Epithelia (pathobiochemistry)

Epithelial cells form continuous sheets (surfaces), called epithelia, that line the internal and external surfaces of the body, or they form trabeculae, glandular acini or tubules. Their plasma membrane it is organized into at least two distinct sections that perform their specialized functions - we say that it is polarized. One side firmly adheres to the neighboring cell with its surface. There are a number of specialized types of epithelia:
 * Secretory epithelial cells are found in most epithelia. They are specialized in excreting various substances on the surface of the epithelial layers. They are the main part of glands with external (exocrine) and internal (endocrine) secretion.
 * Absorbent epithelia, on the other hand, absorb substances needed by the organism. Their surface is therefore increased many times over by protruding tiny villi, called microvilli. Individual epithelial cells are bound to each other by strong intercellular junctions, which maintain a mechanically continuous layer of epithelia and at the same time prevent the passage of small molecules between cells. The entire epithelial layer rests on the so-called basal membrane (lamina basalis). Examples are intestinal epithelia.
 * Ciliary epithelia (ciliated epithelia) have fine hairs on their surface, fluttering synchronously and thus moving the surface mucus with trapped dust or Bacteria, which thus remove e.g. from the surface of bronchial epithelia.

Enterocytes
Intestinal epithelial cell (enterocyte) lines the lumen Small intestine. It has two main functions The luminal (apical) part of the plasma membrane is specialized for absorption. This area is called brush border. Thin finger-like protrusions with a diameter of 100 nm, which are called microvilli, emerge from the surface. The absorption surface is thus increased many times over. Ties provide strength to microvillas Actin filament. The exoplasmic membrane of microvilli contains hydrolytic enzymes: These hydrolytic enzymes are components glycocalyx. Absorbed molecules into the enterocyte are transferred and excreted basolateral membrane into the bloodstream. Transport proteins located in the basolateral membrane are different from those that carry out absorption at the apical end. There are other protein molecules on the basement membrane that mediate anchoring to the basal lamina.
 * 1) absorb from the lumen of the intestine small molecules that were formed by digesting food;
 * 2) then transfer them into the bloodstream.
 * di- and tripeptidases, which cleave oligopeptides into individual ones aminokyseliny;
 * disaccharidases (saccharase, maltase, isomaltase, lactase, trehalase), which split disaccharides into the corresponding monosaccharides and thus enable their absorption.

Classification
Enterocytes can be classified into three cell types.

Absorptive cells (columnar absorptive cells) are lined on the luminal surface by a dense row of microvilli (the so-called brush border), which rest on a network of intracellular microfilaments under the cell membrane. Microvilli (or absorption cells) are the site of final digestion and absorption of food components. Each absorption cell has up to 3000 microvilli (1 x 0.1 μm), so the total area of the microvilli is about 2·108 cm2. On their surface is the apical cover - glycocalyx, which is the seat of hydrolytic enzymes such as disaccharidases (lactase, sucrase-isomaltase, maltase, trehalase), dipeptidases and alkaline phosphatase. Absorptive cells are rich in Mitochondria, Golgi apparatus and Endoplasmic reticulum. Transport across the luminal membrane takes place as follows: Glucose is transported from the intestinal lumen into the interior of the cell across the apical membrane using the glucose/Na+ symporter transporter facilitated diffusion. Na+ ions are pushed out of the enterocyte at the basolateral membrane by the action of the Na+/K+ ATPase pump. A similar absorption mechanism (like symport) also exists for amino acids. Note: Disacharidas deficiency (congenital or acquired) is accompanied by diarrhea and a number of other symptoms. Lactase deficiency is the most common.
 * Absorptive cells

Goblet cells they secrete mucin (acidic glycoproteins) and are deposited regularly between absorptive cells. It protects the intestinal lining and provides it with a lubricating effect.
 * Goblet cells

They are divided into a number of subtypes according to Hormone, which they produce
 * Enteroendocrine cells

M cells (membranous epithelial cells) are specialized as antigen presenting cells that phagocytose various antigeny. They pass them on after processing Immunocompetent cells, lying beneath them in the lymphatic follicles.
 * M-cells

