We can divide the respiratory system into two zones:the respiratory zone - the site of gas exchange and the the conduction zone - the structures that move air to the site of exchange.
These zones are useful in dividing functions of ventilation and gas exchange. We will add to this by looking at the properties of blood that allow it to transfer oxygen to the tissues and remove carbon dioxide.

The conducting zone includes the glottis, larynx, trachea, bronchi, bronchioles.
The respiratory zone is made up principally of the alveoli although there is limited exchange in some bronchioles.

In humans there are estimated to be about 300,000,000 alveoli.
They have an estimated area of about 100 square meters.
The function of gas exchange is facilitated by the large surface area and a small diffusion distance. The air and blood are separated by two thin cells only. (squamous epithelium - alveolar cells and capillary endothelium). These cells often share a basement membrane. The distance between the air and blood is about 2 mm.

Ventilation
Air moves in and out of our lungs because of presssure differences induced by lung volume differences.
Physical properties such as compliance, elasticity and surface tension influence the volume changes.

The lungs are contained within the thoracic cavity. There is very little space between the visceral pleura covering the lungs and the parietal pleura lining the cavity. There is a small amount of fluid to lubricate the surfaces to allow easy movement.
So the lungs expand and contract with the thoracic cavity.

As the volume of the lungs increases, the pressure decreases (Boyle's Law) below atmospheric pressure and air flows in.
Compliance is a measure of the stretchability of the lungs or the ease with which the lungs can be stretched. A lung with low compliance will not stretch easily and will require more energy to increase its volume or will not increase its volume.

Scar tissue contains connective tissue with large amounts of collagen, which has high tensile strength.
Increase in scar tissue or other connective tissue decrease compliance of lungs.

Elasticity
Elasticity is not stretchability but the property of returning to an original shape after distension.
The normal connective tissue in lungs have a high proportion of elastin as their fibrous protein.
This affords compliance but provides some resistance to distension which increases during inspiration.

Surface tension
Fluid is constantly secreted and absorbed by the cells lining the lungs. This fluid has a surface tension. (water molecules are attracted to each other rather than air).
Surface tension acts to close alveoli (Law of Laplace).
Another consequence of surface tension is that it is greater in small alveoli ie pressure is greater and air should be expelled from small alveoli into larger alveoli.

Surfactant
Fortuneately alveolar fluid contains a surface active agent or surfactant.
Surfactant reduces surface tension by getting between water molecules and reducing the attraction between them. Its effect is greater in small alveoli and so it evens out the pressure allowing small and large alveoli to coexist.

Surfactant is produced by type II alveolar cells from about the 8th month of gestation.
Premature babies often have respiratory problems because of low or no surfactant.

Mechanics of Breathing
Increase in volume of the thoracic cavity is normally achieved by muscle contraction and expiration by muscle relaxation and elastic recoil.
An at rest inhalation (inspiration) happens due to the contraction of the diaphragm. To increase the force of inspiration other muscles such as the external intercostals and scalenes are used to raise the ribs.

Expiration at rest is a passive process as a result of elastic recoil of the chest wall and lungs. Forced expiration can be achieved with contraction of internal intercostals and abdominal muscles.

During quiet breathing the amount of air expired with each breath is the tidal volume (about 500ml).
But the lungs are not empty after a quiet expiration. There is usually about 2.2 liters of air still in the lungs (functional residual capacity).
Forced expiration can push out about another 1.0 L (expiratory reserve), leaving a residual volume of about 1.2 L.

A maximal inspiration can increase the volume about 3.0L (inspiratory reserve volume) to give a total lung capacity of about 5.8 L.

One method of analyzing ventilation is to calculate minute volume, i.e. tidal volume x ventilation rate per minute.
At rest the minute volume is around 6 L per minute (VR,12 X TV0.5 = 6L/min). This can increase to 200 L per minute during exercise.

Functionally ventilation systems have some built in inefficiencies.
1. Fresh air takes time to be replaced and so diffusion is only taking place about 50% of the time.
2. On each inspiration, expired air in the "anatomical dead space" is drawn in reducing the anmount of fresh air.

The anatomical dead space is the air in the bronchi, trachea, pharynx and mouth or nasal cavities, about 150ml.
When we breathe in, the first air to enter our lungs is the "stale" air in the anatomical dead space, i.e. air exhaled in the last breath.
As tidal volume increases it becomes less relevant.

