1.

The respiratory system and direct diffusion

Breathing is an involuntary event. How often a breath is taken and how much air is inhaled or exhaled are
tightly regulated by the respiratory center in the brain. Under normal breathing conditions, humans will breathe
approximately 15 times per minute on average. A respiratory cycle consists of an inhalation and an exhalation:
with every normal inhalation, oxygenated air fills the lungs, while with every exhalation, deoxygenated air
rushes back out. The oxygenated air crosses the lung tissue, enters the bloodstream, and travels to organs and
tissues. Oxygen (O2) enters the cells where it is used for metabolic reactions that produce ATP, a high-energy
compound. At the same time, these reactions release carbon dioxide (CO2) as a by-product. CO2 is toxic and
must be eliminated; thus, CO2 exits the cells, enters the bloodstream, travels back to the lungs, and is expired
out of the body during exhalation.
The primary function of the respiratory system is to deliver oxygen to the cells of the body's tissues and remove
carbon dioxide. The main structures of the human respiratory system are the nasal cavity, the trachea, and the
lungs. All aerobic organisms require oxygen to carry out their metabolic functions.
Along the evolutionary tree, different organisms have devised different means of obtaining oxygen from the
surrounding atmosphere. The environment in which the animal lives greatly determines how an animal respires.
The complexity of the respiratory system correlates with the size of the organism. As animal size increases,
diffusion distances increase and the ratio of surface area to volume drops. In unicellular (single-celled)
organisms, diffusion across the cell membrane is sufficient for supplying oxygen to the cell. Diffusion is a
slow, passive transport process. In order to be a feasible means of providing oxygen to the cell, the rate of
oxygen uptake must match the rate of diffusion across the membrane. In other words, if the cell were very large
or thick, diffusion would not be able to provide oxygen quickly enough to the inside of the cell. Therefore,
dependence on diffusion as a means of obtaining oxygen and removing carbon dioxide remains feasible only for
small organisms or those with highly-flattened bodies, such as flatworms. Larger organisms have had to evolve
specialized

respiratory

tissues,

such

as gills,

lungs,

and

respiratory

passages,

accompanied

by

a complex circulatory system to transport oxygen throughout their entire body.

For small multicellular organisms, diffusion across the outer membrane is sufficient to meet their oxygen needs.
Gas exchange by direct diffusion across surface membranes is efficient for organisms less than 1 mm in
diameter. In simple organisms, such as cnidarians and flatworms, every cell in the body is close to the external
environment. Their cells are kept moist so that gases diffuse quickly via direct diffusion. Flatworms are small,
literally flat worms, which breathe' through diffusion across the outer membrane. The flat shape of these
organisms increases the surface area for diffusion, ensuring that each cell within the body is close to the outer

