Kidney Function PDF

Kidney functions: removes nonessential substances from blood- urea, ammonia, creatinine. And recovers essential things like glucose, amino acids, water -​ 2 very important functions: regulate total body water and salt balance Detailed Kidney function -​ Evaluate and regulate ECF volume: (most...

Kidney functions: removes nonessential substances from blood- urea, ammonia, creatinine. And recovers essential things like glucose, amino acids, water -​ 2 very important functions: regulate total body water and salt balance Detailed Kidney function -​ Evaluate and regulate ECF volume: (most important) ECF is all fluid outside of the cells (this is blood plasma). Thus if we drink lots then we have more ECF volume and more blood plasma- thus higher blood pressure. And when we drink less we have less ECF, plasma and lower blood pressure -​ Kidney: they can help restore the blood pressure when this happens- they detect pressure changes -​ Regulate osmolarity: should be at 300 in blood -​ Maintain ion balance: if we have excess ions it will get rid of it to keep the balance -​ Production of Urine: not the most important function- but as blood is being filtered through the kidney it is maintaining ion balance and those that need to be excreted will be through urine -​ Urea: break down of protein -​ Ammonia: break down of protein and nucleic acids -​ Creatine: electron carrier that breaks down into creatinine -​ Maintaining blood pH: if acid or basic then it works with lungs to balance -​ Endocrine organ: it will activate a hormone called erythropoietin- helps with maturation of red blood cells and will activate vitamin D -​ Gluconeogenesis: makes new glucose- it makes it from proteins and lipids- when we are low on glucose Kidney Location: posterior and outside to abdomen cavity at 11th and 12th rib- thus they are retroperitoneal organs Structure: inner side (concave) is where blood enters and exits (through renal artery and vein). -​ Urine will be made by nephrons and they will be funneled by minor calyces, which are then funneled by Calyces- this will collect the urine in the centre part of the kidney- this is called the renal pelvis- the urine will then leave the renal pelvis through a tube called the ureter- it will help urine be removed- it is located on that concave side -​ Urine is collected in the bladder, when it is full there will be the urge to pee and the urine is pushed through a tube called the urethra Artery and veins -​ Renal Artery: brings oxygenated blood to the kidney- it will get smaller and smaller- eventually they will make it to the outer surface (the cortex of the nephron) -​ Cortex has a granular look due to nephrons; these are ball-like structures that sit on the cortex, and are connected to loop-like structures that go down to the medulla, back up to the cortex then terminate back in the medulla -​ Renal Vein: takes blood from kidney to rest of body- has the reabsorbed nutrients in it -​ There will be vessels in the cortex and this will help bring blood to the renal vein Each kidney has on artery, vein and ureter- they all are on concave side Medulla: this is striated due to the nephron. Kidney Stones: due to precipitation and crystallization of higher than normal concentrations of minerals and ions- oxalate, phosphate, calcium, uric Acid. They can form in the renal pelvis and ureter Nephron: each kidney has 1 million -​ Renal Corpuscle: the outside is called the bowman's capsule and inside is where specialized capillary bed is- called glomerulus (it is leaky) -​ The bowman's capsule: which is outside, will filter fluids. It is a fluid-filled structure that surrounds the glomerulus. The outer part of it has epithelial cells and the inner part that connects it to the glomerulus has epithelial cells called podocytes. -​ The fluid that is in this is the filtrate, this area that it collects is called bowman's space -​ The fluid will go through the glomerulus (it connects to the efferent and afferent arterioles) and it has lots of holes in the capillary bed so it allows fluid to be filtered out of the blood and into the bowman's space. The podocytes that surround it will try to stop some of the leakiness. -​ Blood that goes into the glomerulus and the bowman's space is the afferent arteriole (gets blood from renal artery), any blood that does not get filtered into the space will leave through the efferent arteriole. -​ SInce these are arterioles they have smooth muscle which can dilate or contract and control the rate of blood flow- which affects filtration -​ Glomerulus: specialized leaky capillaries -​ Juxtaglomerular apparatus: this is a connection between the late ascending limb (tubule) and arterioles surrounding the capsule. It is next to the two blood vessels that enter and exit the corpuscle called the afferent and efferent arterioles. -​ The late ascending limb has macula densa cells that detect the concentration of sodium and chloride. And the cells next to these are juxtaglomerular cells which are responsible for producing and releasing the enzyme renin. The macula densa cells will detect what is in the filtrate and will communicate to the corpuscle. The juxtamedullary cells are smooth muscle cells that communicate and can alter the afferent arteriole- also release renin into the blood  -​ Tubule: divided by function and structure- layered by epithelial cells that have functional differences on what they select -​ Proximal Tubule -​ Loop of Henle: has descending and ascending (different jobs) -​ Distal Convoluted Tubule -​ Collecting Duct: branches connecting it to other neurons- usually 4-5 nephrons share one duct. At the end of this is the minor calyces Nephron can different: some species have different concentrations of these- dessert have more of juxtamedullary -​ Cortical nephron: these are 80% of our nephrons, they have a short loop of henle and the corpuscle is in the cortex layer- higher. The blood vessels surround the tubule are called peritubular capillaries and they reabsorb filtrate -​ Juxtamedullary nephron: 20%, they are more for water conservation. They have a long loop of henle and the corpuscle is in the cortex layer- but the lower cortex layer. The capillary bed that surrounds the tubule is vasa recti and helps to concentrate urine Cardiac Output: the kidneys get 20% of the CO. -​ Renal Artery-Afferent arteriole- capillary bed in glomerulus (anything that doesn't get filtered goes to..)