Disorders
Some diorders can be diagnosed by a simple forced expiration test. Low force can indicate obstructive pulmonary disorders .
Common disorders of the lungs include:
Asthma - an obstructive disorder caused by constriction of bronchioles (contraction of smooth muscle caused by inflammation or parasympathetic stimulus).
Emphysema - destruction of alveolar tissue causes fewer larger alveoli. Loss of surface area and bronchioles collapse.
Common cause - cigarette smoke stimulates macrophages and leukocytes to secrete proteases that destroy tissue.
Pulmonary fibrosis - build up of fibrous connective tissue - reduces effective surface area and compliance
Caused by small particles such as smoke, dust (coal, asbestos).

Gas Exchange
Gas exchange in the lungs is a passive process. Gasses diffuse across the tissue from air to blood and vice versa by diffusion driven by concentration gradients.
Pressure is a measure of concentration of a molecule in a gas.
Dalton's Law states that the total pressure of a gas mixture is the sum of the pressures of each individual gas (partial pressure).

Dry air pressure at sea level is 760 mm Hg.
O₂ makes up approximately 20.95% of air.
Therefore:Po₂ = 760 x 0.2095 = 159 mm Hg
Nitrogen is 78.6% of air and PN₂ = 760 x 0.7809 = 593
Carbon dioxide CO₂ makes up about 0.03% of air.

Inspired air usually contains some water vapor and by the time it gets to the alveoli, it is fully saturated (PH₂O is 47mmHg or 6.2%), reducing the amount of other gasses.
Pwet air = PN₂ + Po₂ + Pco₂ + PH₂O
Po₂ = (760-47) x 0.2095 = 149

Because of mixing with dead space air, the partial pressures in the alveoli are actually...
PH₂O = 47 mmHg
Pco₂ = 40 mmHg
Po₂ =105 mmHg
PN₂ = 601 mmHg
Total = 760 mmHg

Why do climbers need oxygen climbing Mt. Everest?

Why do football players have trouble with their conditioning at Mile High Stadium in Denver?

Why do some athletes train at high altitudes?

Although the proportions of the gases in the air do not change significantly with altitude, air pressure does change.

At the top of Mt. Everest the air pressure is only about 240 mm Hg.
Partial pressure of O₂ is
240 x 0.2095 = 50 mm Hg
i.e. about 1/3 of oxygen available at sea level.

At Mile High Stadium, air pressure is about 640 mm Hg.
Partial pressure of O₂ is
640 x 0.2095 = 134 mm Hg
i.e. about 85% of oxygen available at sea level.

So why would athletes want to train in such an environment?
Our bodies compensate for the low Po₂
Amongst some changes are:ventilation increases due to change in set point of blood CO₂ levels.
Increased levels of 2,3 DPG

In response to hypoxia, kidneys secrete the hormone erythropoietin EPO, red blood cells increase from 5 million/ml to 8 million/ml at altitudes around 4000m.
People in Himalayas can have hematocrits of 60%.
Consequenial increase in blood viscosity may decrease advantage for athletes.
EPO is one of the "new" performance enhancing drugs banned by the IOC.

When a gas and a liquid come together, the constituants of the gas can dissolve in the liquid, eventually reaching an equilibrium concentration.
The amount of each gas that dissolves, following Henry's Law is determined by the solubility of the gas, the temperature of the fluid, other solutes and the partial pressure of the gas.

You can work out the amount of gas that will dissolve in water (or plasma) at a certain pressure
Vg = a.(Pg/760). VH₂0

Vg = volume of gas at STP
a = solubility coefficient
Pg = partial pressure of gas
VH₂0 = volume of water

At 37°C
a for O₂ = 0.024
a for CO₂ = 0.57
a for N₂ = 0.012

Volume of gases in water at 37°C, in alveoli
oxygen (Po₂ =105 mmHg) = 3.3 ml O₂/L

carbon dioxide (Pco₂ = 40 mmHg) = 30.0 ml O₂/L

Note how much more soluble CO₂ is than O₂.

At any given temperature the amount of gas dissolved in the liquid is dependent on the partial pressure of the gas. For this reason, the partial pressure is often used as a measure instead of amount dissolved.

Systemic arteries have Po₂ of about 100 mmHg and Pco₂ of 40 mmHg.
Systemic veins have Po₂ of about 40 mmHg and Pco₂ of 46 mmHg
If oxygen is far less soluble in blood plasma than carbon dioxide, how then can it function efficiently to distribute oxygen to the tissues?

