cystic fibrosis 2 Flashcards
Organs affected by cystic fibrosis
CFTR is expressed by all epithelia (sheets of cells that form a ………….. between different compartments of the body and line the…………….., airways and many ……….). The epithelia of patients with CF are relatively impermeable to …………. and CF is therefore a multi-organ disease.
In the sweat glands, sweat is produced by cells at the base of the sweat gland and ………….. and ……………… ions are normally reabsorbed by epithelial cells lining the duct, so that only water reaches the surface to cool the skin. In CF, the epithelial cells lining the duct ………… to absorb chloride ions from the secreted sweat, and as a result sodium is also poorly absorbed. As a result of a defect in chloride absorbance, people with CF have unusually salty sweat.
In the pancreas; defective chloride ……………. results in defective transport of ……….- and water into the lumen of the ……….eatic ducts, and the ducts become obstructed. The digestive enzymes, amylase, lipase, and trypsinogen, are not delivered into the gut, resulting in a nutritional insufficiency. Patients require supplementation of their diet with the missing enzymes, given in capsule form before meals.
In the lungs; Defective CFTR results in defective chloride se……….., and increased sodium and water absor………… Clogging and infection of the airways impedes breathing. Infection leads to inflammation and lung damage. In over 90% of cases, res………… failure is the cause of death.
In the gut; defective CFTR leads to defective chloride secretion and increased sodium and water absorption, with dehydration and impaction of f………. matter.
The diagnosis of CF; The ‘diagnostic triad’ for CF is (1) ……….. sweat, (2) recurrent …………. infection and (3) failure to thrive or ………. weight.
Organs affected by cystic fibrosis
CFTR is expressed by all epithelia (sheets of cells that form a barrier between different compartments of the body and line the intestines, airways and many ducts). The epithelia of patients with CF are relatively impermeable to chloride and CF is therefore a multi-organ disease.
In the sweat glands, sweat is produced by cells at the base of the sweat gland and sodium and chloride ions are normally reabsorbed by epithelial cells lining the duct, so that only water reaches the surface to cool the skin. In CF, the epithelial cells lining the duct fail to absorb chloride ions from the secreted sweat, and as a result sodium is also poorly absorbed. As a result of a defect in chloride absorbance, people with CF have unusually salty sweat.
In the pancreas; defective chloride secretion results in defective transport of HCO3- and water into the lumen of the pancreatic ducts, and the ducts become obstructed. The digestive enzymes, amylase, lipase, and trypsinogen, are not delivered into the gut, resulting in a nutritional insufficiency. Patients require supplementation of their diet with the missing enzymes, given in capsule form before meals.
In the lungs; Defective CFTR results in defective chloride secretion, and increased sodium and water absorption. Clogging and infection of the airways impedes breathing. Infection leads to inflammation and lung damage. In over 90% of cases, respiratory failure is the cause of death.
In the gut; defective CFTR leads to defective chloride secretion and increased sodium and water absorption, with dehydration and impaction of fecal matter.
The diagnosis of CF; The ‘diagnostic triad’ for CF is (1) salty sweat, (2) recurrent lung infection and (3) failure to thrive or gain weight.
The diagnosis of cystic fibrosis;
The diagnosis of cystic fibrosis was based initially, and in the absence of genetic screening for cystic fibrosis, on three characteristics in the newborn.
Excessively salty sweat is the result of defective chloride absorption in the sweat glands. Normal values are less than ~4… mM. A sweat test is the mainstay of diagnosis. Pilo…………., a cholinergic agonist, is used to stimulate sweatinh to produce sufficient sweat to measure chlorided ion concentration.
Failure to thrive and gain weight (malnou………….) occurs as the defect leads to dehydrated secretions that block the pancreatic duct and prevents digestive enzymes from being delivered to the gut. Thus, despite apparently good nutrition, babies with CF fail to thrive and gain weight.
Finally, in the first few years of life, babies with CF are repeatedly admitted to hospital with chest infections. Persistent chest infection is due to defective chloride secretion and increased sodium and water absorption in the airways, leading to thick dess…………. secretions that invite infection and infla……………. In 95% of cases lung disease and respiratory failure is the cause of death.