- efferent arteriole- either peritubular or vasa recti- venule-renal vein -​ This is different from normal since after capillary it is normally the venules and there is a secondary capillary bed (peri and vasa) Filtrate production: kidneys make 180L of filtrate a day and yet we only have 1.5-2L of urine a day-these below affect how much fluid/what is excreted. -​ Filtration: from blood and glomerulus to bowman's space (in renal corpuscle) -​ Reabsorption: from filtrate back to capillary bed (water, ions, glucose, amino acids) -​ Secretion: things from blood are added to the filtrate as it goes through the tubule- some medication filter faster here than at the corpuscle -​ Excretion: filtrate collects in renal pelvis and bladder Urine excreted: Filtered+ Secreted- Reabsorbed Glomerulus (capillary): has fenestrations that make it leaky, but the podocytes make it harder for things to move through (like proteins) -​ The endothelial cells of the glomerulus and the podocytes are fused- thus it is two layered -​ The spaces between podocytes or pedicels can widen or narrow -​ WHAT IS BASAL LAMINA Barriers for getting into the corpuscle: only 20% of blood will be filtered 1)​ Size of endothelial pores (fenestration) and size between the endothelial cells (clefts) 2)​ Space between fibres of the basal lamina- this is a sticky tissue that connects endothelial cells of the glomerulus to the podocytes. It is made up of fibers and glycoproteins so the space between these can limit filters. Also since glycoproteins are negatively charge they prevent proteins (which are - charge) from going through 3)​ Spaces between podocytes- these spaces are called slit spaces Things that filter are small ions, molecules (glucose amino acids), water Forces in our corpuscle: sum of these is the net filtration pressure- in a healthy person this is 10mmHg - when NFP is positive the fluid will filter into bowman's space, when it is negative it will not 1)​ Hydrostatic pressure of Glomerular Capillaries: largest force, heart pump pushes blood through capillaries and into the space - drives filtration 2)​ Colloid Osmotic Pressure of Glomerular Capillaries: proteins are incapable of filter (due to size and charge), water has affinity for proteins- water will be drawn to them- thus this inhibits filtration 3)​ Hydrostatic pressure of Bowman's Capsule: As fluid rushes it, the space gets full and there is a back pressure (no more can enter) this limits filtration 4)​ COlloid Osmotic pressure of bowman's capsule: when proteins do get in, water follows- not happening a lot- favours filtration. Thus NFP= (PGC+mBC)- (PBC=mGC) -​ If this is 5mmHg we have less than 180 L being filtered, it if is more than 10mmHG then we have more than 180L (can rupture capillary bed) GFR: quantity of fluid and solute dissolved in water filtered per unit time into bowman's space -​ If blood flow increases, so does NFP and thus GFR. -​ What can also increase GFR is the filtration coefficient which depends on the surface area of glomerular capillaries and its permeability Two internal processes to maintain GFR if blood pressure fluctuates -​ Metabolic response: when BP increases so will blood flow and it will stretch the arteriole which triggers a reflexive contraction of the smooth muscle to decrease blood flow. We would contract the afferent arteriole. -​ Tubuloglomerular feedback: content of the filtrate- the macula densa cells will detect salt composition and rate of fluid flow. If BP increases then GFR increases and we will have  more salt and faster flow. Thus the macula densa cells will release paracrine factor (adenosine) that stimulate the afferent arteriole to constrict -​ The macula densa cells also detect low concentration and low flow- they release nitric oxide and this causes afferent arteriole to relax and increase GFR. Efferent arteriole on GFR: -​ Constriction: less blood leaves, more blood pooling -increasing pressure (increasing GFR) Efferent and afferent constriction on GFR: when angiotensin 2 How to measure GFR: we use urine -​ Excretion=Filtration- reabsorption+secretion -​ But we can see that excretion does not directly equal filtration- instead we need to look at specific items in the urine that are not reabsorbed or secreted -​ Creatinine: this is when creatine breaks down- this is found in skeletal muscle (more skeletal muscle=more creatine and thus creatinine). This is excreted at a constant rate -​ We need to know concentration in blood and then measure how much is excreted in one urine sample, and also how much urine is produce in a day -​ (Conc or C in Urine x Urine Vol)/ Con of C in blood= GFR -​ This is not perfect as some creatinine is secreted in the tubule- thus we slightly over estimate the GFR -​ If it was 1mg/L of creatinine in the blood this means that for every 1 L that is filtered we have 1 mg that is excreted -​ Normal units for GFR is L/day or mL/min (normal is 180L/day or 125mL/min) Other methods: -​ Inulin: this is a plant plant polysaccharide that can be freely filtered into the human kidney- since this is not naturally produced we can have a known concentration and since it cannot be metabolized the rate at which it filtered is the same as the clearance- this method is invasive -​ Blood Urea Nitrogen: urea is reabsorbed by tubules- so excreted does not reflect filtration - but if you measure the conc of urea in blood then you can see how much is being reabsorbed. -​ When kidneys decline it will filter less and thus more urea in blood -​ This is a measure of nitrogen -​ What else increases urea in blood?