Because of Hemogobin.

The blood of vertebrate, including humans, contains a respiratory pigment, hemoglobin (Hb), that reversibly binds O₂ (to form oxyhemoglobin HbO₂) in amounts about 100 X than that carried dissolved in blood plasma.

Hemoglobin is a protein made up of four subunits 2 a (141 amino acids) and 2 b (146 aas), that together form a tetramer a2 b2 .
Each subunit contains an iron containing heme group in a pocket which can attract and bind O₂ molecules.
Hemoglobin is contained inside red blood cell (RBCs, erythrocytes).

One Hb molecule can bind 4 molecules of O₂.
There are 280 million Hb molecules in each RBC.
Each ml of blood contains about 5,000 milion RBCs.

Oxygen Dissociation Curve
The amount of oxygen bound to hemoglobin is dependent upon the partial pressure of oxygen in the air to which it has reached equilibrium.
At the alveoli, Po₂is about 100mmHg producing about 98% saturation of hemoglobin.
As the pressure of oxygen is reduced the percent of hemoglobin binding oxygen declines.
Blood leaving the tissues has a Po₂ of about 40mmHg resulting in about 75% saturation of hemoglobin.

Plotting percent saturation against oxygen pressure produces an oxygen-hemoglobin dissociation curve.
Curve is not linear indicating cooperativity.
Dissociation curves of hemoglobins for different animals vary indicating different oxygen affinity.

Oxygen affinity indicates the readiness of hemoglobin to give up oxygen to tissue.
As blood circulates through the body it gives up oxygen to other cells and so the pressure of oxygen drops to about 40 mmHg at rest and to about 20mm Hg with exercise.

Hb oxygen affinity is altered by a number of factors.
1. Increased acidity decreases the affinity (shifts the curve to the right). (Bohr effect)
2. Increased temperature decreases the affinity.
3. Increased carbon dioxide decreases the affinity.
4. Increase in certain organic phosphates (2,3 DPG; IPP; ATP) decreases affinity.

The effect of pH, CO₂ and 2,3 DPG is called allosteric regulation.
These molecules bind to the Hb molecule in a site other than the oxygen binding site and in doing so change its shape slightly (change some bonds between aas).
The change in shape alters slightly the attraction between heme and oxygen.
This differe from the binding of a competitor such as carbon monoxide which binds to the heme and prevents 0₂ binding

Myoglobin which resembles closely a single subunit of hemoglobin is found in skeletal muscle has a dissociation curve far to the left of hemoglobin and it facilitates movement of oxygen into muscle cells.
It is generally accepted that hemoglobin subunits evolved from myoglobin.

Humans change their hemoglobins during development.
Fetal hemoglobin must be to the left of maternal hemoglobin to absorb oxygen.
.
Control of ventilation
Because of differences in solubility there is a lot more CO₂ than O₂ dissolved in plasma.
Dissolved O₂ actually varies very little because most of the O₂ in whole blood is bound to hemoglobin.
CO₂ however does vary and chemoreceptors monitor the CO₂ levels.
High blood CO₂ stimulates breathing response.

Peripheral chemoreceptors in the carotid bodies and in the aorta are not stimulated by changes in CO₂ directly.
CO₂ + H₂O -> H₂CO₂ -> HCO₂- + H⁺
Chemoreceptors pick up the change in pH.
Chemoreceptors are also located in the medulla oblongata which pick up changes in pH of the cerebrospinal fluid.
Information is integrated in the medullary respiratory centers and the PRG (pontine respiratory group) in the pons.

Another interesting feedback system for ventilation is the Hering-Breuer reflex.
Stimulation of stretch receptors in the lungs inhibits the the respiratory control center and prevents over distension of the lungs.

The control of ventilation is so good that arterial blood concentrations of oxygen, carbon dioxide remain surprisingly constant.
Blood is always fully oxygenated passing through the lungs even during heavy exercise.
pH is effected by CO₂ levels and by lactate production in tissue. This is controlled in the lungs by ventilation and in the kidneys.

Clinical questions

What are the disorders classified under the title COPD (chronic obstuctive pulmonary disease)?

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This webpage was created by Peter King. Please contact the the author with comments at pking@fmarion.edu.
Last edited July 20, 2010.
http://people.fmarion.edu/pking/humanphys/respiration.html
copyright Peter King.