Defective CFTR makes epit………… relatively impermeable to chloride. But chloride ions can move through CFTR in either direction, and in different organs the defect can result in defective absorption (as in sweat) or defective s………………. (as in the lungs and pancreas).
The diagnosis of cystic fibrosis;
The diagnosis of cystic fibrosis was based initially, and in the absence of genetic screening for cystic fibrosis, on three characteristics in the newborn.
Excessively salty sweat is the result of defective chloride absorption in the sweat glands. Normal values are less than ~40 mM. A sweat test is the mainstay of diagnosis. Pilocarpine, a cholinergic agonist, is used to stimulate sweatinh to produce sufficient sweat to measure chlorided ion concentration.
Failure to thrive and gain weight (malnourishment) occurs as the defect leads to dehydrated secretions that block the pancreatic duct and prevents digestive enzymes from being delivered to the gut. Thus, despite apparently good nutrition, babies with CF fail to thrive and gain weight.
Finally, in the first few years of life, babies with CF are repeatedly admitted to hospital with chest infections. Persistent chest infection is due to defective chloride secretion and increased sodium and water absorption in the airways, leading to thick dessicated secretions that invite infection and inflammation. In 95% of cases lung disease and respiratory failure is the cause of death.
Defective CFTR makes epithelia relatively impermeable to chloride. But chloride ions can move through CFTR in either direction, and in different organs the defect can result in defective absorption (as in sweat) or defective secretion (as in the lungs and pancreas).
Schematic of an eccrine sweat gland
Schematic repres…. of an eccrIne sweat gland.
The human sweat gland is a simple-coiled tubular exocrine gland that resides in the dermis and connects to the surface of the skin by a straight absorptive duct.
The secretory coil duct epithelium is composed of clear (CC), dark (DC), and myoepithelial cells (MEC), and is responsible for producing the primary secretion.
The reabsorptive duct ……………. is composed of two layers of cuboidal cells which absorb salt but not water.
The human eccrine sweat gland helps to maintain whole body temperature via the production of sweat in response to a hot environment, exercise, or emotional situations. An individual can secrete up to 4L of sweat in an hour to thermoregulate. Sweat consists primarily of water and salt, mostly …………. but is hypotonic with respect to the …………….. The sweat gets secreted onto the surface of the skin, where heat is lost from the body by the latent heat of eva………….. of the sweat fluid. The ability to lose heat is affected by the prevailing outside temperature as well as humidity.
It is estimated there are 2-4 million sweat glands distributed over the body, with the highest d…………. on the forehead, palms and soles of the feet.
Schematic of an eccrine sweat gland
Schematic representation of an eccrine sweat gland.
The human sweat gland is a simple-coiled tubular exocrine gland that resides in the dermis and connects to the surface of the skin by a straight absorptive duct.
The secretory coil duct epithelium is composed of clear (CC), dark (DC), and myoepithelial cells (MEC), and is responsible for producing the primary secretion.
The reabsorptive duct epithelium is composed of two layers of cuboidal cells which absorb salt but not water.
The human eccrine sweat gland helps to maintain whole body temperature via the production of sweat in response to a hot environment, exercise, or emotional situations. An individual can secrete up to 4L of sweat in an hour to thermoregulate. Sweat consists primarily of water and salt, mostly NaCl but is hypotonic with respect to the interstitium. The sweat gets secreted onto the surface of the skin, where heat is lost from the body by the latent heat of evaporation of the sweat fluid. The ability to lose heat is affected by the prevailing outside temperature as well as humidity.
It is estimated there are 2-4 million sweat glands distributed over the body, with the highest density on the forehead, palms and soles of the feet.
The normal sweat gland
In the normal sweat gland, sweat is produced in response to both cholinergic and …………….. stimulation in the secretory coil, where a salty fluid is first produced.
Cholinergic sweating occurs via a ……….-CFTR dependent mechanism, using an alternative Ca+-activated chloride ion channel (TMEM16A). The major physiological stimulus is acety………………
During fluid secretion that is stimulated adrenergically, Cl- is carried into the cell via the Na/K/Cl co-transporter in the bas…………. membrane of the secretory cell. Cl- leaves the cell at the apical membrane through the CFTR. Chloride ions are normally present at higher concentrations outside the cell, and it moves into the cell down a concentration gradient. Once inside the cell it is forced out by electrical forces through CFTR creating a ……….. potential in the lumen.
