Development of epithelial glands

Most glands develop as epithelial outgrowths into the underlying connective tissue (Figure 2-1). Exocrine glands remain connected to the surface of the epithelium by an excretory duct that transports the secretory product to the outside. Endocrine glands lack an excretory duct, and their product is released into the blood circulation.

Figure 2-1 Development of exocrine and endocrine glands

Endocrine glands are surrounded by fenestrated capillaries and commonly store the secretions they synthesize and release after stimulation by chemical or electrical signals. Exocrine and endocrine glands can be found together (for example, in the pancreas), as separate structures in endocrine organs (thyroid, parathyroid), or as single cells (enteroendocrine cells). Endocrine glands will be studied later in Chapter 18, Neuroendocrine System, and Chapter 19, Endocrine System.

Classification of epithelial glands

Glands are classified according to the type of excretory duct into simple and branched (also called compound) glands. The gland can be simple (Figure 2-2) when the excretory duct is unbranched. The gland can be branched when the excretory duct subdivides (Figure 2-3).

Figure 2-2 Simple glands

Figure 2-3 Glands with branched ducts

The secretory portion can be unicellular or multicellular

An exocrine gland has two components: a secretory portion and an excretory duct. The secretory portion of a gland may be composed of one cell type (unicellular, for example, goblet cells in the respiratory epithelium and intestine) or many cells (multicellular).

According to the shape of the secretory portion (see Figures 2-2 and 2-3), glands can be tubular, coiled, or alveolar (Latin alveolus, small hollow sac; plural alveoli), also called acinar (Latin acinus, grape; plural acini).

Tubular glands are found in the large intestine. The sweat glands of the skin are typical coiled glands. The sebaceous gland of the skin is an example of an alveolar gland.

Shape of the secretory portion

Glands can be classified as simple tubular or simple alveolar (or acinar) according to the shape of the secretory portion. In addition, tubular and alveolar secretory portions can coexist with branching excretory ducts; the gland is called a branched (or compound) tubulo-alveolar (or acinar) gland (for example, the salivary glands). The mammary gland is an example of a branched alveolar gland.

A branched gland (Figure 2-4) is surrounded by a capsule. Septa or trabeculae extend from the capsule into the glandular tissue. Large septa divide the gland into a number of lobes. Branches from the septa separating adjacent lobes divide the lobes into smaller compartments called lobules.

Figure 2-4 Histologic overview of a compound salivary gland

During development, a main excretory duct gives rise to branches that lie either between (interlobar) or within lobes (intralobar). Small branches derived from each of these ducts generate small subdivisions that constitute the lobule of a gland. These branches can be found first between lobules (interlobular) and within lobules (intralobular). Additional details are presented in Chapter 17, Digestive Glands.

Types of secretion

Based on the type of secretion, exocrine glands can be classified as mucous glands, when their products are rich in glycoproteins and water; serous glands, with secretions enriched with proteins and water; and mixed glands, which contain both mucous and serous cells (Figure 2-5).

Figure 2-5 Histologic differences between submandibular, sublingual, and parotid glands

Mechanisms of secretion

Exocrine glands can also be classified on the basis of how the secretory product is released (Figure 2-6).

Figure 2-6 Mechanisms of glandular secretion

In merocrine secretion (Greek meros, part; krinein, to separate), the product is released by exocytosis. Secretory granules are enclosed by a membrane that fuses with the apical plasma membrane during discharge or exocytosis. An example is the secretion of zymogen granules by the pancreas.

In apocrine secretion (Greek apoknino, to separate), the release of the secretory product involves partial loss of the apical portion of the cell. An example is the secretion of lipids by epithelial cells of the mammary gland. Proteins secreted by epithelial cells of the mammary gland follow the merocrine pathway (exocytosis).

In holocrine secretion (Greek holos, all), the secretory product constitutes the entire cell and its product. An example is the sebaceous glands of the skin, which produce a secretion called sebum.

Plasma membrane

A review of major concepts of cytomembranes and organelles and their clinical relevance is presented in this chapter. Epithelial glands are a convenient topic for this integration. We initiate the review by addressing the structural and biochemical characteristics of the plasma membrane. Additional information related to plasma membrane–mediated cell signaling is presented in Chapter 3, Cell Signaling.

The plasma membrane determines the structural and functional boundaries of a cell. Intracellular membranes, called cytomembranes, separate diverse cellular processes into compartments known as organelles. The nucleus, mitochondria, peroxisomes, and lysosomes are membrane-bound organelles; lipids and glycogen are not membrane-bound and are known as inclusions.

