A. Lung Function

1. Oxygen demand ~250mL O2/min in resting adult
2. Carbon Dioxide unloaded ~200mL CO2/min in resting adult
3. O2 demand can increase ~10X on exercise
4. CO2 production can increase to equal O2 consumption on exercise
5. Protection of alveolar spaces from airborne polutants
   1. Ciliary Clearance
   2. Mucus Production
6. Mucus [1]
   1. Consists of fluids rich in proteins called mucins
   2. Mucins are heavily glycosylated, cystein-rich proteins
   3. These proteins give mucus its viscous, gel-forming, and anti-oxidant qualities

B. Respiratory Coefficient (R)

1. Defined as CO2 produced ÷ O2 consumed
2. At rest, R ~ 0.8
3. On exercise, R increases to ~ 1.0

C. Partial Pressures

1. Water vapor P ~ 47mmHg
2. Air ~21% O2
3. Therefore, partial pressure of O2 = 0.21·(760-47) = 150 mmHg in air at sea level
4. Partial pressure gradients determine rates of diffusion through gasses and liquids

D. Ventilation

1. Alveolar ventilation = VA
   1. Determines alveolar CO2 tension, PACO2
   2. PACO2 = FACO2·(760-47)
2. VCO2 (mL/min) = 1000·VA·FACO2
   1. Therefore VCO2 = 1000·VA·PACO2/(760-47)
   2. And VA = K·VCO2/PACO2 where K ~0.86
   3. So PACO2 = K · VCO2 / VA
3. Conclude that carbon dioxide levels depends primarily on alveolar ventilation
4. So decrease in VA leads to increased levels of CO2
5. Control of Ventillation
   1. Ventilation level controlled by respiratory centers in pons and medulla
   2. Medullary chemoreceptors respond to change in pCO2 in arterial blood
   3. May also be sensitive to fall in pH accompanying hypercapnia
   4. Protons and HCO3- are not measured
   5. Hypoxemia increases ventilation via peripheral chemoreceptors in carotid bodies
   6. Sensitivity for hypoxemia is relatively weak compared to CO2 sensors

E. Alveolar / Blood Interaction

1. The lung can be divided into three ventilation / perfusion regions
2. Apex region I, middle region II, and base region III
3. Region III is better ventilated and it is better perfused than the other regions
4. Ventilation
   1. Region III, at rest end expiration, is the most collapsed
   2. This is because it is the dependent part of the lung (lung mass)
   3. Net pleural pressure on it is ~ -2.5cm
   4. The apex (Region I) has a net pleural P at End Expiration ~ -10cm
   5. Region III can expand more on inspiration, so it is better ventilated
5. Perfusion
   1. Region III is better perfused because Pa>Pv>PA
   2. In region II Pa>PA>Pv; but in region I, PA>Pa>Pv
   3. Vasculature in region I is nearly completely closed
   4. This is because the alveolar pressure is > arterial pressure; region II is intermediate
6. Region I has the highest O2 tension and the highest negative pleural pressure
   1. Tuberculosis typically grows in the lung apex, although it is seeded in the basal portions
   2. The highest negative pleural pressure may increase bleb formation
   3. This is particularly prevalent in emphysema
7. Normal Lung Alveolar Structure
   1. Type I alveolar cells (pneumocytes) - very thin epithelial cells
   2. These Type I alveolar cells cover most of the alveolar surface
   3. Cuboidal Type II cells reside at corners of alveoli
   4. These Type II cells produce and recycle surfactant [5]
   5. Type II cells proliferate and differentiate into new Type I during growth and injury
8. Surfactant [4,5]
   1. Hydrophobic liquid composed of specialized proteins and lipids
   2. Produced by Type II alveolar epithelial cells and coats alveolar cell surfaces
   3. Reduces surface tension and prevents end-expiratory atelectasis
   4. Surfactants proteins B and C are hydrophobic proteins that enhance surface-tension lowering effects of surfactant lipids
   5. Hereditary deficiency of surfactan proteins have been described
   6. Inability to produce surfactant protein B can cause a lethal neonatal lung disease
   7. Mutations in surfactant protein C cause a progressive interstitial lung disease [4]

F. Alveolar Gas Equation

1. This is an approximation with
   1. Inspired oxygen of PiO2 < 50% O2
   2. R ~0.8 (at rest)
2. Then PAO2 = PiO2 - PaCO2/R
   1. Where PaCO2 = arterial CO2 , in equilibrium with alveolar CO2
   2. PAO2 = alveolar oxygen concentration
   3. PiO2 ~ 0.21 x (760-47) = 150 mmHg