- high-protein diet and strenuous exercise -​ Serum Creatinine: quick- you measure creatinine in blood to determine if kidneys are functioning normal- if we have an above than normal amount that the kidneys are no longer filtering as much When we age our GFR is going to decrease (a bit lower than 125mL/min- the lower the GFR gets the more close to kidney disease we are- when it is less than 15mL/min then they have kidney failure Week 12: -​ Some things (glucose) are more easy to reabsorb than excrete Filtered Load: how much of each substance is excreted- we need to know the conc of stuff in the blood, and the GFR -​ Filtration load= (substance in plasma) x GFR -​ We need to first get GFR (C conc in Urine x Vol of Urine)/ Con of C in blood -​ We can also find the excretion % of a substance by knowing the concentration in the urine and multiplying it by urine volume then dividing by the filtered load- glucose is normally 0 Normal excretion rates of-if outside of normal ranges it is due to the conc being lower or higher in the blood -​ Sodium: 0.5-2.5% -​ Potassium: 6-9% -​ Magnesium: 3-5% Pathologies based on concentrations -​ Hyponatremia: Lower than usual blood plasma of sodium -​ Hypernatremia: higher than normal blood plasma of sodium -​ Hypokalemia: Lower than normal potassium -​ Hyperkalemia -​ Hypomagnesemia: lower than normal -​ Hypermagnesemia: Proximal Tubules: they reabsorb lots of the filtrate (65%)- like water and solutes (glucose, Na. K, Cl, amino acids) - reabsorbed almost anything -​ Filtrate: has a Na conc of 150mM- this wants to move into the cell so there is a channel or transporter- it can move into the cell (if there was a channel or transporter on the basolateral than NA would come in from there but there is not - we only have active carrier to move from low to high conc) -​ Na/Amino Acid symporter (facilitated): they bind to protein carrier on luminal membrane and this changes shape bringing both to the inside- this depends on Na conc because where Na goes so will amino acids (even if it is high) -​ Not responsive to hormones -​ Amino Acid Uniporter: basolateral membrane- high to low -​ Not responsive to hormones -​ It completes the transcellular transport started by the na/amino -​ Na/Glucose symporter: na moves and glucose follows even if glucose conc is high- on luminal membrane  -​ Not responsive to hormones -​ Glucose uniporter: on basolateral thus finishing transcellular of na/glucose, it is facilitated -​ Not responsive to hormones -​ Na/H exchanger: when Na comes in an H will leave into the filtrate- can be good in acid base balance, on luminal membrane -​ Responsive to hormone: release when Na blood levels are low- called angiotensin 2 (alters speed of this exchanger) -​ Na/K ATPase: basolateral membrane, move Na out and K in, keeps Na low inside -​ Regulated by angiotensin 2 -​ Water Channel: water will move to area of higher solute, found on the luminal membrane and basolateral membrane -​ Not responsive to hormone -​ Paracellular: for water, K and Cl- move high to low- hormones don't do anything Loop of Henle: 20% of filtrate is reabsorbed- theme is reabsorbing water. There is a luminal and basolateral water channel (aquaporin 1- this is for reabsorption)- this is happening since there is a high osmolarity in the ECF of the medulla and the loop of henle dips into the medulla- water is drawn to high osmolarity. There is no paracellular at this point since the tight junction proteins are very close -​ Descending limb: water and na, theme is also reabsorb water. -​ Water channel on basolateral and luminal that are not responsive to hormones -​ This is in the medulla, which has a range in osmotic forces- at the lowest it is 1400mOsm and at the highest it is 300mOsm- and since water likes to move to areas of high osmoles they will move through osmosis to the outside of the cell- basolateral membrane. -​ Na/K pump on basolateral membrane -​ Na+ Channel on luminal membrane -​ Ascending limb: Na, K, Cl- (NO WATER- also no paracellular transport of water) -​ Na: paracellular transport -​ Na Channel: luminal -​ Na/K: basolateral -​ Protein carrier: moves Na, 2 Cl and K- this is an ion multiplier/ion symporter. Na and Cl go down their gradient into they cell and K is going against it into the cell -​ Cl/K symporter: on basolateral membrane- K is going in its concentration gradient and Cl is going against Distal Tubule and collecting duct: 14% of filtrate -​ Distal: Na, K, Cl, Ca - No paracellular -​ Ca channel: this is increased by a hormone- called parathyroid - on luminal -​ Na/C symporter: luminal -​ Na: channel -​ Cl/K symporter: basolateral  -​ Na/ Ca antiporter: basolateral- Na in and Ca out. -​ Na/K on basolateral -​ Collecting Duct: varies based on hormones- water and Na (secretes K). cells here are called principal cells- they respond to hormones -​ Multiple types of epithelial cells- principal cells and two types of intercalated cells -​ Intercalated are responsive to plasma pH change -​ Principal are responsive to hormones that regulate water and sodium balance -​ Water channel: aquaporin 2 on luminal membrane and aquaporin 3 and 4 on basolateral membrane. -​ Aquaporin 2 responds to ADHormone (reabsorption) -​ Na channel: luminal- hormone aldosterone -Na in -​ K Channel: on luminal- responsive to aldosterone - K goes out -​ Na/K: on basolateral- responsive to aldosteron Structure of tubules: there is a single layer of epithelial cells linked by tight junctions. The membrane to the lumen is the luminal/ apical, and the outer is the basolateral -​ Paracellular transport: only reabsorption, between epithelial cells -​ Transcellular: reabsorption and secretion- need a transporter on basolateral and luminal through the epithelial cells -​ This is for glucose, ions, and water. Epithelial cells: they are polarized, this means that one membrane will function differently from the other. Ways of transport -​ CHannels: small openings for passive,-diffusion down con. This is like water channels (human kidneys have 4 subtypes)- aquaporin 2 is hormonally regulated -​ Uniporter: moves a single molecule through the membrane- facilitated- they bind. Like a glucose uniporter -​ Symporters: they move two molecule in the same direction- co transport (one must be down the gradient)- facilitated. Ex is Na/glucose (on luminal side- driven by Na gradient) -​ Antiporters: move two molecules in opposite directions- exchangers. One must go down the gradient.