The plasma membrane consists of both lipids and proteins. The phospholipid bilayer is the fundamental structure of the membrane and forms a bilayer barrier between two aqueous compartments: the extracellular and intracellular compartments. Proteins are embedded within the phospholipid bilayer and carry out specific functions of the plasma membrane such as cell-cell recognition and selective transport of molecules (see Box 2-A).

Phospholipid bilayer

The four major phospholipids of plasma membranes are phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and sphingomyelin (Figure 2-7). They represent more than one half the lipid of most membranes. A fifth phospholipid, phosphatidylinositol, is localized to the inner leaflet of the plasma membrane.

Figure 2-7 Structure of the plasma membrane

In addition to phospholipids, the plasma membrane of animal cells contains glycolipids and cholesterol. Glycolipids, a minor membrane component, are found in the outer leaflet, with the carbohydrate moieties exposed on the cell surface.

Cholesterol, a major membrane constituent, is present in about the same amounts as are phospholipids. Cholesterol, a rigid ring structure, does not form a membrane but is inserted into the phospholipid bilayer to modulate membrane fluidity by restricting the movement of phospholipid fatty acid chains at high temperatures. Cholesterol is not present in bacteria.

Two general aspects of the phospholipid bilayer are important to remember:

Membrane proteins

Most plasma membranes consist of about 50% lipid and 50% protein (Figure 2-8). The carbohydrate component of glycolipids and glycoproteins represents 5% to 10% of the membrane mass. The surface of a plasma membrane is coated by a glycocalyx (see Box 2-B).

Figure 2-8 Peripheral and integral proteins of the plasma membrane

According to the fluid mosaic model of the membrane structure, membranes are two-dimensional fluids in which proteins are inserted into lipid bilayers. It is difficult for membrane proteins and phospholipids to switch back and forth between the inner and outer leaflets of the membrane. However, because they exist in a fluid environment, both proteins and lipids are able to diffuse laterally through the plane of the membrane. However, not all proteins can diffuse freely; the mobility of membrane proteins is limited by their association with the cytoskeleton.

Restrictions in the mobility of membrane proteins are responsible for the polarized nature of epithelial cells, divided into distinct apical and basolateral domains that differ in protein composition and function. Tight junctions between adjacent epithelial cells (discussed in Chapter 1, Epithelium) not only seal the space between cells but also serve as barriers to the diffusion of proteins and lipids between the apical and basolateral domains.

Two major classes of membrane-associated proteins are recognized: peripheral proteins and integral membrane proteins.

Peripheral membrane proteins are not inserted into the hydrophobic interior of the membrane but are, instead, indirectly associated with membranes through protein-protein ionic bond interactions, which are disrupted by solutions of high salt concentration or extreme pH.

Portions of integral membrane proteins are inserted into the lipid bilayer. They can only be released by solubilization using detergents. Detergents are chemical agents that contain both hydrophobic and hydrophilic groups. The hydrophobic domains of the detergent penetrate the membrane lipids and bind to the membrane-inserted hydrophobic portion of the protein. The hydrophilic domains combine with the protein, forming aqueous-soluble detergent-protein complexes.

Numerous integral proteins are transmembrane proteins, spanning the lipid bilayer, with segments exposed on both sides of the membrane. Transmembrane proteins can be visualized by the freeze-fracture technique.

Freeze-fracture: Differences between a surface and a face

The freeze-fracture technique is valuable for the visualization of intramembranous proteins with the electron microscope. This technique provided the first evidence for the presence of transmembrane proteins in the plasma membrane and cytomembranes.

Specimens are frozen at liquid nitrogen temperature (−196°C) and “split” with a knife (under high vacuum) along the hydrophobic core of the membrane. As a result, two complementary halves, corresponding to each membrane bilayer, are produced. Each membrane half has a surface and a face. The face is artificially produced during membrane splitting.

A replica of the specimen is generated by evaporating a very thin layer of a heavy metal (generally platinum with a thickness of 1.0 to 1.5 nm) at a 45° angle to produce a contrasting shadowing effect. The platinum replica is then detached from the real specimen by floating it on a water surface, mounted on a metal grid, and examined under the electron microscope.

Figure 2-9 indicates the nomenclature for the identification of surfaces and faces in electron micrographs of freeze-fracture preparations.

Figure 2-9 Freeze-fracture: Differences between surface and face

The surface of the plasma membrane exposed to the extracellular space is labeled ES, for extracellular surface. The surface of the plasma membrane exposed to the cytoplasm (also called protoplasm) is labeled PS, for protoplasmic surface.

The face of the membrane leaflet looking to the extracellular space (the exocytoplasmic leaflet in the illustration) is labeled EF, for extracellular face. Similarly, the face of the leaflet facing the protoplasmic space (identified as a protoplasmic leaflet) is PF, for protoplasmic face.