G. Alveolar-Arterial (A-a) Gradient

1. In normal lungs, a difference between arteriolar and alveolar oxygen always exists
2. This is called the A-a gradient
3. PA-Pa = {Fi(O2)x(760-47)]-[PaCO2/0.8]} - PaO2 where {} term is PAO2
4. Normal A-a gradient is 10-15 mm Hg or 0.3 x Age
5. The normal A-a gradient is due to the normal, or "Physiologic" Shunt
   1. Shunt occurs when V/Q = 0
   2. Ventillation is 0 (perfusion of non-ventillated areas)
   3. Normally, ~30% of Cardiac Output is Shunted (see above discussion)
   4. Q(ps)/Q(t) = (Ci - Ca)/(Ci - Cv); In normal cases, Q(ps)/Q(t) ~ 20/65 = 0.3
   5. Q(ps) is physiologic shunt blood flow per minute Q(t) cardiac output per minute
   6. Ci is concentration of O2 in arterial blood for ideal ventilation-perfusion ratio (104mm)
   7. Ca is measured concentration of oxygen in arterial blood; Cv in mixed venous blood
6. Abnormalities in A-a Gradient
   1. A-a gradient is only altered in diseases which affect ability of lungs to oxygenate blood
   2. If a low pO2 is due to hypoventilation, then the A-a gradient will not change
   3. The prototype is adult respiratory stress syndrome (ARDS, see below)
   4. Others include pulmonary embolism, severe asthma, emphysema (lung destruction)

