Epithelial Transport Flashcards by Adele Orovec

What are the functions of epithelial cells?

protection, sensation, ion transport and fluid secretion, secretion of chemical mediators, nutrient absorption, excretion, diffusion

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3 basic units in epithelial structure:

cells, tight junctions, basement membrane

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epithelial cells are:

polarized - distinct domains

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apical vs basolateral

facing the lumen vs facing interstitial space

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what is the BM composed of and what does it do?

protein fibers, connects epithelial tissue to underlying connective tissues and provides support

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Tight junctions…

for every Na transported, an anion must also be transported - this depends on permeability of tight junction

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WHat do tight junctions do?

act as a barrier to migration of apical membrane proteins to basolateral membrane, act as a fence to maintain polarity, binds epithelium together = structural support, constitutes an extracellular route for movement of electroyltes

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EPithelial permeability is a hallmark of what?

mucosal inflammation

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Apical Junction Complexes (AJC) play an important role in what?

epithelial defence

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AJCs are made up of…

Tight junctions and adherens junctions

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TJ regulate

paracellular transport of ions and molecules

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AJ important for

initiation and maintenance of cell cell adhesion

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Dysfunction of epithelial junctions is linked to what?

airway disease and may predispose to infections

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Barrier function normally studied by??

Growing cells on semi premeable membrane supports - this has strengths and weaknesses

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Junction function measured by..?

permeability to small ions and analyzing TEER, using permeability probes of different sizes and measuring flux

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Apparent Flux =

Flow rate (surface area X starting concentration)

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molecules that cross paracellularly via TJs should show..?

linear and non saturable permeability

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TJ proteins

claudins, Ig like proteins aka JAM and CAR, MARVEL proteins like occludin, tricellulin and MARVELD3

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AJ proteins

Cadherins plus associated catennins

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In the cytosol there is what protein that link the intracellular domains of TJ components with actin binding proteins?

Zonula Occludens (ZO)

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Intact epithelial junctions prevent..?

inappropriate ligand/receptor interactions

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barrier dysfunction allows for

penetration of particles and anitgens into subeptiehlial space where they encounter immune cells

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Three mechanisms of inducible AJC dysfunciton, not mutually exclusive

Apical junction degraded by extracellular proteases released by inflammatory cells. 2. AJP component expression can be silenced at transcirptional or post transcirptional level. 3. JUnction complexes can be disrupted via internalization or shedding of AJP components

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3 things that cause junction dysfunciton in airways

Air pollution, respiratory virus, cystic fibrosis - all decrease TEER

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What dsitinguishes an epithelial cell from other cell types?

Polarity - ability to segregate different but complimentary proteins between two distinct membrane domains

Polarity is made possible by

Tight junctions

becuase of polarity, these cells can perform

vectoral transport

two pathways for movement -

paracellular and transcellular

EPithelia can also perform selective

absorption and secretion

Sodium Potassium ATPase located

basolateral membrane, 3 Na out, 2 K+ in

basolateral membrane voltage is

negative and predominantely K+ conductive

intracellular concentrations of K+, Na_, and Cl-

100 mM, 10-25mM, 15-25mM

transepithelial transport of Na incolces

primary active transport

Na movement into the cell is always:

downhill via ENaC

net sodium movement produces elevated osmolarity on that side and decrease osmolarity in the lumen which results in

osmotic flow of water across epithelium in same direction as net solute movement

Categorizing epithelium as

absorptive or secretory and leaky or tight

Resistance is

opposition to the passage of an electric current

there is an inverse relationship between transeptiehlial resistance and

ionic permeability

Net transepithelial resistance given by:

Rt = RcRpc/Rc+Rpc

leaky epithelium has ___ resistance TJs

low resistance

tight epithelia has ___ resistance TJs

high resistance

How do you study transepithelial ion movement?

Ussing Chamber

The short circuit current is:

the current that is required to reduce Vt to zero

lsc is

charge flow per unit time when the tissue is short circuited (Vt = 0mV)

electrical resistance Rt is calculated from

Ohm's Law Rt = change in V/ change in I

Vt is the voltage difference between the

apical and basolateral bahting solutions

Electrogenic Na transport

through ENaC and Na pump, Cl paracellularly, Absorption

Active Cl secretion

NKCC and CFTR, Na paracellularly, Secretion

ENaC consists of how many subunits, and what are they?