Parietal (covering) cells of the gastric mucosa
These cells have microvilli on the luminal side of the membrane, the basal side is very well supplied with blood from blood capillaries. They also contain very numerous mitochondria, which indicates their high energy turnover. Their main task is acidification of gastric contents by secretion of HCl up to to a concentration of 0.1 mol/l (pH = 1,0). This is done by the activity of H+/K+ ATPase on the apical side of the membrane. This is similar to Na+/K+ ATPase Erythrocytes membrane, but unlike it, its activity is electroneutral: it expels 1 H+ ion and transfers 1 K+ ion into the cell during one cycle of hydrolysis ATP (with the Na+/K+ pump, 3Na+ is expelled/exchanged for 2K+). The proton concentration gradient between the lumen of the stomach and the cytosol of the parietal cell is 106, that is, a million times higher (pH 1.0 versus pH 7.0). The concentration of OH− in the cytosol would be expected to increase proportionally (based on Eq: [H+] x [OH−] = 10–14mol2). That this does not happen (the pH of the cytosol remains neutral) is due to the fact that the excess OH− reacts with CO2, which diffuses into the cytosol from the bloodstream; arises like this HCO3− and carbonate anhydratase catalysis. Anion HCO3− is transported across the basolateral membrane via an anion exchange protein (similar to band 3 protein in erythrocytes, see also Hamburgerův efekt) in exchange for Cl− into the bloodstream. He also participates in it Cl− - and K+ antiport.

Therapeutic blockade of H+/K+ ATPase in parietal cells will significantly reduce the acidity of gastric secretions, which is used to treat Esophageal reflux, Peptic ulcer and other conditions with excessive gastric acid secretion. This is done by application omeprazole, which is the so-called suicidal substrate of this enzyme, that is, it binds irreversibly to enzyme, which then cannot continue in its function. A gradual restoration of gastric acid secretion occurs in about 24-48 hours, when new (unblocked) parietal cells are formed during their regular renewal from basal cells.

Acinar pancreatic cell
Similar to the enterocyte (they share a common embryonic basis), it has two functional areas: The basolateral part of the membrane is surrounded by blood capillaries and is where nutrients come from. On its surface, it has numerous receptors for peptide hormones regulating the formation and secretion of zymogens according to the food received. These hormones originate from the epithelia of the stomach and small intestine. Pancreatic cells form (with about a dozen identical cells) a small spherical formation – pancreatic acinus. The central cavity of the mouth of the acinus is lined with ductal cells (centroacinar cells). Acinar cells contain zymogenic granules in which pancreatic hydrolytic enzymes are stored in an inactive form: trypsinogen, chymotrypsinogen, elastase, procarboxypeptidases, aminopeptidases, ribonucleases, etc amylase a lipasa.
 * 1) One part synthesizes and stores the hydrolytic enzymes necessary to digest food in the intestine.
 * 2) The apical part, where clusters of secretory vesicles gather, is the site of secretion zymogenů.

Renal tubule cells
The main function of the renal tubular cells is the transport of water and substances filtered by the glomeruli into the "primary" urine. Transport across tubular cells is an example of epithelial transport that occurs by multiple, polarized mechanisms across multiple biological membranes. Renal tubule cells can be classified into the following categories according to location in Nephron:

Proximal tubule cells
They line the first part of the 1st order coiled canals. There are so-called tight connections between them (tight junction), they contain numerous mitochondria that supply energy Active transport, on the luminal side, they are endowed with a brush border that passes into the basolateral membrane. They have a number of water channels, the reabsorption of water and electrolytes is proportional, the filtrate in the lumen is isotonic. Reabsorption occurs first by equalization Osmotic pressure. In the basolateral membrane there is: In the brush border is placed:
 * Na+/K+ ATPasa, which reabsorbs Na+ výměnou za K+.
 * Furthermore, passive reabsorption takes place here Na+ s HCO3− and passive reabsorptionK+ over K+ channels.


 * cotransport for reabsorption of Na+-solutes and Na+/H+ antiport (reabsorbs Na+ and secretes H+);
 * anion exchange transport that reabsorbs Cl− in exchange for formate.
 * There is also osmotic reabsorption of H2O, secretion of organic cations in exchange for H+ and exchange of urate anions (proximal reabsorption and distal secretion).

Descending arm of the loop of Henle (thin part)
It is highly permeable to water and moderately permeable to most solutes. Contains few mitochondria (little or no active transport). The tubule lumen leaves more water than solutes (filtrate is hypertonic). The filtered water is reabsorbed here by Osmosis and minimal passive reabsorption of solutes.