Sodium follows the movement of chlorine and passes between the cells through a path called the ‘tight junction’ which does not allow the movement of water or chloride. Where salt goes water follows, and water moves osmotically across the cell (tran………… movement of water) via aquaporins and a salty solution is produced in the secretory coil.
As the sweat passes out of the gland thro the absorptive duct, NaCl but not water is reabsorbed, the salt passes back towards the blood, so that the sweat that reaches the skin is mostly water with very little salt in it. The duct cells express the highest levels of CFTR and reabsorption of chloride ions depends on an active CFTR in both the apical and (unusually) basal membranes.
Both of the processes of secretion and absorption are driven by the Na/K pump in the basal membrane. This pump keeps Na concentration low in the cell, and sodium is able to diffuse into the cell down a concentration gradient. Because the attraction of chloride ions for sodium is strong then chloride ions follows the movement of sodium. Both CFTR and ENaC work in parallel, unlike in the airway epithelium, in which CFTR limits ENaC activity.
The normal sweat gland
In the normal sweat gland, sweat is produced in response to both cholinergic and adrenergic stimulation in the secretory coil, where a salty fluid is first produced.
Cholinergic sweating occurs via a non-CFTR dependent mechanism, using an alternative Ca+-activated chloride ion channel (TMEM16A). The major physiological stimulus is acetylcholine.
During fluid secretion that is stimulated adrenergically, Cl- is carried into the cell via the Na/K/Cl co-transporter in the basolateral membrane of the secretory cell. Cl- leaves the cell at the apical membrane through the CFTR. Chloride ions are normally present at higher concentrations outside the cell, and it moves into the cell down a concentration gradient. Once inside the cell it is forced out by electrical forces through CFTR creating a negative potential in the lumen.
Sodium follows the movement of chlorine and passes between the cells through a path called the ‘tight junction’ which does not allow the movement of water or chloride. Where salt goes water follows, and water moves osmotically across the cell (transcellular movement of water) via aquaporins and a salty solution is produced in the secretory coil.
As the sweat passes out of the gland thro the absorptive duct, NaCl but not water is reabsorbed, the salt passes back towards the blood, so that the sweat that reaches the skin is mostly water with very little salt in it. The duct cells express the highest levels of CFTR and reabsorption of chloride ions depends on an active CFTR in both the apical and (unusually) basal membranes.
Both of the processes of secretion and absorption are driven by the Na/K pump in the basal membrane. This pump keeps Na concentration low in the cell, and sodium is able to diffuse into the cell down a concentration gradient. Because the attraction of chloride ions for sodium is strong then chloride ions follows the movement of sodium. Both CFTR and ENaC work in parallel, unlike in the airway epithelium, in which CFTR limits ENaC activity.
The CF sweat gland
Why is CF sweat salty?
In CF the sweat glands do not respond to adrenergic stimulation and this is one of the hall marks of CF. However, the CF sweat gland responds normally to cholinergic stimulation and produces an initial salty sweat, through a different kind of calcium-activated chloride ion channel (TME………..).
The initial salty sweat moves up through the absorptive duct, either CFTR is a………. or it is non-functioning as a chl………. channel, so that chloride ions can not enter the duct cell through the apical membrane or leave thro the basal membrane. Consequently, sweat leaves the duct nearly as salty as it arrived.
Therefore one of the most obvious physi……… defects in CF is that sweat is salty. The sweat iontophoresis test stimulates sweat production through the cholinergic agonist applied iontophoretically to the skin of the forearm, and the sweat is collected and analysed for electrolytes. Chloride ion con………… > …….mM is diagnostic of CF.
Although not normally a major clinical problem, during hot and humid weather, CF patients can lose exce……….. salt and water and are prone to dehyd…….. and heat prostration.
Why is CF sweat salty?
