1. Overview
2. Mechanics of Breathing
3. Gas Exchange in the Lungs
4. Gas Transport
5. Control of Ventilation
6. High Altitude

1. Overview

Major lung functions:

1. deliver O₂ from air to blood
2. warming and humidification
3. filtration and cleaning

Respiration:

• External Respiration: ventilation, gas exchange
• Internal respiration: oxygen utilization by the tissues

Respiratory Zones:

• Conducting zone: mouth, nose, pharynx, larynx, trachea, bronchi
• Respiratory zone: respiratory bronchioles, alveoli

Gas Exchange

Gas exchange occurs by diffusion from the blood to the lungs across to cell layers: an endothelial cell layer surrounding the capillary and a lung alveolar cell.

1. Mechanics of Breathing

• Breathing muscles: diaphragm, external and internal intercostals
• Interpleural space lies between two membranes: parietal and visceral

• Boyles law:

, PV = constant (at T=37^oC), so if – V® ¯ P

• Compliance and elasticity:

• . Compliance is how much a compartment will expand if the pressure in that compartment is change. A balloon has a high compliance because a small pressure increase inside the balloon will greatly expand the balloon. A rigid tube has a low compliance because a small pressure increase inside the rigid tube will not result in a significant increase in the volume of the rigid tube.
• Elasticity: tendency to return to initial structure after being distended

• Lung volumes:

• Tidal volume (TV)
• Inspiratory reserve volume (IRV)
• Expiratory reserve volume (ERV)
• Residual volume (RV)

• Lung Capacities

• Total lung capacity = IRV + ERV + TV + RV
• Vital capacity = IRV + ERV + TV
• Functional residual capacity: ERV +RV. This volume is the equilibrium volume for the lung and the chest wall. Inspiration is active, requiring muscle contraction and expiration is passive, involving muscle relaxation. Thus at the end of passive expiration the lung (and chest wall) have relaxed back to there equilibrium position. This position corresponds to a lung volume equal to the functional residual volume.

• Surface tension

• Surface tension in the alveolus is created by interacting water molecules which direct a force inward and could caused the alveoli to collapse.

• . Comparing two different alveoli with the same surface tension, the smaller the radius the greater the pressure created by a given surface tension. Air will flow from high pressure (smaller alveoli) to lower pressure (larger alveoli). Thus smaller alveoli are more likely to collapse.
• Surfactant lowers the surface tension. This will

1. Lower the pressure inside the alveoli making it easier to inflate the alveoli when breathing.
2. Prevent collapse of the smaller alveoli because surfactant lowers the surface tension to a greater extent on smaller alveoli than larger alveoli.

• Force Vital Capacity

• FEV_1.0: Forced expiratory volume in one second: the volume of gas that can be exhaled in 1 second after maximal inspiration.
• FVC: Forced vital capacity: the maximum volume that can be rapidly expired after maximal inspiration (it is approximately equal to the vital capacity, which is the maximum volume with slow expiration)
• Fox Textbook (7^th ed) Figure 16.17, page 494: shows

. Normally FEV_1.0 is 80% FVC

• Obstructive lung disease: increased resistance to airflow caused by a reduction in the diameter of the conducting pathways. Asthma, chronic bronchitis, emphysema. Chronic obstructive pulmonary disease is chronic bronchitis and emphysema.
• Restrictive lung disease: scarring of lung tissue mainly due to fibrosis

• – elastic recoil
• ¯ lung compliance

1. Gas Exchange in the Lungs

• Gas Laws

• Daltons Law: P_N2 + P_O2 + P_CO2 + P_H20 = Total Pressure
• The maximum amount of water in air depends on the temperature of the air. At 37^o (temperature in the airways), the partial pressure of water is 47 mm Hg.

• Henry's Law:

: the amount of O₂ in the blood is proportional (proportionality =S_O2) to the partial pressure of O₂.

• Solubility of CO₂ is greater than solubility of O₂

• partial pressures of inspired air, alveolar air, and expired air (see Figure).

• Inspired air: 79% N₂, 21% O₂, low in CO₂
• Alveolar air: humidified so P_H2O = 47 mm Hg, so ↓ P_O2 and ↓ P_N2. ↑ P_CO2 due to metabolism
• Expired air: ↓ P_CO2 and ↑ P_O2 due to mixing with conducting air which has lower CO₂ content and higher O₂ content.

1. Gas transport

• Hemoglobin: Deoxyhemoglobin + O₂ « Oxyhemoglobin

• oxygen-hemoglobin dissociation curve

• amount of O₂ in blood: amount dissolve plus amount bound to hemoglobin

• pH, temperature, and 2,3 DPG, all effect the O₂ dissociation curve.