Ascending arm of the loop of Henle (thick part)
It is impermeable to H2O. Passive reabsorption of solutes occurs in the thin ascending segment. The thick ascending segment contains mitochondria (for active transport). The output of solutes from the lumen rises more as the filtrate progresses through the ascending segment and therefore the filtrate becomes hypotonic. The basolateral membrane houses the Na+/K+ ATPase and channels for passive Cl− reabsorption and channels for passive K+ reabsorption. In the brush border there is a reabsorption cotransporter Na+/K+/2 Cl− and a secretory channel for K+.

Cells of the distal tubule (proximal diluting segment)
They are impermeable to water and urea, contain mitochondria to support active transport. There is a macula densa for feedback control of secretion renin. Solutes leave the lumen as the filtrate progresses and the filtrate becomes hypotonic. It contains the same channels as the thick ascending limb of the loop of Henle.

Cells of the distal tubule (farther segment)
There are 2 types of cells: principal and intercalary. Permeability for water and urea varies with antidiuretic hormone secretion (ADH). In the absence of ADH reabsorption of NaCl causes the filtrate in the lumen to become progressively more hypotonic; in the presence of ADH, water is reabsorbed along the medullary gradient and the filtrate gradually becomes hypertonic. The basolateral membrane contains Na+/K+ ATPase (in principal cells) and H+ ATPase in intercalary cells – the latter is responsible for the formation of acidic urine by H+ secretion. Furthermore, there are reabsorption K+ and Cl- channels.

Collecting duct cells
The antidiuretic effect of ADH consists in increasing the water permeability of the apical membrane of the cells of the lower segment of the nephron. The mechanism is as follows: In the absence of ADH with aquaporiny 2 (AQP2) they are found outside the plasma membrane, but near it in specific vesicles - aquaphores. Stimulation of the cell ADH induces signal transduction aquaphor fusion with by the adjacent apical membrane and forms water channels in it; this makes the apical membrane permeable to water molecules. In the absence of ADH, water channels are pulled from the membrane back into vesicles by endocytosis. This whole sequence is repeated during the next stimulation. Intracellular transduction of the ADH signal occurs through a specific receptor for vasopressin (V2), which is part of the G-protein family, to form a second messenger – cAMP –and protein kinase A (PAK) activation. Another aquaporin (AQP3) is located on the basolateral membrane, which in turn facilitates the exit of water from the cell.

Clinical notes
Renal tubular epithelia line the lumen of the renal tubules. The human kidney is composed of approximately 1.2 million tubules, which must maintain their tubular structure in order to perform their function properly.

In autosomal dominant polycystic kidney disease, cysts are formed in the kidneys by disordered dilation of the tubules. Disease is caused Mutation genu PKD 1 or PKD 2. PKD 1 encodes a membrane protein called polycystin 1, which is required for cell-cell or cell-extracellular matrix interaction. The PKD 2 gene encodes polycystin 2, a membrane channel protein (non-selective Ca2+-regulated cation channel - permeable to Ca2+, Na+ and K+). Polycystin 1 and polycystin 2 together form a heterodimer, which is necessary for the translocation of polycystin 2 from the inside of the cell, where it is formed, to the cell membrane, where it performs its function. Both are required for proper renal tubule morphology and function.
 * Polycystic kidneys

Bartter's syndrome is characterized by hypokalemia due to significant urinary K+ losses, metabolic alkalosis, and low or normal blood pressure; at the same time, the production of renin (hyperplasia of the juxtaglomerular apparatus) and aldosterone is increased; furthermore, the responsiveness of the pressor effects to the infusion of angiotensin II is reduced. The production of prostaglandin E2, prostacyclin, kallikrein and bradykinin is often increased. The level of Mg2+ is usually reduced for hypermagnesiuria. The inheritance of the disease is autosomal recessive. Mutation of the gene for the renal Na+-K+-Cl- cotransporter (rarely) and chloride channel mutation (more often) have been demonstrated. In contrast, Gitelman syndrome, which is a clinically milder variant with hypercalciuria and elevated plasma Ca (but ionized Ca is normal), with normal prostaglandin production; it is caused by a mutation in the gene for the renal thiazide-sensitive Na+-Cl- cotransporter. In the treatment of Bartter's syndrome, an increased supply of K+ and Na+ is recommended, and in the case of hypomagnesemia, Mg is also recommended for hypermagnesiuria. Spironolactone reduces urinary K+ losses. In some patients, it is useful to administer prostaglandin synthetase inhibitors and angiotensin-converting enzyme inhibitors.
 * Bartter syndrome