Now that we have an understanding of what surface and face represent, remember that faces are chemically hydrophobic and surfaces are chemically hydrophilic. One last point: Note that a transmembrane protein stays with the protoplasmic leaflet, leaving a complementary pit in the opposite exocytoplasmic leaflet. Why? Cytoskeletal components may be directly or indirectly attached to the tip of the protein exposed to the cytoplasmic side and will not let go.

Transporter and channel proteins

Most biological molecules cannot diffuse through the phospholipid bilayer. Specific transport proteins, such as carrier proteins and channel proteins, mediate the selective passage of molecules across the membrane, thus allowing the cell to control its internal composition.

Molecules (such as oxygen and carbon dioxide) can cross the plasma membrane down their concentration gradient by dissolving first in the phospholipid bilayer and then in the aqueous environment at the cytosolic or extracellular side of the membrane. This mechanism, known as passive diffusion, does not involve membrane proteins. Lipid substances can also cross the bilayer.

Other biological molecules (such as glucose, charged molecules, and small ions—H⁺, Na⁺, K⁺, and Cl⁻) are unable to dissolve in the hydrophobic interior of the phospholipid bilayer. They require the help of specific transport proteins (Figure 2-10) and channel proteins, which facilitate the diffusion of most biological molecules.

Figure 2-10 Transporters

Similar to passive diffusion, facilitated diffusion of biological molecules is determined by concentration and electrical gradients across the membrane. However, facilitated diffusion requires one of the following:

Carrier proteins transport sugars, amino acids, and nucleosides. Channel proteins are ion channels involved in the rapid transport of ions (faster transport than carrier proteins), are highly selective of molecular size and electrical charge, and are not continuously open.

Some channels open in response to the binding of a signaling molecule and are called ligand-gated channels. Other channels open in response to changes in electric potential across the membrane and are called voltage-gated channels.

Endoplasmic reticulum

The endoplasmic reticulum is an interconnected network of membrane-bound channels within the cytoplasm, part of the cytomembrane system and distinct from the plasma membrane.

The endoplasmic reticulum system, consisting of cisternae (flat sacs), tubules, and vesicles, divides the cytoplasm into two compartments:

The smooth endoplasmic reticulum lacks ribosomes and is generally in proximity to deposits of glycogen and lipids in the cytoplasm. The smooth endoplasmic reticulum has an important role in detoxification reactions required for the conversion of harmful lipid-soluble or water-insoluble substances into water-soluble compounds more convenient for discharge by the kidneys. It also participates in steroidogenesis (see Chapter 19, Endocrine System).

Products released into the luminal compartment of the endoplasmic reticulum are transported to the Golgi apparatus by a transporting vesicle and eventually to the exterior of the cell by exocytosis. One can visualize the sequence in which the lumen of the cytomembrane system is interconnected and remains as such in an imaginary stage; you can visualize that the luminal compartment of a secretory cell is continuous with the exterior of the cell (Figure 2-11). The surrounding space is the cytosolic compartment in which soluble proteins, cytoskeletal components, and organelles are present.

Figure 2-11 Intracellular compartments

Now, let us visualize the membrane of each component of the cytomembrane system as consisting of two leaflets (Figure 2-12):

Figure 2-12 Leaflets of cytomembranes and plasma membrane

Let us imagine that exocytoplasmic and protoplasmic leaflets form a continuum. During the freeze-fracturing process, the knife fractures the membrane as it jumps from one fracture plane to the other across the hydrophobic core and splits membranes into two leaflets. The knife cannot stay with a single membrane because cytomembrane-bound organelles occupy different levels and have random orientations within the cell. This randomness will be apparent during the examination of the replica.

The sample may contain a combination of exocytoplasmic and protoplasmic leaflets which, in turn, can expose surfaces and faces. Membrane proteins tend to remain associated with the cytoplasmic (protoplasmic) leaflet and appear as particles on the PF (protoplasmic face). A shallow complementary pit is visualized in the EF (exocytoplasmic face).

Rough endoplasmic reticulum

The rough endoplasmic reticulum is recognized under the light microscope as a diffuse basophilic cytoplasmic structure called ergastoplasm.

The rough endoplasmic reticulum is involved in the synthesis of proteins, carried out by their attached ribosomes (Figure 2-13). In contrast, the membranes of the smooth endoplasmic reticulum lack attached ribosomes (see Figure 2-13). Most proteins exit the rough endoplasmic reticulum in vesicles transported to the cis portion of the Golgi apparatus (see Figures 2-16 and 2-17

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