• ¯ pH shifts the curve to the right, unloading O₂
• – 2,3 DPG shifts the curve to the right, unloading O₂. 2,3 DPG is a by product of glucose metabolism.
• – Temperature shifts the curve to the right, unloading O₂
• – P_CO2 shifts the curve to the right, unloading O₂

• CO₂ transport

1. dissolved (10%)
2. carbaminohemoglobin (25%)
3. bicarbonate (HCO₃^-) (65%)

• Movement of CO₂ from cells to lungs

1. CO₂ is produced by the cells
2. CO₂ diffuses from into a red blood cell inside a blood vessel
3. CO₂ is converted to HCO₃^- (requires the enzyme carbonic anhydrase)
4. HCO₃^- is transported out of the red blood cell into plasma
5. HCO₃^- is transported via the circulation to the lungs
6. HCO₃^- is transported back into a red blood
7. HCO₃^- is converted back to CO₂ (requires the enzyme carbonic anhydrase)
8. CO₂ diffuses from the red blood cell to the alveolar sac
9. CO₂ is then expired.

1. Control of Ventilation

• Anatomy:

• Rhythmicity center

• Ventral respiratory group: controls diaphragm via phrenic nerve
• Dorsal respiratory group: controls intercostal muscles

• apneustic center
• pneumotaxic center

• Chemoreceptors

Central	medulla oblongata	pH directly, PCO2 indirectly
Peripheral	aortic and carotid bodies	pH, PCO2, PO2 directly

• Blood P_CO2 is the primary controller of ventilation
• Chemoreceptors in the medulla respond directly to the pH (H⁺ ions) in the cerebral spinal fluid.
• 70-80% of ventilation produced by activation of the central receptors but this takes several minutes.

• Ventilation and arterial P_CO2

	VE (L/minute)	f (#/minute)	Arterial PCO2 (mm Hg)
Normal	4-5	8-10	40
¯ Ventilation	2	4	80	hypercapnia – PCO2(arterial)
– Ventilation	8	16	20-25	hypocapnia ¯ PCO2 (arterial)

V_E= f x V_tidal

V_E: Ventilation rate

f: breathing frequency

V_tidal: tidal volume

• Hyperventilation results in hypocapnia
• Hypoventilation results in hypercapnia

1. High Altitude

Compensation mechanisms:

1. increase ventilation to increase O₂ delivery to the blood. An increase in ventilation will increase the partial pressure of O₂ in the alveoli, but it cannot make the partial pressure in the alveoli greater than the partial pressure of O₂ in the atmosphere. Thus on Mt Everest, the highest that the alveolar partial pressure of O₂ can be is 45 mm Hg.
2. increase the production of 2,3 DPG by red blood cells. This decreases the affinity of hemoglobin for O₂, and thus more O₂ is released to the cells. An increase in 2,3 DPG will shift the oxygen hemoglobin dissociation curve to the right.
3. the kidneys secrete erythropoietin which stimulates production of hemoglobin and red blood cells.

• RENAL PHYSIOLOGY

1. Anatomy
   1. Gross Anatomy
   2. Nephrons
   3. Blood supply to the kidney
2. Filtration, reabsorption, secretion and excretion
3. Glomerular Filtration
4. Reabsorption
   1. Proximal tubule
   2. Loop of Henle
   3. Cortical Collecting ducts
5. Renal Regulation
   1. Renin-angiotensin-aldosterone system
   2. Acid-Base

1. ANATOMY
2. Gross Anatomy

• 2 kidneys one on each side of the body
• renal cortex: other region of the kidney; contains many capillaries
• renal medulla: inner region, striped appearance due to the way blood vessels run through it (see later in lecture)
• ureter: long ducts that channel urine from the kidneys to the bladder
• urinary bladder: storage sac for urine, surrounded by smooth muscle; has two sphincter muscles (one smooth and one skeletal muscle) that prevents urine from leaving bladder
• urethra: duct that drains from the bladder to outside world.