A relatively rare mutation of the AVPR2 gene, which codes for the production of the V2 antidiuretic receptor, or a more common mutation of the AQP2 gene causes familial nephrogenic diabetes insipidus. AQPR2 mutations have been classified into 3 types: 1. type of mutated receptor does not reach the membrane surface; in type 2, the receptor is on the membrane but does not have the ability to bind AVP; The 3rd type is either completely inactive or degraded quickly after formation. The consequence is a disorder of the kidney's ability to concentrate, polyuria, polydypsia, hyposthenuria, which does not improve after the application of vasopressin. There is drug nephrogenic diabetes insipidus: Demeclocycline non-competitively inhibits the activity of adenylate cyclase; lithium salts cause vasopressin resistance by inhibiting adenylate cyclase by stimulating the inhibitory activity of Gi-protein.
 * Familial diabetes insipidus

Skin epithelium
After gastrulation, a single layer of pluripotent ectoderm covers the surface of the embryo. Soon after, as the mesenchymal cells settle under the ectoderm, the epidermis and its appendages begin to form. Ectoderm turns into skin. Skin epithelia are separated from the underlying mesenchyme by the basal lamina of the extracellular matrix. The mesenchyme determines what type of epithelia and their accessory structures are formed. This means that when whole skin with hair follicles is transplanted into an area of skin without hair (e.g. palm or flat), hair follicles will also form in that place. The skin therefore knows which appendages to create and the mesenchyme provides the appropriate stimuli for this.

Epidermal cells
The epidermis (skin) is a constantly renewing multi-layered organ whose cells are in constant differentiation. The interstitial part has 2 main zones of cells (keratinocytes):
 * 1) the inner zone of vital cells (stratum germinativum);
 * 2) the outer layer of cornified cells (stratum corneum).  Another 3 layers can be distinguished in the stratum germinativum: (i) basal, (ii) spinous and (iii) granular; each representing advancing stages of differentiation and keratinization. The final stage is the dead, compressed cells of the stratum corneum on the surface of the skin . Epidermal cells develop by mitotic division from basal cells, resting as a single layer of cubic cells on the basal lamina. These become polyhedral during differentiation towards the surface as they synthesize increasing amounts of cytokeratin. The mutual adherence of epidermal cells is maintained by desmosomes, containing several intracellular proteins:


 * desmoplakin – causing pemphigus vulgaris as a paraneoplastic autoantigen ;
 * transmembrane desmoglein, which can become an autoantigen in both pemphigus folaceus and pemphigus vulgaris.

With continued differentiation, keratohyaline granules (granular layer of keratocytes) appear in the cells. These granules produce the protein filaggrin, which induces the aggregation of cytokeratin filaments into parallel layers, making the cells "chemoresistant". The insolubility and protective properties of the stratum corneum are given by:


 * by the amount of keratin fibers covered by keratohyalin in cornocytes;
 * thickening of cornocyte membranes or their cornified cover;
 * deposition of glucosylceramide and acylceramines in the intercellular space of cornocytes.

This sealant substance forms a very important barrier that prevents water from escaping from the surface of the organism. It was a necessary prerequisite for life on land. In the stratum lucidum, cytokeratin filaments are embedded in a mass containing eleidin. The basal layer of the epidermis has a constant population of germ cells. New keratinocytes take about 14 days to develop into cells of the stratum granulosum and another 14 days to reach the surface of the stratum corneum and slough off.

Melanocytes
Melanocytes are round cells with irregular, very long processes, through which they penetrate between the cells of the stratum basale and stratum spinosum. Their ends extend into invaginations on the surface of keratinocytes. Melanocytes are attached to the basal lamina by a system of hemidesmosomes. Desmosomes are not developed between melanocytes and neighboring keratinocytes. The function of melanocytes is the synthesis of melanin, a pigment formed from tyrosine oxidized by tyrosine oxidase to dihydroxyphenylalanine (DOPA) and further metabolized to melanin. It enters the granules, where it goes through several stages of development. The final stage is the formation of a melanosome. Mature melanosomes are transmitted by cytoplasmic protrusions to keratinocytes in the stratum basale and stratum spinosum (cytocrine secretion). In the cytoplasm of keratinocytes, melanin granules settle in the area above the nucleus; thus protecting them (during cell division) from the harmful effects of UV radiation (290–320 nm). The cells in which the melanin has been placed are called melanophores.