membrane surface and has access to oxygen. If the flatworm had a cylindrical body, then the cells in the center
would not be able to get oxygen.
2. Mammalian systems and protective mechanisms
In mammals, pulmonary ventilation occurs via inhalation when air enters the body through the nasal cavity. Air
passes through the nasal cavity and is warmed to body temperature and humidified. The respiratory tract is
coated with mucus that is high in water to seal the tissues from direct contact with air. As air crosses the
surfaces of the mucous membranes, it picks up water. This equilibrates the air to the body, reducing the damage
that cold, dry air can cause. Particulates in the air are also removed in the nasal passages. These processes are all
protective mechanisms that prevent damage to the trachea and lungs.
From the nasal cavity, air passes through the pharynx and the larynx to the trachea . The function of the trachea
is to funnel the inhaled air to the lungs and the exhaled air out of the body. The human trachea, a cylinder about
10-12cm long, 2cm in diameter found in front of the esophagus, extends from the larynx into the chest cavity. It
is made of incomplete rings of hyaline cartilage and smooth muscle that divides into the two primary bronchi at
the mid-thorax. The trachea is lined with mucus-producing goblet cells and ciliated epithelia that propel foreign
particles trapped in the mucus toward the pharynx. The cartilage provides strength and support to the trachea to
keep the passage open. The smooth muscle can contract, causing a decrease in the trachea's diameter, which
propels expired air upwards from the lungs at a great force. The forced exhalation helps expel mucus when we
cough.
The end of the trachea bifurcates to the right and left lungs, which are not identical. The larger right lung has
three lobes, while the smaller left lung has two lobes. The muscular diaphragm, which facilitates breathing, is
inferior to the lungs, marking the end of the thoracic cavity.
As air enters the lungs, it is diverted through bronchi beginning with the two primary bronchi.
Each bronchus divides into secondary, then into tertiary bronchi, which further divide to create smaller diameter
bronchioles that split and spread through the lung. The bronchi are made of cartilage and smooth muscle; at the
bronchioles, the cartilage is replaced with elastic fibers. Bronchi are innervated by nerves of both the
parasympathetic and sympathetic nervous systems that control muscle contraction or relaxation, respectively. In
humans, bronchioles with a diameter smaller than 0.5 mm are the respiratory bronchioles. Since they lack
cartilage, they rely on inhaled air to support their shape. As the passageways decrease in diameter, the relative
amount of smooth muscle increases.
The terminal bronchioles then subdivide into respiratory bronchioles which subdivide into alveolar ducts.
Numerous alveoli (sing. alveolus) and alveolar sacs surround the alveolar ducts . The alveolar ducts are attached

to the end of each bronchiole; each duct ends in approximately 100 alveolar sacs. Each sac contains 20-30
alveoli that are 200-300 microns in diameter. Alveoli are
made of thin-walled, parenchymal cells that are in direct
contact with capillaries of the circulatory system. This
ensures that oxygen will diffuse from alveoli into the blood
and that carbon dioxide produced by cells as a waste product
will diffuse from the blood into alveoli to be exhaled. The
anatomical arrangement of capillaries and alveoli emphasizes
the relationship of the respiratory and circulatory systems. As
there are so many alveoli (around 300 million per lung)
within each alveolar sac and so many sacs at the end of each
alveolar duct, the lungs have a sponge-like consistency. This
organization produces a very large surface area that is
available for gas exchange.
The air that organisms breathe contains particulate matter
such as dust, dirt, viral particles, and bacteria that can
damage the lungs. The respiratory system has protective
mechanisms to avoid damage. In the nasal cavity, hairs and
mucus trap small particles, viruses, bacteria, dust, and dirt to prevent entry. If particulates make it beyond the
nose or enter via the mouth, the bronchi and bronchioles contain several protective devices. The lungs produce
mucus that traps particulates. The bronchi and bronchioles contain cilia, small hair-like projections that line the
walls of the bronchi and bronchioles. These cilia move mucus and particles out of the bronchi and bronchioles
back up to the throat where it is swallowed and eliminated via the esophagus.
In humans, tar and other substances in cigarette smoke destroy or paralyze the cilia, making the removal of
particles more difficult. In addition, smoking causes the lungs to produce more mucus, which the damaged cilia
are unable to move. This causes a persistent cough, as the lungs try to rid themselves of particulate matter,
making smokers more susceptible to respiratory ailments.
3. The Mechanics of Human Breathing
The relationship between gas pressure and volume helps to explain the mechanics of breathing. Boyle's Law is
the gas law which states that in a closed space, pressure and volume are inversely related. As volume decreases,
pressure increases and vice versa. When discussing the detailed mechanics of breathing, it is important to keep
this inverse relationship in mind.

The thoracic cavity, or chest

cavity, always has a slight,
negative pressure which aids in
keeping the airways of the
lungs open. During the process
of inhalation, the lung volume
expands as a result of the
contraction of the diaphragm
and intercostal muscles (the muscles that are connected to the rib cage), thus expanding the thoracic cavity. Due
to this increase in volume, the pressure is decreased, based on the principles of Boyle's Law. This decrease of
pressure in the thoracic cavity relative to the environment makes the cavity pressure less than the atmospheric
pressure . This pressure gradient between the atmosphere and the thoracic cavity allows air to rush into the
lungs; inhalation occurs. The resulting increase in volume is largely attributed to an increase in alveolar space
because the bronchioles and bronchi are stiff structures that do not change in size.