H. Hemoglobin [2,3,6]
[Figure] "Oxygen-Hemoglobin Dissociation Curve"

1. Hemoglobin (Hb) is essential for oxygen transport
   1. Normal Hb consists of two alpha and two beta polypeptides
   2. Also contains a porphyrin ring with ferrous (Fe2+ iron) atom
   3. Molecular weight is 64.5K
   4. Deoxyhemoglobin is in a tense (T) conformation with low O2 affinity
2. There are multiple oxygen-binding sites on Hb
   1. One O2 molecule can bind to ferrous atom
   2. This induces changes in conformation of Hb leading to changes in conformation
   3. These changes lead to relaxed conformation and ~500 fold increase in Hb affinity for O2
   4. In addition, there is a cooperativity among O2 binding sites
   5. Thus, occupancy of O2 binding sites leads to increased affinity
3. The relationship between O2 saturation on Hb and O2 pressure is therefore sigmoidal
   1. The curve is described fairly well by the Hill Equation (figure above)
   2. Thus, (O2 tension/P50)exp(N)={(O2 Sat)/(100-O2 Sat)}
   3. P50 is the pressure (in mmHg) at which 50% of O2 binding sites are occupied
   4. Normal Hb affinity for O2 is measured by P50, and is 26.3mmHg for normal adults
   5. Abnormal Hb's have abnormal values of P50
   6. For O2 saturation 15-95%, the value of N (Hill Coefficient) is ~2.7, range 2.4-2.9
4. Modulators of Hb Affinity for O2 [6]
   1. Oxygen, the primary ligand, induces increased affinity for itself (homotropic effector)
   2. There are three major heterotropic effectors
   3. These are hydrogen ion (pH), carbon dioxide (CO2), red-cell 2,3-diphosphoglycerate (DPG)
   4. Hydrogen ions (decreased pH) and CO2 reduces O2 binding of Hb (Boehr Effect)
   5. O2 binding to Hb reduces its affinity for CO2 (Haldane Effect)
   6. Reduction in Hb affinity for O2 shifts O2-Hb dissociation curve to the right
   7. In addition, temperature and DPG increases reduce O2 affinity (similar to acid)
   8. These concepts explain much of O2 delivery physiology between lung and tissue
5. O2 Delivery to Tissues
   1. Because tissues are more acidic than blood due to increased CO2 and lactate production
   2. Both CO2 and acid leads to reduced affinity of Hb for O2
   3. Thus, O2 is released by Hb in tissues, and CO2 is absorbed onto the Hb
   4. In the lung, high O2 concentrations drive O2 binding by Hb and lead to CO2 release
6. Red Cell DPG
   1. Red blood cells (RBC, erythrocytes) depend solely on glycolysis for energy production
   2. 2,3 DPG is normally a metabolic intermediate derived from 1,3 DPG
   3. The enzyme responsible is 2,3-DPG synthetase
   4. This pathway is normally minor, with most of 1,3 DPG converted to ATP and 3-MPG
   5. In RBC, 2,3-DPG is sequestered by deoxyhemoglobin and acumulates at high levels
   6. In other cell types, 2,3 is not sequestered and concentrations are very low
   7. DPG binds to Hb, stabilizes the T conformation, and reduces O2 affinity
   8. In addition, DPG binding also lowers intracellular pH
   9. In chronic acidosis, reduced RBC DPG levels compensate partially for drop in pH
7. Hb and Nitric Oxide
   1. Hb scavenges nitric oxide (NO) through high affinity Fe2+ binding sites
   2. The affinity of Hb for NO is ~8000 times that for O2
   3. Hb can carry NO through an S-nitrosothiol moiety
   4. O2 binding to Hb increases its affinity for NO
   5. NO release is enhanced in hypoxic tissue
   6. Since NO is a potent vasodilator, NO release in hypoxic tissue increases blood flow there
   7. Note that NO binding sites are essentially independent of O2 binding sites
8. Hb and Carbon Monoxide
   1. Hb affinity for carbon monoxide (CO) is ~200 times that for O2
   2. CO binding sites are the same as O2 binding sites on Hb (carboxyhemoglobin, carboxyHb)
   3. Therefore, during pulmonary transit, Hb binds alveolar CO preferentially over O2
   4. CO binding also increases Hb affinity for O2 and reduces ability of Hb to release O2
   5. Therefore, CO reduces Hb's O2 carrying capacity as well as ability to deliver O2
   6. Blood carboxyHb concentration underestimates true tissue O2 deficit
   7. CO is especially harmful in the placental circulation
   8. Smoking tobacco and chronic smoke inhalation are serious problems during pregnancy
   9. Smoking 1 pack per day, fetal arterial O2 saturation drops from 75% (normal) to ~58%
9. Hb and Acid-Base Disorders
   1. Acute acidosis increases P50, favors oxygen unloading from Hb
   2. Chronic acidosis has reduced RBC DPG, leading to essentially normal P50
   3. Acute alkalosis has reduced P50, favors O2 binding and reduces O2 unloading
   4. Chronic alkalosis has essentially normal P50 due to increased RBC DPG
   5. Acute alkalinization in chronic acidosis can cause markedly reduced P50
   6. This is especially problematic in cerebral tissues, where alkali causes vasoconstriction
   7. Therefore, O2 delivery and unloading to cerebral tissues are reduced (may be severe)
10. Oxygen Delivery and Consumption [6]
    1. Artrerial Oxygen Concentration (CaO2) = (Hb·1.34·SaO2)+(PaO2·0.003)
    2. Oxygen Delivery (DO2) = Cardiac Output (CO) · CaO2
    3. Oxygen Consumption (VO2) = CO · (CaO2 - CvO2)
    4. VO2 = (Hb·1.34·(SaO2-SvO2) + ((PaO2 - PvO2)·0.003))

I. Pulmonary Mechanics

1. Getting O2 into lungs depends on the A-a pressure gradient
2. The respiratory portion should be thought of as a two compartment system:
   1. Airways, characterized by a resistance Raw
   2. Lung parenchyma, characterized by a compliance, Crs
3. From Ohm's law, it follows that: PA (alveolar pressures) = VI·Raw + VT/Crs
   1. VI is inspiratory flow rate
   2. Raw units cm / liter / sec = cm·sec/liter, which is airway Resistance
   3. Crs units liters / cm, which is lung Capacitance (distensibility)
   4. VT is tidal volume Raw·Crs = time constant (seconds)
   5. The time constant is the time taken to get (1-1/e)·FVC air into the lungs
   6. It is also the time to get (1/e)·FVC out of the lungs
4. In certain diseases, flow is compromised ("airflow limitation;" see below)

J. Introduction to Lung Airflow

1. Flow through a rigid tube
   1. V (flow) = delta P/R
   2. When V = 0, then delta P must be 0
   3. With complete obstruction, R = infinity
2. Expiration is normally a passive process
   [Figure] "FEV1 and FVC"
   1. PEL is major determinant in normal lungs
   2. At maximal inspiration (FVC), Flow is highest
   3. See also below (Flow-Volume Relationships)
3. Pressures in the Lung on Expiration
   [Figure] "Pulmonary Pressures"