- facilitated. Example is Na/H- driven by Na gradient -​ Primary active: need ATP, Na/k pump both are against the gradient -​ Regulated transporter: transporter or channel that changed its function due to the response of a hormone Regulation at cellular location: Channels and transporters only work in the correct location- if removed it will not work. Regulation at activity: carriers have limited capacity to bind to specific molecule and change shape- hormones can make them faster Regulation at gene expression: more can be moved if you have more channels, cells can be instructed to make more of the mRNA which will then be translated. Tubules: have higher K inside and higher Na outside. -​ The filtrate that flows through the lumen is high in Na too- has a conc of 150mM- this is why things are driven by the Na conc- it wants to go inside the cell. -​ We have a channel on the luminal membrane and an active carrier on the basolateral membrane (ensures that Na will leave and be low inside the cell) Diabetes Mellitus: nephron is not capable of reabsorbing all the glucose present in the filtrate- which means we have increased urine volume and more glucose in urine - can be from type 1 or type 2. -​ Can happen since the Na/Glucose symporter in the proximal tubule are saturated which means more glucose in filtrate- called glucosuria and since water will follow glucose we will also have more water excreted -​ When we have an increase in urine volume due to an increased level of solute excretion this is called osmotic diuresis. Week 15: -​ When hydrated we have lots of diluted urine, when dehydrated we have less but concentrated urine. -​ We regulate the water and salt excretion Water regulation: balanced by ADH (antidiuretic hormone) -​ Normally we expel 1.5 L of urine per day but it can be 0.4 to 2.5L. The minimal amount of urine we need to expel is call obligatory urine loss -​ ADH: how much is in our blood determines how much water is reabsorbed, it will cause more water to be reabsorbed and thus less urine. -​ ADH also is a vasopressin and will affect blood vessels. Neuroendocrine cells: neurons that release hormones- the cell body for these are in the hypothalamus and axons will go to the posterior pituitary. -​ The hypothalamus and pituitary will communiticate via hormones Posterior Pituitary: it secreted hormones- not makes them (made by hypothalamus) -​ Oxytocin and vasopressin -​ The terminal ends of the neuroendocrine cells will release ADH into blood Reduction of Water: sensed by body- via blood pressure changes (baroreceptors) and osmolarity (osmoreceptors), information goes to the hypothalamus ADH is released from axon it pituitary -​ Low body water means low volume of ECF this means low blood pressure. But also low body water means the ratio between solutes and water will increase (4:2- 4:1) which increases osmolarity. Baroreceptors: sensory receptors in aortic arch and carotid sinus that always send baseline signals.  -​ Low BP: less action potentials to brain - release of ADH -​ High BP: more action potentials to brain Osmorecpetors: located in hypothalamus- they change in volume and this change will affect frequency of AP, when they shrink they have an AP and an excitatory neurotransmitter is released at the synapse with neuroendocrine cells- thus they will release ADH -​ High Osmolarity: more AP, ADH released -​ Low Osmolarity: less AP, water moves into osmoreceptor and body swells- there is no AP Collecting Duct: ADH regulation at level of location -​ ADH will circulate in the blood and be detected by receptors on plasma membrane of cells- in the collecting duct these cells are principal cells -​ ADH will bind and it will cause more aquaporin 2 channels to move to the luminal membrane for reabsorption. Some of these channels were stored in vehicles and ADH helps them be released from these. -​ When ADH is not in blood, the aquaporin channels are removed and stored back into the vesicles= more water excreted and increased urine volume. Decrease in blood volume due to decrease in water will result in a decrease in MAP, this pressure change is detected by baroreceptors- which means less AP going to the cardiovascular centre in the medulla oblongata. This means neuroendocrine will release ADH- eventually blood volume is restored and no more ADH is released (baroreceptors give normal amount of AP) Thirst: when water level is low we want to consume more water. The osmoreceptors when osmolarity is high will also trigger the brain to have thirst to increase the total body water Movement of water: Water moves with osmosis and follows solutes (we need a solute gradient) -​ Medullary interstitium has a solute concentration gradient with 300 mOsm high up and 1400mOsm lower down- water will move by osmosis until there is an equilibrium reached between the lumen and interstitial space -​ So if we can increase the osmolarity of interstitial then we can increase osmosis??? Urine: most concentrated it can be is 1400 and lowest is 100- this is controlled by ADH and medullary concentration -​ Some animals have higher medullary osmolarity and can concentrate their urine better- due to different ratio of cortical and juxtamedullary nephrons (species dependent ratio) Nephron pathway -​ Bowmans: has 300mOsm, filtrate is same as blood just without cells and protein -​ Proximal tubule: absorbs a lot and water follows thus filtrate volume decreases as more is being reabsorbed- 300mOsm  -​ Descending limb: reabsorbed mostly water- this is in medula now, and will reabsorb until reached equilibrium with interstitial. This means the top of this has 300mOsm but the bottom has 1400mOsm -​ Ascending limb: reabsorbs ions but no water which means that the ratio decreases (4:1 to 4:3), this means that the filtrate will be more dilute as the ions are being taken but not water (osmolarity decreases) here the filtrate is not going to e at equilibrium with interstitial since ions are moving through transports and not osmosis. At the top of this it is 200mOsm -​ Distal convoluted tubule: reabsorbs ions here without water- so won't be at equilibriums since moving through transport- rate decreases again and is 50-100mOsm -​ Collecting duct: depends on ADH Diuresis: increase in urine volume- they create an imbalance of water in the body -​ Alcohol: makes more urine=dehydration, it block ADH release -​ Caffeine: myth- instead we have increased contractility of smooth muscles impacting the bladder and creating an urgency to pee- does not affect water balance -​ Diabetes