglobulins which bind to specific receptors on the basolateral surface of the cells are taken "into" the cell in endocytic vesicles, and are transported to the apical side of the cell via the endocytic vesicles (or transport vesicles), where the membrane of the transport vesicles fuses with the inner surface of the apical membrane of the cell and releases the immunoglobulin into the the lumen of the alveolus. As the transport vesicles traverse the cell they do not seem to interact with the Golgi, secretory vesicles or the lipid droplets. Some serum albumin may be transported across the epithelial cells by this mechanism. There is not a serum albumin receptor, however, serum albumin molecules probably are internalized into the cell along with the immunoglobulins which are taken up by transport vesicles. Paracellular Pathway: Because of the tight junctions between epithelial cells, there is little or no "flow" of anything between the cells, except perhaps water and some ions. Anytime something passes between the cells through the tight junction, this is called the paracellular pathway. When the udder is inflamed, such as during mastitis or involution, or when oxytocin is causing milk ejection, the tight junctions open some or become 'leaky'. This allows lactose and potassium to move from the lumen into the extracellular space, and for sodium and chlorine to move into the lumen from the extracellular space. This results in a change in electrical conductivity of the milk (as used in detecting mastitis), as well as an increase in concentrations of lactose and other milk-specific components in the blood. Lactose can be measured in the urine of a cow during the peripartum period. Milk proteins can be detected in the cow's blood during lactation and early involution. Other components that can enter the lumen without passing through the epithelial cells are leukocytes (discussed in Mastitis Module). The leukocytes comprise the vast majority of the somatic cells in the milk. These cells pass between the epithelial cells and in the process they "break open" the tight junctions between the epithelial cells and enter via the paracellular pathway. Of course, this also allows other extracellular components like salts to diffuse into the lumen and milk components to diffuse out of the lumen into the extracellular fluid. [This is one reason why there is a change in electrical conductivity in the milk during mastitis. Glactopoesis: Galactopoiesis is the maintenance of lactation once lactation has been established. Two key interrelated components contribute to the maintenance of lactation, galactopoietic hormones, and removal of accumulated milk. Because of the importance of galactopoietic hormones in milk production, sometimes the word galactopoiesis also is used to indicate an enhancement of lactation, especially in dairy animals. Inhibition of secretion of key galactopoietic hormones will depress milk production to varying degrees depending on the species, stage of lactation, and the particular hormone is suppressed. The role of galactopoietic hormones such as prolactin in the maintenance of lactation is well established. Prolactin is released at the time of milk removal in ruminants and nonruminants, and it remains a key systemic modulator of milk secretion during lactation. Conversely, growth hormone is generally considered to be the predominant galactopoietic hormone in ruminants. Inhibition of prolactin secretion or administration of prolactin to lactating cows has little effect on milk yields. Regardless of the hormones involved, all attempts to evaluate milk secretion must account for the continued removal of milk. This is a reminder of the critical role of local mammary factors in the maintenance of milk secretion. One such factor that plays a major role in regulating milk secretion in many species is a feedback inhibitor of lactation (FIL) found in milk. FIL is thought to be produced by the mammary cells as they synthesize and secrete milk. Accumulation of FIL in the milk-producing alveoli results in feedback inhibition of milk synthesis and secretion. Frequent removal of milk from the gland minimizes local inhibitory effects of FIL and increases milk secretion. Milk removal involves several mechanisms that impact milk production, including removal of local inhibitory components, regulation of local blood flow, and even physical factors in the alveolus. The effects of the frequency of milk removal are tied closely with the local regulation of milk secretion.