In CF the sweat glands do not respond to adrenergic stimulation and this is one of the hall marks of CF. However, the CF sweat gland responds normally to cholinergic stimulation and produces an initial salty sweat, through a different kind of calcium-activated chloride ion channel (TMEM16A).
The initial salty sweat moves up through the absorptive duct, either CFTR is absent or it is non-functioning as a chloride channel, so that chloride ions can not enter the duct cell through the apical membrane or leave thro the basal membrane. Consequently, sweat leaves the duct nearly as salty as it arrived.
Therefore one of the most obvious physiological defects in CF is that sweat is salty. The sweat iontophoresis test stimulates sweat production through the cholinergic agonist applied iontophoretically to the skin of the forearm, and the sweat is collected and analysed for electrolytes. Chloride ion concentration > 60mM is diagnostic of CF.
Although not normally a major clinical problem, during hot and humid weather, CF patients can lose excessive salt and water and are prone to dehydration and heat prostration.
The normal pancreas
The defect in the function of CFTR in the pan……….has profound effects on pancreatic function. The pancreas is both an exocrine gland, secreting the digestive enzymes amy…….., lip………, tryp……… and chymotrypsinogen, as well as an endocrine gland producing insulin and gluca…….
The slide shows the role of CFTR in the normal pancreas. One of the most important features is the need for the pancreas to secret large amounts of bicarbonate ions into the intestine to ne……….. the effect of acid from the stomach.
The pancreatic ac……… cells secrete enzymes into the tubules and the movement of enzymes along the ducts and into the intestine depends on the secretion of a large volume of fluid which literally serves to wash them through. Initially the enzymes are produced in a salty fluid similar to sweat, and production of this fluid is independent of CFTR which is not expressed in …………… cells.
The subsequent secretion of fluid depends on the secretion of HC……..-, and ultimately on CFTR. Bicarbonate can not diffuse freely thro cell membranes, but depends on special transport mechanisms, including the chloride/bicarbonate exchanger. The addition of HCO3- to the lumen of the tubule is completely dependent on its exchange for chloride entering the cell at the apical membrane via the exch……… The energy of the chlo……. ions moving into the cell down a concentration gradient is used by the exchanger to push HCO3- out of the cell. The bicarbonate secretion is also dependent on CFTR because chloride is recycled back into the lumen thro CFTR as chloride detects the negative potential inside the cell. Each cycle moves another bicar……….. into the lumen, which accumulates there. Sodium follows the bicarbonate and is attracted into the lumen thro the tight junctions, the paracellular route, together with water, forming a solution of bica………… CFTR can directly add bicarbonate to the solution, but CFTR is about 5-times more permeable to chloride than bicarbonate ions.
The normal pancreas
The defect in the function of CFTR in the pancreas has profound effects on pancreatic function. The pancreas is both an exocrine gland, secreting the digestive enzymes amylase, lipase, trypsinogen and chymotrypsinogen, as well as an endocrine gland producing insulin and glucagon.
The slide shows the role of CFTR in the normal pancreas. One of the most important features is the need for the pancreas to secret large amounts of bicarbonate ions into the intestine to neutralise the effect of acid from the stomach.
The pancreatic acinar cells secrete enzymes into the tubules and the movement of enzymes along the ducts and into the intestine depends on the secretion of a large volume of fluid which literally serves to wash them through. Initially the enzymes are produced in a salty fluid similar to sweat, and production of this fluid is independent of CFTR which is not expressed in acinar cells.
The subsequent secretion of fluid depends on the secretion of HCO3-, and ultimately on CFTR. Bicarbonate can not diffuse freely thro cell membranes, but depends on special transport mechanisms, including the chloride/bicarbonate exchanger. The addition of HCO3- to the lumen of the tubule is completely dependent on its exchange for chloride entering the cell at the apical membrane via the exchanger. The energy of the chloride ions moving into the cell down a concentration gradient is used by the exchanger to push HCO3- out of the cell. The bicarbonate secretion is also dependent on CFTR because chloride is recycled back into the lumen thro CFTR as chloride detects the negative potential inside the cell. Each cycle moves another bicarbonate into the lumen, which accumulates there. Sodium follows the bicarbonate and is attracted into the lumen thro the tight junctions, the paracellular route, together with water, forming a solution of bicarbonate. CFTR can directly add bicarbonate to the solution, but CFTR is about 5-times more permeable to chloride than bicarbonate ions.
