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 plasmatická membrána 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 bakteriemi, which thus remove e.g. from the surface of bronchial epithelia.

Enterocytes
Intestinal epithelial cell (enterocyte) lines the lumen tenkého střeva. 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 aktinových 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 mitochondrie, Golgiho aparát and endoplazmatické retikulum. 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

Pohárkové buňky 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 hormonů, 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 imunokompetentním buňkám, 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 erytrocytov 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 ezofageálního refluxu, peptického vředu 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 enzym, 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 amylasa 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 nefronu:

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 aktivnímu transportu, 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 osmotického tlaku. 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 osmosou 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 reninu. 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 mutací 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): Ve stratum germinativum je možno rozlišit další 3 vrstvy: (i) bazální, (ii) spinózní a (iii) granulární; každá představuje postupující stádia diferenciace a keratinizace. Konečným stádiem jsou mrtvé, stlačené buňky stratum corneum na povrchu pokožky. Epidermální buňky se odvíjejí mitotickým dělením z bazálních buněk, spočívajících jako jedna vrstva kubických buněk na bazální lamině. Ty se při diferenciaci směrem k povrchu stávají polyhedrické tak, jak syntetizují vzrůstající množství cytokeratinu. Vzájemnou adherenci epidermálních buněk udržují desmosomy, obsahující několik intracelulárních proteinů: S pokračující diferenciací se v buňkách objevujé keratohyalinní granula (granulární vrstva keratocytů). Tato granula vytvářejí protein filagrin, který navozuje agregaci cytokeratinových vláken do paralelních vrstev, čímž se buňky stávají „chemicky odolné“. Nerozpustnost a ochranné vlastnosti stratum corneum jsou dány: Tato tmelová substance tvoří velmi důležitou bariéru, která zabraňuje unikání vody z povrchu organismu. Byla nutným předpokladem života na souši. Ve stratum lucidum jsou cytokeratinová filamenta zalita hmotou obsahující eleidin. Bazální vrstva epidermis má stálou populaci germinálních buněk. Nové keratinocyty potřebují asi 14 dnů, aby se vyvinuly do buněk stratum granulosum a dalších 14 dní, aby se dostaly k povrchu stratum corneum a odlouply se.
 * 1) inner zone of living cells (stratum germinativum);
 * 2) outer layer of cornified cells (stratum corneum).
 * desmoplakin – způsobující jako paraneoplastický autoantigen pemfigus vulgaris;
 * transmembránový desmoglein, který se může stát autoantigenem při pemfigus folaceus i pemfigus vulgaris.
 * množstvím keratinových vláken obalených keratohyalinem v kornocytech;
 * ztluštěním membrán kornocytů nebo jejich zrohovatělým obalem;
 * depozicí glukosylceramidu a acylceraminů v mezibuněčném prostoru kornocytů.

Melanocyty
Melanocyty jsou kulaté buňky s nepravidelnými, velmi dlouhými výběžky, kterými pronikají mezi buňky stratum basale a stratum spinosum. Jejich konce zasahují do invaginací na povrchu keratinocytů. Melanocyty jsou připojeny k bazální lamině systémem hemidesmosomů. Mezi melanocyty a sousedními keratinocyty nejsou desmosomy vyvinuty. Funkcí melanocytů je syntéza melaninu, pigmentu vznikajícího z tyrosinu oxidovaného tyrosinoxidasou na dihydroxyfenylalanin (DOPA) a metabolizovaného dále až na melanin. Ten se dostává do granul, kde prodělává několik vývojových stádií. Konečným stadiem je vznik melanosomu. Zralé melanosomy jsou předávány cytoplasmatickými výběžky keratinocytům ve stratum basale a stratum spinosum (cytokrinní sekrece). V cytoplasmě keratinocytů se melaninová granula usadí v oblasti nad jádrem; chrání je tak (při dělení buňky) před škodlivým účinkem UV-záření (290–320 nm). Buňky, do nichž byl melanin umístěn, se nazývají melanofory.