The number of melanocytes varies in different areas of the body's skin. On the back there are about 1000 per 1 mm 2, on the scrotum 2000 per 1 mm 2. The number of melanocytes is not (!) affected by gender or race; skin color is determined by the amount of melanin granules in keratocytes. Skin darkening (tanning) after UV exposure is the result of a two-step process:


 * 1) physico-chemical reaction – darkening of already existing melanin and its rapid transport to keratinocytes;
 * 2) increasing the synthesis of melanin in melanocytes, thereby increasing its total amount.

Cortisol deficiency e.g. in Addison's disease (insufficiency of the adrenal cortex) it leads to increased ACTH secretion and increased skin pigmentation due to a lack of feedback. Epidermal cell turnover decreases with age (it drops to 50% between the ages of 30 and 70). The loss of elastin and collagen fibers in the skin contributes to the paper-thin appearance, transparency and increased vascular fragility. The increase in cross-links between collagen and elastin chains causes greater rigidity of the skin ("Old" skin returns to its original position when contracted, only very slowly). Qualitative changes in dermal collagen(its substitute for amorphous basophilic mass) causes wrinkling of the skin, especially on the face and neck. Every decade, the number of enzymatically active melanocytes decreases by 10-20%, which leads to the formation of irregular pigment spots and graying of hair.

Other cell types
Langerhans dendritic cells are in the stratum spinosum; belongs to the monocytomacrophage system, a group of antigen-presenting cells. They have a star shape and there are usually 400-1000 of them in the epidermis (possibly in the dermis) per 1 mm 2. Merkel cells are found in the skin of the thick type ( planta pedis or manus). They are similar in shape to keratinocytes. These are probably mechanoreceptors, although other authors believe that they belong to the group of neuroendocrine cells. The boundary between epidermis and dermis is not straight; the projections of the dermis (papillae) interdigitate with the evagination of the epidermis (epidermal ridges), which thus strengthen the dermo-epidermal connection. Basal cells are connected to the basal lamina by hemidesmosomes, anchoring intermediate filaments and collagen VII fibrils in the dermis. Elastic fibers are attached to the basal lamina by fibrillin microfibrils; fibronectin is also involved in the connection. With age, the number of Langerhans cells decreases by 50% (decrease in immunoreactivity).

Clinical notes
Psoriasis is a chronic skin disease with a genetic predisposition ( HLA antigens BW17, B13, BW37; the candidate gene for predisposition is probably on chromosome 3q21 locus PSORS5, gene SLC12A8 ) manifesting as erythematous papules and plaques with silvery thick scales, easily removed and localized mainly above skin protrusions (elbow, knees) but also elsewhere. The etiology is unknown. In the pathogenesis, there is a significant proliferation of epidermal cells (7 times higher acceleration of the cell division cycle). It only takes 3-4 days (normally 28 days) for keratinocytes to reach the surface of the stratum corneum from the basal layer; there is increased keratinization, which leads to thickening of the epidermis (papules, plaques) and parakeratinous changes in the stratum corneum(silvery scales). A glycoprotein, called corneodesmosin, has been identified in cells with advanced differentiation , which is likely involved in keratinocyte adhesion and is likely a susceptibility factor for psoriasis. It is much more pronounced in skin lesions.

Psoriasis is currently considered an inflammatory dermatosis arising from abnormal homeostasis of the epidermis and characterized by hyperproliferation and abnormal differentiation of keratinocytes with preceding activation of the skin immune system. It is a multifactorial disease with both hereditary and environmental pathogenetic mechanisms. Two types are distinguished: familial and sporadic. Psoriasis is thought to be an autoimmune disease with the involvement of T-lymphocyte activation, releasing a series of cytokines (IL-8, INFγ) that induce abnormal activation and differentiation of keratinocytes. The goal of the therapy is to suppress the proliferation of keratinocytes and the inflammatory reaction of the skin. Steroids are applied locally, ointments with tar and anthraniline, as well as UVB or UVA irradiation and combinations. Psoralen, more recently calciprotriene ointment ( vitamin D derivative – reduces proliferation) is used orally. Antimetabolites and antimitotics ( methotrexate, azathioprine, hydroxyurea) and etretinate (retinoid) are used systemically (in resistant cases).

related articles

 * Kidneys
 * Epithelium
 * Stomach
 * Pancreas

Source

 * MASOPUST, Jaroslav, et al. Pathobiochemistry of the cell. 1st edition. Prague: Charles University, 2nd Faculty of Medicine, 2003. 344 pp.  ISBN 80-239-1011-6.