Destruction of the CF pancreas
The fundamental defect in CF is not with secretion of the enzymes, but with bicarbonate secretion. If, as in CF, there is no active CFTR chloride channel, then the secretion of bicarbonate will be limited, since chloride will accumulate in the cell from a functional ……… -/chloride exchanger, and is not recycled. If bicarbonate secretion is limited so is water movement into the lu………. and the amount of water needed to carry the dige………. enzymes thro to the intestine will be severely limited.
Without fluid in the ducts, the enzymes remain co………….., perhaps abnormally visc…….. and leave the pancreas more slowly than normal. Clearly this effect is dangerous as the digestive enzymes become autoa………… and begin to digest components of the pancreatic tubules and cells. The process occurs slowly over months or years as small du……… become damaged and the enzyme-producing acini lost.
As the ………… is slowly destroyed the amount of digestive enzymes produced becomes insufficient to support normal digestion.
In some patients the destruction progresses to loss of the i…………. producing cells of the pancreatic islets and the need for insulin therapy for CF-related diabetes.
The defect in the secretion of the digestive en………..leads to nutritional insufficiency in many CF patients and the need to treat the patients by oral replacement therapy with the missing enzymes. There are a number of diagnostic tests for pan……… insufficiency. These include examination of the stool for fat globules and lack of fecal chymo……… The loss of CFTR function in the membrane correlates well with the loss of pancreatic function, and is therefore more severe when CFTR or chloride transport is absent (Class ….. mutations) than when it is defective (Class ….. mutations).
Destruction of the CF pancreas
The fundamental defect in CF is not with secretion of the enzymes, but with bicarbonate secretion. If, as in CF, there is no active CFTR chloride channel, then the secretion of bicarbonate will be limited, since chloride will accumulate in the cell from a functional HCO3 -/chloride exchanger, and is not recycled. If bicarbonate secretion is limited so is water movement into the lumen and the amount of water needed to carry the digestive enzymes thro to the intestine will be severely limited.
Without fluid in the ducts, the enzymes remain concentrated, perhaps abnormally viscous and leave the pancreas more slowly than normal. Clearly this effect is dangerous as the digestive enzymes become autoactivated and begin to digest components of the pancreatic tubules and cells. The process occurs slowly over months or years as small ductules become damaged and the enzyme-producing acini lost.
As the pancreas is slowly destroyed the amount of digestive enzymes produced becomes insufficient to support normal digestion.
In some patients the destruction progresses to loss of the insulin producing cells of the pancreatic islets and the need for insulin therapy for CF-related diabetes.
The defect in the secretion of the digestive enzymes leads to nutritional insufficiency in many CF patients and the need to treat the patients by oral replacement therapy with the missing enzymes. There are a number of diagnostic tests for pancreatic insufficiency. These include examination of the stool for fat globules and lack of fecal chymotrypsin. The loss of CFTR function in the membrane correlates well with the loss of pancreatic function, and is therefore more severe when CFTR or chloride transport is absent (Class 1-3 mutations) than when it is defective (Class 3-4 mutations).
CFTR in the normal bronchial epithelium
CFTR is expressed in the large airways, ie the bronchi, and so we are considering its function in bronchial epithelial cells.
In the normal bro………. epith……… chlo….. ions are secreted at the apical membrane through CFTR and into the airway lu………. The channel is activated by phosphorylation. Increases in c………. in the cell activate protein ki………. ………, an enzyme that ph…………… a wide range of proteins including CFTR. Secretion also occurs thro alternate calcium-activated chloride channels, although most appears to be thro active CFTR.
So…….. and w………. follow the electro………….. gradient (resulting from the secretion of chloride ions) through the paracellular pathway increasing hydration of airway surface liquids (ASL). Some bicar……….. is also secreted through CFTR and serves to incr……. the p…. of A……..