3, alpha, beta and gamma

airway epithelia absrob Na via

amiloride sensitive electrogenic transport

ENaC is important for the maintenance and composition of

ASL

which subunits are expressed in type 2 alveolar cells?

alpha and gamma, not beta

what does the heterogeneity of ENaC along airway surface suggest

differential regulation of liquig absorption by channels of various subunit composition

CFTR dysfunciton is linked to what?

increase in ENaC activity

Why is ENaC important for fluid clearance?

at birth, important to clear liquid from alveoli, alpha ENaC knowckout mice die at birth, reduced alpha ENaC expression results in delayed resolution of pulmonary edema after injury

What is the predominant ion transport pathway present in alveolar epithelium?

Na+, dominant mechanism of alveolar liquid clearance

Na enters via ___ and exits the basolateral membrane by _____

ENaC and Na-K ATPase

ENaC is inhibited by

amiloride

Na transport can be regulated by increasing what?

ENaC gene expression by glutocorticoids

ENaC must be ___ by what to be active?

cleaved by intracellular furin type or extracellular serine proteases

protease inhibitors lead to

silent ENaC - sits in membrane until proteolytically cleaved

Claved by 3 things -

intracellular convertase type proteases, extracellular cell attached proteases, soluble proteases such as trypsin and neurophil elastase

What happens after cleavage of ENaC?

inhibitor regions of e/c loops are the alpha and gamma subunits are removed

Most important ion transport process of alveolar epithelial cells is

active sodium transport from alveolar lining fluid into interstitum

Na moves _____ electrochemical gradient created via _____

down, Na pump

Cl moves ___

paracellularly

Na transport is critical for?

re-absorption of edema fluid following alveolar flooding

Patient with ALI and ARDS have higher morbidity and mortality if...

alveolar fluid clearance mechanisms are imparied

Pulmonary edema is caused by???

cardiac failure or gdamage to alveolar cells

Reactive oxygen species can ____ Na transport and ____

decrease, fluid clearance

infection with what can inhibit Na transport/liquid movement

Pseudomonas aeruginosa

ALI stands for

Acute Lung Injury

ARDS

Acutre respiratory distress syndrome

Both ALI and ARDS are chacrterized by

acute inflammation that affects gas exchange

ALI and ARDS can result from 2 things..?

direct pulmonary injury (pneumonia) or indirect blood borne insults (spesis)

What does ARDS present with clinically?

breathlessness and pulmonary edema

What distinguishes ALI from ARDS

severity of hypoxemia

VALI?

ventilatory associated lung injury - high mortality rates

Pathophysiology Early phase is associated with

acute inflammation of alveolar capillary membrane, necorsis of type 1 cells denudes BM causing hyaline membrane, protein rich edema fluid in intersitium and alveolus, inflammation associated with activated neutrophuls and alveolar macrophages which secrete inflammatory mediators

what do inflammatory mediators do in ALI/ARDS?

impair durfactant production by ATII

neutrophils are activated by what?

cytokines - TNF-alpha, IL-1, 6, and 8

What else occurs?

thrombosis and extravascular fibrin deposition

VALI can further the problem by...

inducing release of more proinflammatory cytokines

Name a symptom of ALI

1. protein rich hyaline membrane 2. neutrohpils adhere to capillary endothelium and migrate to alveolus 3. loss of membrane integrity 4. impaired surfactant secretion 5. capillary microthrombi and extravascular deposition 6. increase pulmonary dead space 7. hypoxemia

Do most patients recover from acute inflammatory phase?

yes

How do people recover?

type 2 cells proliferate in response to epithelial GF to recover the denuded BM, type 2 cells are progenitors for noth type 1 and 2, epithelial barrier is restored, hyaline membrane is phagocytosed by macrophages

If lung injury is too severe or epithelial repair is impaired what happens?

fibroproliferative phase can develop - mesenchymal cells proliferate, neovascularization, alveolar space gets filled with fibroblasts that make collagen, thickening walls

What marks the final stage of ALI/ARDS

intra-alveolar fibrosis - decreases compliance, sevrer hypozia and ventilatory dependence, lung scarring, cyst development

Epithelial Transport Flashcards

(88 cards)