insipidus: large volume of urine since tubules do not reabsorb enough, cannot release ADH, or no response to ADH by principal cells Na balance: balanced by kidney for homeostasis -​ Low: renin angiotensin-aldosterone system (RAAS) is activated- releases A and A -​ High: RAAS pathway is decreased and release of atrial natriuretic peptide happens Na on BP: Na is high and ECF expands which means BV is higher and so is BP. When Na is low hen ECF shrinks and with it BV and BP shrinks -​ These changes of pressure and composition can be detected RAAS pathway: Renin is made by the juxtamedullary cells, it responds to low Na levels. Only when Na is low will renin be released (thus it is the rate limiting step in the RAAS pathway) This will act and cleave angiotensinogen (which is released from the liver always-as a non active peptide). Once cleaved it is angiotensin 1 and this inactive peptide can be now recognized by ACE (which is always in the lung capillary endothelial cells). The angiotensin 1 will be only 8 peptides in length and called angiotensin 2 which is active -​ Angiotensin 2 is a hormone- can affect how things act Adrenal Gland: this is on top if the kidney and will make a hormone aldosterone- but this is only going to be released when angiotensin 2 is present (so also limited by renin) -​ Aldosterone can also be released by high concentration of K -​ When released either by angiotensin or K it will be able to cross the plasma membrane and bind to intracellular receptors (angiotensin cannot cross) -​ It binds in the principal cells and gives both a slow and quick response -​ Slow: binds to DNA sequences in the nucleus and will increase production of mRNA so that they can then be translated into protein which will become channels and carriers  -​ Quick: it causes more channels to move to the membrane and also increase activity of the channels -​ Na: more moved and made -​ Na/K: increase expression and how many -​ K: can sometimes make more- move to luminal to secrete K Chemoreceptors and Macula Densa: detect decreased Na in late ascending tubule- when detected it will secrete a chemical messenger which is picked up by the juxtaglomerular cells to release renin Baroreceptors: the neurons of baroreceptors will synapse with the juxtaglomerular cells and so when BP is low it will signal to release renin Angiotensin 2 binding: moves Na out of lumen and into blood -​ Na/H exchanger: activity is increase, more Na in and H out -​ Na/K ATPase: activity increased, more Na out into interstitial to be reabsorbed Angiotensin 2 as a Vasoconstrictor: acts on the afferent and efferent arterioles -​ Afferent constriction: this will decrease GFR which means that less Na is excreted since less is being filtered through - and since the flow of fluid through the lumen is slower it is allowing more Na to be reabsorbed through Na/H exchanger -​ Efferent constriction: decrease GFR ANP: released when Na is high. Hormone made and released by cardiac atrial cells. The cardiac atrial cells are mechanoreceptors and detect stretch when there is increase blood volume and pressure- they release ANP -​ This causes less Na reabsorption by preventing aldosterone from being released from the adrenal gland, and it will also increase the GFR by dilating the afferent arteriole, which means more Na is being filtered but also the flow of things is faster and thus less can be reabsorbed through Na/H and more is excreted Lungs: divided into lobes so if one is damaged the other are fine -​ Right has three and left has 2 - each lobe has a independent supply of air -​ Air is brought to our lungs via the trachea Functions of the lung 1)​ Gas exchange: O2 diffuse out and into capillaries, CO2 diffuses into the lungs- simple 2)​ Regulation of pH: can change pH faster than kidneys 3)​ Speech: air needs to pass vocal cord to make noise 4)​ Host defence: have defense system 5)​ Trapping/ dissolving blood clots 6)​ Change Chemical messenger concentrations: has ACE in all of lung capillaries Lung location: thoracic cavity- below ribs, above diaphragm Functional areas of the lungs -​ Conducting zone: this is trachea, and it divided into primary bronchi, which divides into secondary and then tertiary (all so far are made of cartilage), after this they divide into bronchioles which have no cartilage- bronchioles will split into terminal (which is the end of the conducting zone) and respiratory -​ All of these have smooth muscle but it is only evident in bronchioles since they have no cartilage cover -​ Respiratory zone: this is the respiratory bronchioles (they will have singular alveolus on them), which lead to alveolar duct and alveolar sacs (clusters of alveoli) -​ Each alveoli is wrapped in pulmonary capillaries -​ Gas exchange at the blood gas barrier which is very thin to maximize GE- it is only made up of type 1 epithelial cells and capillary epithelial cells Conducting zone; keeps you healthy- tube walls have bronchial epithelial cells, and they have cilia that on top of these cells projecting into the lumen and they perform coordinated sweeping functions. On top of the cilia is a sticky layer of mucus that the things we breathe in will get stuck to and the sweeping of cilia will move this mucus to the mouth to be coughed out or swallowed -​ We say that our bronchial epithelial cells are ciliated -​ Smoking can lead to uncoordinated cilia and poor sweeping Alveoli: -​ Type 2 epithelial cells: make surfactant- helsp lungs function normally -​ Type 1 cells: make up the walls-sqaumous shaped. make up the blood gas barrier. -​ Alveolar macrophage: these cells keep the aveloi free from bacteria- they take up particles via endocytosis Alveolar ventilation: this is getting air into the alveoli -​ When low we have poor gas exchange -​ This is measured by -​ pulmonary ventilation (Ve): the amount of air that enters the trachea -​ We meausre the volume of 1 breathe (tidal volume) and the respiratory rate (how many breaths per minute) -​ Ve= Vtx RR -​ How much air is in the conducting zone or in antaomical dead space (Vd) – air stuck in here means it did not cross the BGB. -​ Each pound you weigh is eqaul to 1 ml of Vd for every breath. -​ Vd= weight x RR -​ Now we know how much we have coming into the trachea and how