Regulatory protein networks link CFTR to the epithelial sodium channel, ENaC, thro which sodium ions are normally absorbed. Active CFTR neg……….. regulates ENaC and suppresses its activity, and limits sodium uptake in the airway.
At the basal mem………. , chloride ions are transported into the cell via the Na/K/Cl co-transporter, and electrochemical gradients push Cl- out thro CFTR. Energy derived from the sodium/potassium p…….. drives the system, and keeps the sodium concentration in the cell low, so that sodium is able to move into the cell down a concentration gradient.
CFTR in the normal bronchial epithelium
CFTR is expressed in the large airways, ie the bronchi, and so we are considering its function in bronchial epithelial cells.
In the normal bronchial epithelium chloride ions are secreted at the apical membrane through CFTR and into the airway lumen. The channel is activated by phosphorylation. Increases in cAMP in the cell activate protein kinase A, an enzyme that phosphorylates a wide range of proteins including CFTR. Secretion also occurs thro alternate calcium-activated chloride channels, although most appears to be thro active CFTR.
Sodium and water follow the electrochemical gradient (resulting from the secretion of chloride ions) through the paracellular pathway increasing hydration of airway surface liquids (ASL). Some bicarbonate is also secreted through CFTR and serves to increase the pH of ASL.
Regulatory protein networks link CFTR to the epithelial sodium channel, ENaC, thro which sodium ions are normally absorbed. Active CFTR negatively regulates ENaC and suppresses its activity, and limits sodium uptake in the airway.
At the basal membrane, chloride ions are transported into the cell via the Na/K/Cl co-transporter, and electrochemical gradients push Cl- out thro CFTR. Energy derived from the sodium/potassium pump drives the system, and keeps the sodium concentration in the cell low, so that sodium is able to move into the cell down a concentration gradient.
CFTR expression in bronchial submucosal glands
CFTR is a key component of active chl……. secretion and water secretion. It is expressed in the airways predominantly by the serous cells of the submuc…. glands. These cells are present in the serous ac…….. of the glands, which are present in the bronchi, but the not the respiratory br…………… CFTR is also expressed by the ciliated surface epith…….. cells, but at much lower levels than the gland cells.
Mucus is a product of both the submu……… glands and the goblet cells of the surface epithelium. The remaining su………… epithelial cells are mainly the ciliated epithelial cells. There are many submucosal glands in the trachea and bronchi (~…./ mm2) and quantitatively these are a more important source of mucus than the g……. cells. Irritation of the tr………. and bronchi sti………. m……… secretion from m……… producing cells in the glands.
The mucus is produced by cells proximal to the airway, and washed into the airways by fluid secreted by the serous cells in the terminal ac….., the main site of CFTR expression. Secretion of water is driven by ac……. chlo…… secre……. thro CFTR, with the passive movement of water and sodium, as in the sweat gland.
In the CF airways there is a change in the balance between the mucus secreting and water secreting elements of the mucus glands. Mucus glands are increased in size (hype………) and there is a conversion of water-secreting serous cells into mucus secr……cells. More mucus and less water results in excessively vi…… secretions that are poorly shifted by the …….. and are therefore re……… in the airways, and accumulate with significant consequences for airway disease.
CFTR expression in bronchial submucosal glands
CFTR is a key component of active chloride secretion and water secretion. It is expressed in the airways predominantly by the serous cells of the submucosal glands. These cells are present in the serous acini of the glands, which are present in the bronchi, but the not the respiratory bronchioles. CFTR is also expressed by the ciliated surface epithelial cells, but at much lower levels than the gland cells.
Mucus is a product of both the submucosal glands and the goblet cells of the surface epithelium. The remaining surface epithelial cells are mainly the ciliated epithelial cells. There are many submucosal glands in the trachea and bronchi (~1/ mm2) and quantitatively these are a more important source of mucus than the goblet cells. Irritation of the trachea and bronchi stimulate mucus secretion from mucus-producing cells in the glands.
The mucus is produced by cells proximal to the airway, and washed into the airways by fluid secreted by the serous cells in the terminal acini, the main site of CFTR expression. Secretion of water is driven by active chloride secretion thro CFTR, with the passive movement of water and sodium, as in the sweat gland.