The lungs, chest wall, and diaphragm are all involved in respiration, both inhalation and expiration. During this
process, the chest wall expands out and away from the lungs. The lungs are elastic; therefore, when air fills the
lungs, the elastic recoil within the tissues of the lung exerts pressure back toward the interior of the lungs. These
outward and inward forces compete to inflate and deflate the lung with every breath. Upon exhalation, the lungs
recoil to force the air out of the lungs. The intercostal muscles relax, returning the chest wall to its original
position . During exhalation, the diaphragm also relaxes, moving higher into the thoracic cavity. This increases
the pressure within the thoracic cavity relative to the environment. Air rushes out of the lungs due to the
pressure gradient between the thoracic cavity and the atmosphere. This movement of air out of the lungs is
classified as a passive event since there are no muscles contracting to expel the air. Each lung is surrounded by
an invaginated sac. The layer of tissue that covers the lung and dips into spaces is called the visceral pleura. A
second layer of parietal pleura lines the interior of the thorax. The space between these layers, the intrapleural
space, contains a small amount of fluid that protects the tissue by reducing the friction generated from rubbing
the tissue layers together as the lungs contract and relax. If these layers of tissues become inflamed, this is
categorized as pleurisy: a painful inflammation that increases the pressure within the thoracic cavity, reducing
the volume of the lung.
4. Transport of oxygen in the blood

Although oxygen dissolves in blood, only a small amount of oxygen is transported this way. Only 1.5
percent of oxygen in the blood is dissolved directly into the blood itself. Most oxygen, 98.5 percent, is
bound to a protein called hemoglobin and carried to the tissues.
Hemoglobin, or Hb, is a protein molecule found in red blood cells (erythrocytes) made of four subunits: two
alpha subunits and two beta subunits . Each subunit surrounds a central heme group that contains iron and binds
one oxygen molecule, allowing each hemoglobin molecule to bind four oxygen molecules. Molecules with
more oxygen bound to the heme groups are brighter red. As a result, oxygenated arterial blood where the Hb is
carrying four oxygen molecules is bright red, while venous blood that is deoxygenated is darker red.
The protein inside red blood cells that carries oxygen to cells and carbon dioxide to the lungs is hemoglobin (b).
Hemoglobin is made up of four symmetrical subunits and four heme groups. Iron associated with the heme
binds oxygen. It is the iron in hemoglobin that gives blood its red color.
It is easier to bind a second and third oxygen molecule to Hb than the first molecule. This is because the
hemoglobin molecule changes its shape, or conformation, as oxygen binds. The fourth oxygen is then more
difficult to bind. The binding of oxygen to hemoglobin can be plotted as a function of the partial pressure of
oxygen in the blood (x-axis) versus the relative Hb-oxygen saturation (y-axis). The resulting graph, an
oxygen dissociation curve, is sigmoidal, or S-shaped . As the partial pressure of oxygen increases, the
hemoglobin becomes increasingly saturated with oxygen.
Factors That Affect Oxygen Binding
The oxygen-carrying capacity of hemoglobin determines how much oxygen is carried in the blood. In addition,
other environmental factors and diseases can also affect oxygen-carrying capacity and delivery; the same is true
for carbon dioxide levels, blood pH, and body temperature. When carbon dioxide is in the blood, it reacts with
water to form bicarbonate (HCO3) and hydrogen ions (H+). As the level of carbon dioxide in the blood
increases, more H+ is produced and the pH decreases. The increase in carbon dioxide and subsequent decrease
in pH reduce the affinity of hemoglobin for oxygen. The oxygen dissociates from the Hb molecule, shifting the
oxygen dissociation curve to the right. Therefore, more oxygen is needed to reach the same hemoglobin
saturation level as when the pH was higher. A similar shift in the curve also results from an increase in body
temperature. Increased temperature, such as from increased activity of skeletal muscle, causes the affinity of
hemoglobin for oxygen to be reduced.
Diseases such as sickle cell anemia and thalassemia decrease the blood's ability to deliver oxygen to tissues and
its oxygen-carrying capacity. In sickle cell anemia, the shape of the red blood cell is crescent-shaped, elongated,
and stiffened, reducing its ability to deliver oxygen . In this form, red blood cells cannot pass through the