much we left in the condutcing zone- the difference is what went to alveoli for exchange -​ Va=Ve-Vd What can chnage Va -​ Type of breathe: Shallow quick breaths vs Slow big breaths will give same Ve but may give different Va since more can be stuck in dead space Pleural Membranes: pressure between will help lung from collapsing- they are continuous with on e another- teh fluid helps them glide over each other as we breath. The space between is teh intrapleural space -​ Parietal Pleura: on the diaphragm and rib cage- more outer, thun -​ Visceral: directly on lung Boyles Law: pressure and volume are inversly related. Types of pressure: blood and air will move down pressure gradients -​ Intrapulmonary pressure: inside teh lungs- we can change this -​ Atmospheric pressue: Pressur eof air we breath in- cannot change- it is 760mmHg Breathing at rest: -​ When we inhale we need the intrapulmonary pressure to be lower so that air can move down a pressure gradient and into the lungs. Thus based on boyles law to decrease the pressure we should increase volume (increase thoracic cavity) -​ Increase volume by pulling diaphragm down and ribs up/out (contraction/active) -​ Between breaths the pressures of intra and atmo is the same (760mmHg) -​ When we exhale we want intrapulmonary pressure higher so we decrease the volume by relaxing our diaphragm and pull ribs in/down (relaxtaion/passive) Muscles at rest: external intercostal muscles and diaphragm (this is the main muscle) Breathing when active: we have bigger Vt since we have bigger breaths, we also have faster -​ When we inhale the diaphragm and external intercostal will contract harder and faster and this increases volume -​ When we exhale we need the relaxation of diaphragn and external intercostal (passive), but we need active contracting to help too- internal intercostal, abdominal, obliques We never empty our lungs completely. Intrapleural space and pressure: the pressure will always be lower than the intrapulmonary pressure to prevent collapse of the lung -​ If we do have lung collapse we have pneumothorax- the transpulmonary pressure is 0 Transpulmonary pressure: difference in intrapulmonary pressure and intrapleural pressure. Shouldnt be 0 since this means they are equal in pressure -​ IPul-IPlu -​ How to get 0: if we puncture the parietal (outer) pleura- the atmospheric air can get in and they wil eqaulize meaning it will be 760mmHg there. Or if we puntcure the visceral (inner) then the intrapulmonary can eqaulize with the intrapleural- again both 760. -​ spontaneous pneumothorax (young slim males, belbs rupture) Pneumothorax looks like: lung falling inward, chest wall moves outward- normally they move together but without they pressure holding them they will be opposite.  -​ Chest pains, shortness of breath -​ When you insert a chest tube you will hear the air rush out of the intraplueral space. Lung walls: have elastin- it makes up ⅓ of teh lungs recoil force, the other ⅔ is due to surface tension- these are forces that help recoil but can also lead to lung collapse -​ Surface Tension: water molecules are attracted to each other and this attraction causes an elastic leike tension on the surface), this is found in the alveoli. The air we breathe has some water in it- but also there is a layer of fluid under our type 1 and type 2 epithelial cells- so where this fluid meets the air is called the air-liquid interface. -​ The attraction water molecules have is due to charges- oxygen molecule has a slight negative charge while the H has positive- water molecules will join through hydrogen bonds. -​ Air does not have a charge and thus is not attracted to water- this means that the water will only be attracted on the sides and downward- the unstability will result in water moveing inward and causing alveolar collapse. -​ Luckliy we have pulmonary surfactant which is in type 2 cells- it is made of phospholipids and porteins, it lays on top of teh air-liquid interface and its tails are hydrophobic and heads are hydrophilic- so the heads lay on the water and will result in a balanced distribution and no inward attraction- thus a decrease in surface tension. Surfactant: can be damaged or not produced in the lung- this can lead to lung collapse. Lung Compliance: stretchability on inhalation. -​ Low compliance means that for the lungs to fill with air there needs to be a bigger pressure gradient- we need to make more volume which is more work for the diaphragm and extenral intercostals. -​ Also low compliance if we have too much elastin and recoil (resisting stretch) Diseases: -​ Neonatal Respiratory distress syndrome: when born too early the lungs are not well developed and we do not have enough type 2 epithelial cells to make surfactant -risk of alveolar collapse, poor lung function and hypoxia- can treat by administering surfactant (from cows)/ placing on ventilator -​ COPD: umbrella term- higher lung compliance -​ Emphysema: smokers disease, damage to alveoli and destroys walls/elastin/ less alveoli (poor gas exchange)-more air in Vd -​ The membrane is impacted -​ Chronic Bronchitis: disease of larger airways- excess mucus is made and block airways- they will cough. Spirometry: used for pulmonary function tests- measures lung volume - different types of volume can be used for different disease. For lung tests you need to plug the nose -​ Tidal volume: Normal tidal volume is 500mL  -​ Residual volume -​ Inspiratory reserve volume -​ Expiratory reserve volume -​ Forced vital capacity: Old lung function test vs new: -​ Old: Tube to mouth was connected to another tube on machine- machine is filled with water and a tube with air- top of this there was a bell and when someone would breath in the bell would sink and if they breathed out it would rise. -​ Pen attached wrote down the waves (breath it it would rise and out it would fall) -​ New: mouth peice with tube and a rubber seal that moves when you breathe- movement is recorded by computer. Graphs: -​ Tidal volume: normal breaths, from peak to bottom this is about 500mL -​ Inspiratory reserve: very big breath in and normal breath out- we measure this from the peak of a big breath and the peak of a normal breath. -​ This is bigger than expiratory reserve volume since we