In the CF airways there is a change in the balance between the mucus secreting and water secreting elements of the mucus glands. Mucus glands are increased in size (hypertrophied) and there is a conversion of water-secreting serous cells into mucus secreting cells. More mucus and less water results in excessively viscous secretions that are poorly shifted by the cilia and are therefore retained in the airways, and accumulate with significant consequences for airway disease.
CFTR in normal airway epithelial cells
In the normal human airway, CFTR is expressed both in the surface epit………. and more predominantly in the submucosal glands. In normal airways a thin film of fluid ………….. the entire surface of the epithelium. The vo……… and com…….. of the airway fluid is determined by the relative contribution of salt reabs………. and salt secretion processes.
Salt secretion is mainly due to the secretion of chloride ions through the CFTR ion channel. CFTR normally has a negative reg………… effect on the epithelial sodium channels, which limits the uptake of sodium ions via this route, and thus the amount of water that is reabsorbed.
Salt reab……….. is mainly due to the passive diffusion of sodium down concentration gradients into the cell through the epithelial s………. channel (ENaC). The intracellular sodium con………….. is maintained at low levels by the activity of the Na/K pump in the basolateral membrane of the cells which pumps sodium back out of the cell.
Because sodium r…………….. is limited in the normal airway the epithelium that lines the airway is a secretory epithelium, ie there is net movement of water into the airway, to produ…… the watery fluid that lines the airway. The fluid layer is the height of the cilia that are present on the …………. surface of airway epi………….. cells and permits the synchronous beating of the ci………
Inhaled dirt and debris, bacte……. and viruses, collect in a thin layer of mucus that is prod…….. by goblet cells and the submucosal glands and sits on top of this fluid layer. The mucus is normally removed by the continuous beating of cilia on the surf……. of the epithelium which sweep the debris towards the mouth where it is ……………..
CFTR in normal airway epithelial cells
In the normal human airway, CFTR is expressed both in the surface epithelium and more predominantly in the submucosal glands. In normal airways a thin film of fluid coats the entire surface of the epithelium. The volume and composition of the airway fluid is determined by the relative contribution of salt reabsorption and salt secretion processes.
Salt secretion is mainly due to the secretion of chloride ions through the CFTR ion channel. CFTR normally has a negative regulatory effect on the epithelial sodium channels, which limits the uptake of sodium ions via this route, and thus the amount of water that is reabsorbed.
Salt reabsorption is mainly due to the passive diffusion of sodium down concentration gradients into the cell through the epithelial sodium channel (ENaC). The intracellular sodium concentration is maintained at low levels by the activity of the Na/K pump in the basolateral membrane of the cells which pumps sodium back out of the cell.
Because sodium reabsorption is limited in the normal airway the epithelium that lines the airway is a secretory epithelium, ie there is net movement of water into the airway, to produce the watery fluid that lines the airway. The fluid layer is the height of the cilia that are present on the apical surface of airway epithelial cells and permits the synchronous beating of the cilia.
Inhaled dirt and debris, bacteria and viruses, collect in a thin layer of mucus that is produced by goblet cells and the submucosal glands and sits on top of this fluid layer. The mucus is normally removed by the continuous beating of cilia on the surface of the epithelium which sweep the debris towards the mouth where it is swallowed.
CFTR in the CF bronchial epithelium
In the CF bronchial epithelial cell, CFTR is absent or defective. This leads to reduced chloride channel activity , and reduced chloride secretion thro CFTR into the airway lumen (although the alternate chloride channels are still present and active). The absence of a functional CFTR removes the ne……….. regul………effect of CFTR on the epithelial sodium channel, which leads to a massive increase in epithelial sodium absorption, estimated to be 10x greater than normal.
This massive increase in sodium absorption is dealt with by a compensatory increase in the activity of the Na/K pump in the basal membrane.
Therefore, although the primary genetic defect is in the chloride channel, the primary electrophysiological defect is in the sodium channel activity.
Chloride ions and water follow the movement of sodium, through the paracellular route, leading to the dehydration of ASL.