2. Nephron

The kidney is made up of more than one million nephrons. The nephron is the basic functional unit of the kidney. It can be divided into a number of segments

• Bowmans capsule (glomerular capsule)
• Proximal convoluted tubule
• Loop of Henle
• Distal convoluted tubule
• Collecting duct

There are two basic types of nephrons

• Cortical nephrons: these nephrons have loops of Henle that extend only into the renal cortex.
• Juxtamedullary nephrons: these nephrons have loops of Henle that extend down into the renal medulla. Though they do not make up a large fraction of the total number of nephrons, juxtamedullary nephrons play an important role in the concentration of the urine

3. Blood Supply to the Kidney

The kidney is slightly different than other organs because it has two capillary beds in series:

• the glomerular capillaries (glomerulus)
• the peritubular capillaries

Since the kidney has two capillary beds in series it will have two arterioles, one before each capillary bed:

• the afferent arteriole
• the efferent arteriole

2. FILTRATION, REABSORPTION, SECRETION, AND EXRETION

• Filtration: a fraction of the total blood that flows into the glomerular capillaries is filtered through the glomerular capillary walls into Bowman’s capsule. In a normal healthy person about 20% of the blood is filtered. With a cardiac output of about 5 liters per minute, this corresponds to 180 L/day. The amount filtered at the glomerulus is called the glomerular filtration rate or GFR.
• Reabsorption: once in Bowmans capsule a large fraction of the amount filtered reabsorbed back from the nephron tubule into the blood.
• Secretion: a small amount of fluid is secreted from the peritubular capillaries into the nephron tubules.
• Thus fluid goes into the nephron tubules by two mechanisms: filtration through the glomerulus and secretion from the peritubular capillaries.
• Excretion: the amount remaining at the end of the nephron is excreted into the bladder. This is a very small amount compared to the amount filtered into the glomerulus.

3. GLOMERULAR FILTRATION

Three barriers for fluid to cross when it goes from the glomerulus to Bowman’s capsule:

1. Endothelial cells: contain fenestrations
2. Basement membrane: a thin layer of negatively charged glycoproteins
3. Podocytes: octopus like cells with many arms that extend into fingers (pedicels) that wrap around the blood vessel.

The combination of these three layers restricts the passage of proteins. Thus for a normal individual, no proteins make it into Bowmans capsule.

3. REABSORPTION

1. Proximal Tubule

Proximal Tubule: approximately 65% of the filtered fluid is reabsorbed in the proximal tubule. This involves mostly electrolytes (sodium, potassium, chloride) and nutrients (glucose, amino acids).

Epithelial cells that line the nephron contain passive and active transporter that transport different substances across the epithelial layer.

Sodium-Glucose Transport

1. Sodium and glucose are transported across the apical membrane via a sodium glucose cotransporter. This is an active transporter which used the sodium gradient to transport glucose.
2. Glucose is transported via a glucose transporter across basolateral membrane. This is passive transport of glucose down its concentration gradient.
3. Sodium is transporter via the sodium-potassium ATPase across the basolateral membrane. This is an example of active transport.

Transport Maximum

If all of the Na⁺-glucose cotransporters are saturate, the proximal tubule can no longer reabsorb all the glucose and therefore some glucose is left in the nephron and ends up in the urine. This saturation of the glucose transport mechanism occurs when the concentration of glucose in plasma gets too high. The higher the plasma glucose concentration, more glucose will be filtered into the nephron. The point at which more glucose cannot be reabsorbed is called the transport maximum.

In diabetes milletus, the body does not produce insulin. Insulin is used to help transport glucose into cells. In diabetes milletus, glucose cannot enter cells and remains in plasma, and the plasma glucose concentration gets very high.

Sodium reabsorption

Epithelial cells in the proximal tubule reabsorb large amounts of sodium. Sodium is the major extracellular cation and makes up a large fraction of the osmolarity of the extracellular space. The extracellular space includes the interstitial space and plasma. Thus when sodium is reabsorbed this increases the osmolarity of plasma and draws water from the nephron tubules into plasma. Thus sodium reaborption increases water reabsorption.

1. Loop of Henle

Countercurrent Multiplication

Countercurrent multiplication serves to increase the amount of solutes in the interstitial space, by increasing the amount of sodium chloride in the interstitial space of the renal medulla. Juxtamedullary nephrons with long loops of Henle perform this task.

1. Thick ascending loop: Allows active transport of NaCl and is impermeable to water. Active transport by the thick ascending limb transport sodium chloride into the interstitial space in the renal medulla.
2. Thin descending loop: no active transport of NaCl, but very permeable to water. The increase in sodium chloride concentration in the renal medulla increases the osmolarity of the renal medulla and draws water from the thin descending loop into interstitial space. This makes the fluid in the thin descending limb more concentrated.
3. Flow down the nephron (due to pressure in the glomerulus) pushes this concentrated fluid around the loop of Henle up to the thick ascending limb. The thick ascending limb can now transport even more NaCl into the interstitial space since the amount transported is proportional to the concentration of NaCl in the nephron in the thick ascending limb

