Download nrosci-biosc 1070-2070 - Pitt Honors Human Physiology

NROSCI-BIOSC 1070-2070
October 5, 2016
Respiration 1
Pulmonary Disease
 Every year, close to 350,000 Americans
die of lung disease. Lung disease is
America's number three killer,
responsible for one in seven deaths.
 Lung disease is not only a killer, most
lung disease is chronic. More than 35
million Americans are now living with
chronic lung disease.
 Most pulmonary disease is self-inflicted,
and results from smoking.
Blood
 Blood is essentially a two-phase fluid consisting of formed
cellular elements suspended in a liquid medium, plasma.
 The formed elements are red cells (erythrocytes), white
cells (leukocytes), and platelets. If a blood sample is
centrifuged in a tube, the cellular elements will settle to the
bottom. The red cells will lye on the bottom of the tube, and
will occupy 40-45% of the total volume of blood. The white
cells, being less dense, will settle on top of the red cells,
and will occupy about 5% of blood volume. The remaining
50-55% of blood volume is contributed by the plasma.
 The volume of red blood cells present in blood is referred to
as the hematocrit.
 Blood plasma contains a variety of plasma proteins (e.g.,
albumin, globulin), electrolytes, hormones, enzymes, and
blood gases.
Production of Blood Cells
 After birth, red
blood cells are
produced
exclusively in the
bone marrow; in
adults, the
production is
confined to
membranous
bones (e.g., rib).
Production of
Erythrocytes
 In the bone marrow,
pluripotential hemopoietic
stem cells are generated that
differentiate to form all the
cellular elements of blood. A
number of different
differentiation inducers can
influence the differentiation
process. Any chemical factor
that influences the growth or
differentiation of blood cells is
called a cytokine. One
cytokine is erythropoietin, a
hormone made by the kidney
in response to poor tissue
oxygenation. As its name
implies, erythropoietin acts to
increase erythrocyte
production. If erythropoietin
levels are low, few red blood
cells will be produced.
Production of Erythrocytes
Characteristics of Erythrocytes
 An important constituent of erythrocytes is
the oxygen-carrying molecule
hemoglobin.
 Red blood cells can circulate in the blood
for several months. Damaged red blood
cells are removed from the circulation by
the spleen, as well as other tissues.
Anemia
 Obviously, a lack of red blood cells can cause
a deficiency in the ability of the blood to carry
oxygen. A lack of red blood cells is referred to
as anemia.
 There are several types of anemia, including:
 that associated with hemorrhage
 damage to bone marrow (aplastic anemia)
 genetic diseases that result in erythrocytes being
easily damaged or malformed (hemolytic anemia
including sickle-cell disease)
 lack of iron consumption (required for production of
the heme group of hemoglobin)
 Low vitamin B12 consumption or
absorption(pernicious anemia)
Polycythemia
 The production of too
many erythrocytes
can also be harmful,
as blood viscosity
increases. This
condition is called
polycythemia, which
is often associated
with pulmonary
disease.
Blood Clotting
 If a break develops in a blood vessel, that hole must
be repaired while allowing blood to flow through the
blood vessel to reach the tissues that it perfuses. This
process is called hemostasis.
 As a first step, pressure in the vessel must be
decreased until a mechanical seal in the form of a
blood clot is produced.
 Once the clot is in place and bleeding has stopped,
more permanent repair mechanisms can begin.
 As the wound heals, enzymes gradually dissolve the
clot and scavenger white blood cells ingest and
destroy the debris.
Platelets
 Platelets as well as plasma proteins play an important
role in the clotting process.
 Platelets are cell fragments produced in the bone
marrow from huge cells called megakaryocytes.
 Platelets are smaller than red blood cells, are colorless,
and have no nucleus; their cytoplasm contains
mitochondria, smooth endoplasmic reticulum, and many
granules filled with clotting proteins and cytokines.
 Platelets are present in the blood at all times, but they
are not active until damage has occurred to endothelial
cells lining the blood vessels.
 Platelets typically have a life span of about 10 days in the
bloodstream.
The Clotting Process
 Endothelin released from damaged endothelial
cells induces local vasoconstriction; this
mechanism is an early step in hemostasis.