CFTR in the CF bronchial epithelium
In the CF bronchial epithelial cell, CFTR is absent or defective. This leads to reduced chloride channel activity , and reduced chloride secretion thro CFTR into the airway lumen (although the alternate chloride channels are still present and active). The absence of a functional CFTR removes the negative regulatory effect of CFTR on the epithelial sodium channel, which leads to a massive increase in epithelial sodium absorption, estimated to be 10x greater than normal.
This massive increase in sodium absorption is dealt with by a compensatory increase in the activity of the Na/K pump in the basal membrane.
Therefore, although the primary genetic defect is in the chloride channel, the primary electrophysiological defect is in the sodium channel activity.
Chloride ions and water follow the movement of sodium, through the paracellular route, leading to the dehydration of ASL.
Dehydrated secretions are retained in CF airways, inviting infection and inflammation
The link between the defect in the CFTR in the airways epithelium and infections in the CF lung has only recently been recognised, mainly because of the difficulty in sampling the fluid ………. the lower airways. The CFTR is expressed both in the surface …………….. and more predominantly in the sub…………….l glands which are enlarged, or hyperplastic, in CF patients. Mucus is secreted by the g……….. cells of the bronchial epithelium and by the subm………….. glands, which are the primary source and produce visco………….. secretions which accumulate in the airways. Airway epithelial cells also have altered ion transport properties.
The absence or defective functioning of CFTR results in red………… chloride secretion into the airways and therefore a reduced movement of water into the airways. CFTR normally has a negative regulatory influence on the E……. and when this is removed, as it is in CF, there is a massive increase in the uptake of sodium through ENaC, and with it reabsorption of ex………….. amounts of water. The relative deh……….. of the secreted mucus results in thick, sticky secretions that invite infection. Recurrent and chronic respi…………. infections are responsible for most of the morbidity and mortality of the disease. When CF was described in 1938 most patients died by the age of 5years due to staphy………… aureus infection. As antibiotic therapy improved, with penicillin to treat stap……………. aureus, so did the life expectancy of the patients. In the last two decades the most prevalent pathogen in the airways has been Pseud…………aeruginosa and CF patients are chronically infected with this organism.The altered sec…… of the respiratory tract leading to the accumulation of ………… mucus is thought to be responsible for these persistent infections. Acc…………. of thick mucus have even been described in foetuses with CF and pulmonary infection in CF children as young as 3 months. An altered composition of the airway fluid may also favour bacterial growth.
A neutrophilic inflam………. resp……… is mounted to try to fight the infection.
Dehydrated secretions are retained in CF airways, inviting infection and inflammation
The link between the defect in the CFTR in the airways epithelium and infections in the CF lung has only recently been recognised, mainly because of the difficulty in sampling the fluid lining the lower airways. The CFTR is expressed both in the surface epithelium and more predominantly in the submucosal glands which are enlarged, or hyperplastic, in CF patients. Mucus is secreted by the goblet cells of the bronchial epithelium and by the submucosal glands, which are the primary source and produce viscoelastic secretions which accumulate in the airways. Airway epithelial cells also have altered ion transport properties.
The absence or defective functioning of CFTR results in reduced chloride secretion into the airways and therefore a reduced movement of water into the airways. CFTR normally has a negative regulatory influence on the ENaC and when this is removed, as it is in CF, there is a massive increase in the uptake of sodium through ENaC, and with it reabsorption of excessive amounts of water. The relative dehydration of the secreted mucus results in thick, sticky secretions that invite infection. Recurrent and chronic respiratory infections are responsible for most of the morbidity and mortality of the disease. When CF was described in 1938 most patients died by the age of 5years due to staphylococcus aureus infection. As antibiotic therapy improved, with penicillin to treat staphylococcus aureus, so did the life expectancy of the patients. In the last two decades the most prevalent pathogen in the airways has been Pseudomonas aeruginosa and CF patients are chronically infected with this organism.The altered secretions of the respiratory tract leading to the accumulation of thick mucus is thought to be responsible for these persistent infections. Accumulations of thick mucus have even been described in foetuses with CF and pulmonary infection in CF children as young as 3 months. An altered composition of the airway fluid may also favour bacterial growth.
A neutrophilic inflammatory response is mounted to try to fight the infection.