Počet melanocytů se liší v různých oblastech kůže těla. Na zádech je asi 1000 na 1 mm2, na šourku 2000 na 1 mm2. Počet melanocytů není (!) ovlivněn ani pohlavím ani podle rasy; barva kůže je dána množstvím melaninových granul v keratocytech. Tmavnutí pokožky (opálení) po expozici UV je výsledkem dvoustupňového pochodu: Nedostatek kortisolu kupř. u Addisonovy choroby (insuficience kůry nadledvin) vede pro nedostatek zpětné vazby ke zvýšené sekreci ACTH a zvýšené pigmentaci pokožky. Věkem se snižuje obrat epidermálních buněk (klesá na 50% mezi 30. a 70. rokem). Ztráta elastinových i kolagenních vláken v kůži přispívá ke vzniku vzhledu tenkého papíru, transparentnosti a větší lomivosti cévek. Zmnožení křížových vazeb mezi kolagenními i elastinovými řetězci způsobuje větší rigiditu kůže („Stará“ kůže se vrací do původní polohy, je-li shrnuta, jen velmi pomalu). Kvalitativní změny dermálního kolagenu (jeho náhrada za amorfní bazofilní hmoty) způsobuje zvrásnění kůže zejména na obličeji a krku. Za každou dekádu se snižuje o 10–20 % počet enzymaticky aktivních melanocytů, což vede k vytváření nepravidelných pigmentových skvrn a k šednutí vlasů.
 * 1) fyzikálně-chemická reakce – tmavnutí již existujícího melaninu a jeho rychlý transport do keratinocytů;
 * 2) zvýšení syntézy melaninu v melanocytech, čímž se zvýší jeho celkové množství.

Další typy buněk
Langerhansovy dendritické buňky jsou ve stratum spinosum; patří do monocytomakrofágového systému, do skupiny buněk prezentujících antigen. Mají hvězdicový tvar a bývá jich v epidermis (event. v dermis) 400–1000 na 1 mm2. Merkelovy buňky se vyskytují v kůži tlustého typu (planta pedis nebo manus). Tvarově se blíží keratinocytům. Jde pravděpodobně o mechanoreceptory, i když jiní autoři se domnívají, že patří do skupiny buněk neuroendokrinních. Hranice mezi epidermis a dermis není rovná; výběžky dermis (papily) interdigitují s evaginací epidermis (epidermální lišty), které tak zpevňují dermo-epidermální spojení. Bazální buňky jsou spojeny s bazální laminou hemidesmosomy, kotvící intermediární filamenta a v dermis fibrily kolagenu VII. Elastická vlákna jsou připojena k bazální lamině fibrilinovými mikrofibrilami; na spojení se podílí též fibronektin. Věkem se počet Langerhansových buněk snižuje o 50 % (snížení imunoreaktivity).

Klinické poznámky
Psoriáza je chronické onemocnění kůže s genetickou predispozicí (HLA antigeny BW17, B13, BW37; kandidátní gen predispozice je asi na chromosomu 3q21 lokus PSORS5, gen SLC12A8) projevující se erytémovými papulkami a plaky se stříbřitými silnými šupinami, snadno odstranitelnými a lokalizovanými především nad kožními výběžky (loket, kolena) ale i jinde. Etiologie není známa. V patogenezi je výrazná proliferace epidermálních buněk (7x vyšší urychlení cyklu buněčného dělení). Doba, kdy se keratinocyty dostanou z bazální vrstvy až na povrch stratum corneum trvá pouze 3–4 dny (normálně 28 dní); dochází ke zvýšené keratinizaci, což vede ke ztluštění epidermis (papulky, plaky) a parakeratinózním změnám stratum corneum (stříbřité šupiny). V buňkách s pokročilou diferenciací byl identifikován glykoprotein, nazvaný korneodesmosin, který se pravděpodobně účastní adheze keratinocytů a je pravděpodobně faktorem náchylnosti k psoriáze. U kožních lézí je mnohem výrazněji exprimován.

Psoriáza je v současné době považována za zánětlivou dermatózu, vznikající pro abnormální homeostázu epidermis a charakterizovanou hyperproliferací a abnormální diferenciací keratinocytů s předcházející aktivací kožního imunitního systému. Jde o multifaktoriální onemocnění s patogenetickými mechanismy hereditárními i enviromentálními. Rozlišují se dva typy: familiární a sporadická. Soudí se, že psoriáza je autoimunitní onemocnění s podílem aktivace T-lymfocytů, uvolňujících řadu cytokinů (IL-8, INFγ), které navodí abnormální aktivaci a diferenciaci keratinocytů. Cílem terapie je potlačení proliferace keratinocytů a zánětlivé reakce kůže. Lokálně se aplikují steroidy, masti s dehtem a anthranilinem, dále ozařování UVB nebo UVA a kombinace. Perorálně se užívá psoralen, nověji kalciprotrienové masti (derivát vitaminu D – snižuje proliferaci). Systémově (u rezistentních případů) se nasazují antimetabolity a antimitotika (methotrexát, azathioprin, hydroxyurea), dále etretinát (retinoid).

Související články

 * Ledviny
 * Epitel
 * Žaludek
 * Pankreas