capillaries. This is painful when it occurs. Thalassemia is a rare genetic disease caused by a defect in either the
alpha or the beta subunit of Hb. Patients with thalassemia produce a high number of red blood cells, but these
cells have lower-than-normal levels of hemoglobin. Therefore, the oxygen-carrying capacity is diminished.
5. Transport of carbon dioxide in blood
Carbon dioxide molecules are transported in the blood from body tissues to the lungs by one of three methods:
1.

Dissolution directly into the blood 2. Binding to hemoglobin 3. Carried as a bicarbonate ion
Several properties of carbon dioxide in the blood affect its transport. First, carbon dioxide is more soluble in
blood than is oxygen. About 5 to 7 percent of all carbon dioxide is dissolved in the plasma. Second, carbon
dioxide can bind to plasma proteins or can enter red blood cells and bind to hemoglobin. This form transports
about 10 percent of the carbon dioxide. When carbon dioxide binds to hemoglobin, a molecule
called carbaminohemoglobin is formed. Binding of carbon dioxide to hemoglobin is reversible. Therefore, when
it reaches the lungs, the carbon dioxide can freely dissociate from the hemoglobin and be expelled from the
body.
Third, the majority of carbon dioxide molecules (85 percent) are carried as part of the bicarbonate buffer
system. In this system, carbon dioxide diffuses into the red blood cells. Carbonic anhydrase (CA) within the red
blood cells quickly converts the carbon dioxide into carbonic acid (H2CO3). Carbonic acid is an unstable,
intermediate molecule that immediately dissociates into bicarbonate ions (HCO3) and hydrogen (H+) ions.
Since carbon dioxide is quickly converted into bicarbonate ions, this reaction allows for the continued uptake of
carbon dioxide into the blood, down its concentration gradient. It also results in the production of H+ ions. If too
much H+ is produced, it can alter blood pH. However, hemoglobin binds to the free H+ ions, limiting shifts in
pH. The newly-synthesized bicarbonate ion is transported out of the red blood cell into the liquid component of
the blood in exchange for a chloride ion (Cl-); this is called the chloride shift. When the blood reaches the lungs,
the bicarbonate ion is transported back into the red blood cell in exchange for the chloride ion. The H+ ion
dissociates from the hemoglobin and binds to the bicarbonate ion. This produces the carbonic acid intermediate,
which is converted back into carbon dioxide through the enzymatic action of CA. The carbon dioxide produced
is expelled through the lungs during exhalation.
The benefit of the bicarbonate buffer system is that carbon dioxide is "soaked up" into the blood with little
change to the pH of the system. This is important because it takes only a small change in the overall pH of the
body for severe injury or death to result. The presence of this bicarbonate buffer system also allows for people
to travel and live at high altitudes. When the partial pressure of oxygen and carbon dioxide change at high

altitudes, the bicarbonate buffer system adjusts to regulate carbon dioxide while maintaining the correct pH in
the body.
Carbon Monoxide Poisoning
While carbon dioxide can readily associate and dissociate from hemoglobin, other molecules, such as carbon
monoxide (CO), cannot. Carbon monoxide has a greater affinity for hemoglobin than does oxygen. Therefore,
when carbon monoxide is present, it binds to hemoglobin preferentially over oxygen. As a result, oxygen cannot
bind to hemoglobin, so very little oxygen is transported throughout the body . Carbon monoxide is a colorless,
odorless gas which is difficult to detect. It is produced by gas-powered vehicles and tools. Carbon monoxide can
cause headaches, confusion, and nausea; long-term exposure can cause brain damage or death. Administering
100 percent (pure) oxygen is the usual treatment for carbon monoxide poisoning as it speeds up the separation
of carbon monoxide from hemoglobin.