can inhale more than we exhale- cant exhale all air (which is why on the graph we are not close to 0). -​ Expiratory reserve volume: big breath out and normal in- distance from lowest at normal and lowest for big. -​ The amount of air left in the lung after we do a big exhale is called the residual volume- we cannot know this number Total lung capacity: this is teh residual volume, expiratory reserve volume, tidal volume and inspiratory reserve volume- add all up and it should be 5-6L Vital Capacity: big in and big out with no time (peak in inspiratory and lowest in expiratory- this is the movemable air- thus when you subtract VC from TLC we get residual volume. Forced Vital capacity: big in and big out as quick as possible (how fast we can empty our lungs- how well air is moving through our airways) -​ We do the peak of inspiratory- vally in expiratory Forced Expiratory Volume in 1 second: this is measured how much we can exhale in one second after we did a big inhale. Do FEV1/FVC: this is a ration that shows what percentage of our lung volume is exhaled in one second -​ In normal lungs this will be higher percentage, and in COPD it will take longer to exhale thus the percentage is lower ( the FEV1 is what is affected) Asthma: 1 in 10 people have, airways are narrowed due to smooth muscle contractions- the walls are inflamed and tighten, and the cells of the lung make more mucus than normal -​ Some people have asthmatic triggers  -​ Even when there is no asthma attack asthmatic airways are always inflamed- and are hyperresponsive- constrict when shouldn’t Restrictive lung disease vs Obstructive: obstructive effects exhalation, while restriction effects inhalation -​ Restrictive: mostly affects FVC- these diseases will have a higher FEV1 and FVC ratio Pulmonary fibrosis: feeling you cant get enough air- scaring of soft tissue makes it hard and this thickens the BGB and make the lungs have lower compliance (we decrease FVC-restrictive ) -​ When there is no known cause it is called idiopathic pulmonary fibrosis, but is normally from things like asbestos, coal mining, pollution Partial Pressure of Oxygen in Total Atmospheric pressure: 21%x760mmHg= 159.6mmHg -​ When we breath in atmospheric air this is the partial pressure of O entering our lungs but since we do not breath out all the air in our lungs there will be some CO2 remaining and thus the atmospheric oxygen will mix with this and make the alveolar PO2 lower than the atmospheric- it is about 100mmHg -​ Thus when it simple tissues into the vein it will do so to equilibrium and this means the pulmonary vein will have PO2 of 100mmHg -​ In the heart it will remain the same and the systemic artery -​ At the tissue the oxygen needs to diffuse- go down a pressure gradient, thus the tissue PO2 will be lower than 100mmHG- it is either 40mmHg or 20-30 mmHG (when active tissue) -​ The systemic arteries will be leaving the tissue area at equilibrium with the tissue and will go back to the heart at either 40 or 20-30 mmHg -​ When at the lungs we know the alveolar PO2 is 100 and thus teh pulmonary artery will be getting up to 100mmHg Partial pressure of CO2: 0.04%x760=0.304mmHg. Since we do not breath out all of the CO2 (left over air is called stale air), the alveolar partial pressure is 40mmHg. The pulmonary artery that is passing will be also 46mmHg and deliver CO2 to be exhaled, the pulmonary vein will then be at equilibrium with the alveoli and the heart and systematic arteries will also be 40mmHg. When it gets to a tissue it depends on it if is at rest or not. -​ If it is at rest the PCO2 of the tissue is 46mmHg and since the blood is lower the CO2 will move into the blood, if the tissue is active then it will have a higher PCO2. But either way the systemic vein will get to equilibrium and go back to the heart. This blood will then leave the heart as the pulmonary artery and this will be at 46+mmHg Both O and CO2 pass the BGB by simple diffusion since they are small. Hydrophobic (non-polar) -​ The BGB is good for simple diffusion since there is a large pressure gradient (PO2 high in alveoli- low in blood) and the membrane area is large, also membrane is very thin- it is just two cells thick (type 1 and capillary endo) Simple diffusion: only happens at capillaries- gases down a pressure gradient If we have decreased Va then we will have a lower PO2 in the alveoli and thus the PO2 in the pulmonary arteries will be lower- and the rest of the cycle. How is oxygen carried: carried on red blood cells (erythrocytes) and in plasma -​ Erythrocytes: have hemoglobin- This is made up of 4 polypeptide chains and each chain is called globin and each has a heme groups with an Fe in the centre- a hemoglobin can carry 4 oxygens -​ Heme: most of oxygen is bound- when bound it is called oxyhemoglobin and when it is not bound it will be deoxyhemoglobin. -​ Globin -​ Plasma: a small out is dissolved in this Chart on oxygen and hemoglobin (sigmoidal curve): On the left is saturation, we know that each can carry 4 (100% S) and the bottom is the PO2 as this influences how many oxygens bind -​ When PO2 is low we have low hemoglobin saturation since when this is low we would have had to drop off our oxygen to increase the PO2. -​ When PO2 is high we don't need to drop off oxygen and thus we hold onto it, we have higher saturation- however we will not have 100% saturation since this graph looks at all hemoglobin in the body -​ Middle PO2- when there is about 40 PO2 we have a saturation of 75% still, and this is because our body will carry more oxygen just increase the tissue is active- remember it would have a lower PO2 and we would need to give more oxygen. -​ At the 100 PO2 which is in alveoli we have very little change in saturation when we decrease PO2- so even if we are in an atmosphere with less PO2 it will not affect the saturation of our hemoglobin much- helps lung dysfunction How is CO2 carried: -​ Erythrocytes: blood cells carry 23% of it on their globin chains- this is carbamino transport -​ Plasma: 7% will be dissolved in the plasma - CO2 is more soluble in fluids -​ Alternate form: Most CO2 will combine with water and will be converted into carbonic acid by the carbonic anhydrase, but this is an unstable form so it will turn