3. The Cortical Collecting Ducts

Antidiuretic Hormone (ADH)

Water Permeability (P_H2O)

– ADH ® – # water channels ® – P_H2O ® – H₂O reabsorption

¯ ADH ® ¯ # water channels ® ¯ P_H2O ® ¯ H₂O reabsorption

ADH is produced by cells in the hypothalamus

Osmoreceptors that respond to changes in osmolarity trigger the release of ADH

– Na⁺ in body ® – plasma osmolarity ® – ADH release from the hypothalamus

dehydration ® – plasma osmolarity ® – ADH release from the hypothalamus

Diabetes

• Diabetes Mellitus: decreased insulin release or decreased insulin sensitivity. Glucose cannot enter into cells. This leads to an increase in plasma glucose and an increase in glucose in the urine.
• Diabetes Insipidus: decreased ADH release. This leads to a decrease in water reabsorption and therefore an increase in water excretion.

3. RENAL REGULATION

One of the major roles of the kidneys is to maintain the appropriate concentration of electrolytes.

• Sodium: Major extracellular cation — important in determine blood volume and therefore blood pressure
• Potassium: important for proper electrical functioning of excitable tissues (heart, brain, muscle)
• Hydrogen and Bicarbonate (HCO₃^-): important for acid-base balance

1. Renin-Angiotensin-Aldosterone System

1. Angiotensinogen is secreted by the liver
2. Angiotensinogen is converted to angiotensin I by the enzyme renin which is secreted by granular cells in the juxtaglomerular cells in the kidney
3. Angiotensin I is converted to angiotensin II by the enzyme angiotensin converting enzyme (ACE).
4. Angiotensin II stimulates the release of aldosterone from the adrenal cortex.

Juxtaglomerular apparatus:

• Granular cells: cells in the afferent arteriole that release renin
• Macula densa: cells at the beginning of the distal convoluted tubule. Can sense changes in sodium flow in the nephron.

A decrease in blood pressure and blood volume stimulates renin release by 3 mechanisms:

1. The baroreceptor reflex is activated which increases sympathetic activity and stimulates renin release
2. Pressure receptors in the kidney sense the drop in pressure and release a substance which stimulates renin release
3. Decreased blood pressure results in decreased blood flow to the macula densa and results in release of a substance which stimulates renin release.

Aldosterone

Secreted by the adrenal cortex and acts on the principal cells is the cortical collecting ducts.

– Aldosterone ® – Na⁺ reabsorption and – secretion

If no aldosterone then 2% of the sodium filtered would be excreted

With aldosterone then almost all of the sodium filtered is reabsorbed

If no aldosterone then no potassium is excreted

With aldosterone then 50x the amount of potassium filtered is excreted.

Mechanism:

• Sodium goes across apical membrane via sodium channels
• Sodium moves across basolateral membrane via Na⁺-K⁺-ATPase
• Potassium moves across basolateral membrane via Na⁺-K⁺-ATPase.
• Potassium moves across apical membrane via potassium channels.

2. Acid-Base

Arterial blood pH is tightly regulated between pH 7.35-7.45

A typical western (meat eating) diet produces

80 moles (a lot) of CO₂. This is eliminated by the lungs.

80 mMoles (1 mMole = 10^-3 moles). This is eliminated by the kidneys.

CO₂ + H₂O ® H₂CO₃ ® H⁺ + HCO₃^-

The first reaction (combining CO₂ and H₂O) required the enzyme carbonic anhdyrase. This enzyme is found in:

1. The lung (used to help eliminate CO₂.
2. Red blood cells: helps buffer H⁺ changes in blood
3. Kidney: involved in HCO₃^- reabsorption.

H⁺ concentration in blood is 35-45 nM

HCO₃^- concentration in blood 24 mM

Mechanism of HCO₃^- reabsorption:

1. H⁺ is secreted kidney epithelial cells in the proximal tubule
2. HCO₃^- combines with H⁺ to for H₂CO₃
3. The presence of carbonic anhydrase in the nephron lumen results in the formation of CO₂
4. CO2 diffuses across the apical membrane and combines with H₂O to reform H⁺ and HCO₃^- inside the kidney epithelial cell
5. The H⁺ is secreted (again) into the nephron lumen
6. HCO₃^- is transported across the basolateral membrane

In order to secrete H⁺ the kidneys pump H⁺ into the nephron lumen. At some point the nephron lumen pH drops to low and the pumps can no longer pump against the steep concentration gradient. In order to excrete the H⁺ there are two main tubular fluid buffers: phosphate and ammonia.