K. Airflow Limitation

1. As PALV increases, there is an increase in airflow
2. Eventually, PALV may increase, but airflow will remain constant
3. So increase in PPL will eventually not increase flow
4. This is called Airflow Limitation
   1. At low lung volumes, airflow limitation occurs at low pressures
   2. At high lung volumes, limitation occurs at high pressures and flows
   3. Normal subjects cannot reach airflow limit at high lung volumes
5. Maximal Flow = VMAX ~ (PEL-PTM)/RS (see derivation below)

L. Mechanisms of Airflow Limitation

1. Collapse of Airway Tubes
2. Airway tubes will collapse at a certain transmural pressure difference (delta PTM)
3. Normally, Pressures are measured as PIN - POUT = delta PTM
   1. For simple, weak walled tube, PTM must be < 0 leads to collapse
   2. For rigid tubes, PIN must be << POUT in order for collapse to occur
4. PTM' is defined as the Collapsibility of a Tube
   1. PTM' < 0 implies a rigid tube
   2. PTM, > 0 implies a highly collapsible tube
   3. Note that PTM' is opposite in sign to PTM
   4. In asthma, for example, PTM' increases its value and may actually be > 0
5. Not yet clear if airway actually closes vs. flutters to produce this characteristic
6. Derivation of Vmax Flow Equation (ie. for obstructive diagnoses)
   1. Goal is to characterize maximal Expiratory Flow (V) behavior mathematically
   2. By Ohm's Law, VMAX = (PALV-PX)/RS
   3. PX = pressure at point of collapse
   4. On expiration, PALV = PEL + PPL
   5. PX = PPL + PTM' (vector pressures in same direction)
   6. Therefore, VMAX = [(PEL + PPL)-(PPL + PTM')]/RS
   7. In conclusion, VMAX = (PEL-PTM')/RS
7. Disease Relationships
   [Figure] "Pulmonary Pressures"
   1. PEL decreases in emphysema
   2. PTM' increases in asthma
   3. RS increases in bronchitis and severe asthma

M. Four Lung Capacities
[Figure] "Lung Volumes"

1. Total Lung Capacity (TLC) = RV + VC
2. Vital Capacity
   1. VC = Inspiratory Capacity + Expiratory Residual Volume
   2. VC = TLC - RV
   3. Body Plethysmography P1V1 = P2V2
3. Inspiratory Capacity (IC)
4. Functional Residual Capacity

N. Four Lung Volumes

1. Inspiratory Reserve Volume
2. Tidal Volume - normal breath volume ~ 500mL
3. Expiratory Reserve Volume
4. Residual Volume: methods for determination
   1. Open circuit: 100% Oxygen breathing with Nitrogen washout
   2. Helium Dilution
   3. Body Plethysmography: Panting for gas compression
5. Notes on RV Determination
   1. Methods 4a and b above underestimate true volume in low ventilation areas because they only measure gas in connection with conducting areas
   2. Body plethysmography measures everything surrounded by pleural pressure and so is more accurate in obstructive (such as bullous) disease

O. Changes in Disease
[Figure] "Pulmonary Pressures"

1. Restrictive
   1. Stiff chest wall = kyphoscoliosis, rib fractures, ankylosing spondyloarthropathy
   2. Stiff Lung = Fibrosis, pneumonia, pulmonary edema
   3. Muscle Weakness = Guillain-Barre Syndrome, poliomyelitis, spinal cord injury, myopathy
2. Obstructive
   1. Combinations of the following changes:
   2. Increased Airway Resistance (increased R)
   3. Decreased Elastic Recoil (decreased P-EL)
   4. Increased Airway Tone (increased P-TM')
3. Defects in Lung Gas Transfer
   1. Lung Surface Area Reduction
   2. Respiratory Distress Syndromes
4. Lung Surface Area Reduction
   1. Emphysema
   2. Pneumonectomy
   3. Atelectasis
5. Respiratory Distress Syndrome (RDS)
   1. Adult (ARDS)
   2. Infant RDS - Hyaline Membrane Disease of the Newborn

References

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2. Weatherall DJ and Provan AB. 2000. Lancet. 355(9120):1169
3. Hsia CCW. 1998. NEJM. 338(4):239
4. Nogee LM, Dunbar AE III, Wert SE, et al. 2001. NEJM. 344(8):573
5. Whitsett JA and Weaver TE. 2002. NEJM. 347(26):2134
6. Klein HG, Spahn DR, Carson JL. 2007. Lancet. 370(9585):415