to bicarbonate and a proton- this is how most of CO2 is carried -​ Carbonic anhydrase will be able to reverse the reaction too- depends on the concentration of the things on each side of the equation Bicarbonate: This can leave the red blood cell through a transporter on the cell membrane and will exist in the plasma, this is so that when the bicarbonate builds up we can continue the reaction going to the right -​ But at the lungs we want to convert bicarbonate back to CO2 to be exhaled- so the transporter will bring it back into the red blood cell and having a high conc will make the equation go left. -​ As the CO2 leaves the blood cells and goes into the lungs it will lower the left side and this will allow the direction to continue leftward  -​ When blood comes into the lungs it is high in bicarbonate and H (acidic) and as the reaction goes left to make CO2 it will begin to lose these H, this means as the blood is leaving the lung the blood is base -​ At systemic tissue: we want to turn the CO2 into bicarbonate so we can continue to take up CO2, this means that blood going into the tissue is low in bicarbonate and H (basic) and as it leaves it is acidic Decreasing affinity of Oxygen: if we do this then heme would give more -​ When CO2 is high, or pH is low then hemoglobin will give more oxygen for any given PO2. (when PO2 is 40mmHg, hemoglobin should be 75% saturated, but when CO2 is high or pH is low then the saturation can be 50%) -​ This happens since when CO2 is high it stimulates a metabolically active tissue (high temp too) and will change the structure of hemoglobin- it will cause a rightward shift in the oxyhemoglobin dissociation curve (at higher PO2 we will have lower saturation) -​ When low CO2/temp, or high pH we have a leftward shift- meaning at lower PO2 we have higher saturation- higher affinity) Homeostasis: setpoints- PO2 for artery is 100mmHg, PCO2 is 40mmHG and pH is 7.4 -​ We have chemoreceptors that sense this and send signals (send more or less depending if it is high or low). -​ The Control Centre will compare the information to the set point- located in respiratory centre -​ Effectors will get signals from respiratory centre and send signals to diaphragm, intercostals and abdominal Chemoreceptors: two types that sense different things -​ Central: pH- found in medulla, they send high freq of action potentials to respiratory centre- goal to increase Va. -​ These are bathed in CS fluid- they do not have access to arterial blood -​ Peripheral: Do PCO2, PO2 and pH- in aortic arch, carotid sinus- they monitor blood flow in systemic arteries -​ Low CO2, Low O2 and low pH?? There is an increase in AP sent to respiratory centre- to increase Va. Blood Brain Barrier: the capillaries here have tight intercellular clefts that do not allow paracellular- so things must move through transcellular (H+ cannot move across since it is charged) -​ CO2 can move across- when we have high CO2 we have low H. When CO2 gets across this it will be in the CS fluid (which surrounds the brain) and once inside it will combine with water to make bicarbonate- this is how H gets in and out. -​ When pH is low we have more AP to respiratory centre to increase Va (thus decreasing CO2 so we have less bicarbonate and H being made)  -​ When pH is high we have less AP to respiratory centre thus decrease in Va and this increases CO2 so we can make more bicarbonate and H (meaning a lower pH) Kidneys helping with pH: not the best at it- the excretory system is better. -​ Acidic: when too acidic the body will try to excrete protons and conserve bicarbonate. \ -​ Basic: body will try to reabsorb protons and excrete bicarbonate The filtrate in the corpuscle will reabsorb bicarbonate right away (in proximal tubule) this happens regardless of pH. Then in the collecting duct it will asses on what to do -​ Intercalated type a: will secrete protons when too acidic, they become activated- there will be an increase in H inside the cell -​ There is an H ATPase on the luminal membrane and it will push H against its gradient out into the lumen -​ Intercalated type b: will secrete bicarbonate when too basic- too much bicarbonate in blood and interstitial- the bicarbonate will be secreted into the lumen via the bicarbonate/Cl exchanger on the luminal membrane Bicarbonate is a buffer- it is easily filtered into bowman's space- it normally gets reabsorbed by the proximal tubule through.. -​ Na/H exchanger: This puts H out into the lumen and it binds with bicarbonate to make CO2 and water. The water will move through water channels and CO2 can diffuse into the cell- then once inside there will be carbonic anhydrase and this makes bicarbonate and H again -​ Basolateral membrane has transporter Acidosis Respiratory Causes: High CO2 means high H (low pH), thus any condition that causes poor exhalation -​ Hypoventilation: underventilation-shallow breaths -​ Pulmonary Fibrosis- walls thicken- gas exchange is harder -​ Emphysema- alveolar walls break down- reduced surface area High CO2 and low pH are vasodilators Alkalosis respiratory causes: PCO2 is low and H is low (basic), thus when we have overventilation- exhale out excess CO2 -​ Hyperventilation- breathing excessively- enhancing binding of O to Hemoglobin and this reduced the amount in tissues -​ Pulmonary embolism: Low CO2 and low H are vasoconstrictors- reduce blood flow to brain For respiratory the lungs are the issue so the brain cannot help- we need help of the kidneys -​ Acidosis: can use type a to secrete H and we can increase the amount of bicarbonate through increasing the bicarbonate/cl exchanger -​ Alkalosis: type b cells will secrete bicarbonate and can increase H in the blood Metabolic acidosis: High H and high CO2/ little bicarbonate  -​ Kidney disease: filtration is affected and H can remain in blood -​ Prolonged Diarrhea: in the GI tract bicarbonate is abundant and we will excrete a lot, we lose the buffer and too much H is in blood Can counter this through breathing- expel more CO2 ( increasing Va), kidneys can also help Metabolic Alkalosis: low H and low CO2, too high bicarbonate -​ Prolonged vomiting: stomach has lots of HCL that will be gone Counter this by breathing more in and little out, decrease Va, kidneys can help too