 Next, platelets stick to the damaged blood
vessel wall (platelet adhesion) and to each
other (platelet aggregation). This collection of
platelets forms a platelet plug which blocks the
hole in the vessel.
 The exposure of collagen from the damaged
endothelial cells as well as other chemical
factors released from the cells activates the
platelets and induces the clotting process.
The Clotting Process, Cont.
 Serotonin and other factors released from the
aggregating platelets induce more platelet
aggregation as well as local vasoconstriction.
 Next, the coagulation cascade begins.
Inactive plasma proteins are converted into
active enzymes, and these activated enzymes
in turn activate other inactive plasma enzymes.
 In the last stages of the cascade, thrombin
converts the plasma protein fibrinogen into
fibrin fibers that intertwine with the platelet
plug. Another chemical factor converts the
fibrin into a cross-linked polymer that stabilizes
the platelet plug. This completes the formation
of the clot.
Inhibiting the Clotting Process
 The clot formation process operates in a positive
feedback manner. If this process were unchecked, the
clot would spread throughout the circulatory system.
 To prevent this from happening, undamaged endothelial
cells release a modified 20-carbon fatty acid called
prostacyclin that blocks platelet aggregation and
adhesion.
 Nitric oxide, which is released from endothelial cells when
exposed to sheer stress, also inhibits clot formation. This
makes sense, as nitric oxide release normally occurs
when blood is accumulating in an area. Under such
conditions, the triggering of clot formation could be
detrimental.
 Thus, a combination of platelet attraction to an injury site
and repulsion from uninjured tissue limits the size of the
blood clot.
Breaking Down Blood Clots
 As cell growth and division repairs the injured
blood vessel, the clot retracts and slowly
dissolves due to the presence of plasmin within
the clot.
 This enzyme’s precursor, plasminogen, is present
within the clot from the beginning, and is
activated when the injured tissues and
endothelial cells release tissue plasminogen
activator once they begin to heal.
 Tissue plasminogen activator converts
plasminogen into plasmin, which then starts the
slow process of clot degradation. Plasmin acts
by breaking down fibrin in a process called
fibrinolysis.
Blood Clotting: Summary
Blood Clotting: Summary
The Coagulation Cascade
 Two pathways contribute to thrombin
production: the intrinsic and extrinsic
pathways
 The so-called intrinsic pathway requires
nothing that is not ordinarily present in
plasma, and is induced when collagen
becomes exposed to plasma.
 The extrinsic pathway is activated when a
substance called tissue factor (factor III) is
released from the damaged tissue.
The Coaggulation
Cascade
Missing in hemophilia A
Anticoagulants
 Heparin, which interferes with the actions of a
number of the clotting factors, is a natural
anticoagulant. Mast cells near the lung capillaries
secrete heparin, which makes sense as clots often
start to form in slowly-flowing venous blood. It is
practical to inhibit this clot formation before blood
reaches the first capillary bed after the venous
circulation, that in the lungs.
 Heparin is also commonly used in the laboratory to
prevent blood samples from clotting in collection
tubes.
 Daily aspirin consumption is recommended for
persons at risk of heart attack, as this drug helps
prevent platelet aggregation (and lessens the
chance that a blood clot will block a narrowed
coronary artery).
Vitamin K and Blood Clotting
 One condition that impedes blood clot
formation is Vitamin K deficiency. Vitamin K is
necessary for formation of 5 of the clotting
factors, so absence of this cofactor will abolish
the ability for clotting.
 Coumadin, a commonly-prescribed
anticoagulant, works by impeding Vitamin K
metabolism.
 Patients taking Coumadin are instructed to
avoid eating a large amount of green leafy
vegetables, as increases in ingestion of Vitamin
K can offset the actions of the drug.
Tissue Plasminogen Activator
 Tissue plasminigen activator (tPA) can
be manufacured through
recombinant DNA technology
(placing the gene for the protein in a
cell line, which then produces large
quantitites of the protein).
 It is injected into patients following
heart attacks or strokes to break-down
the blood clots that produced these
conditions.
Tissue Plasminogen Activator
 If given within 3 hours of a stroke (the
earlier the better), blood flow can be
returned before permanent injury to
the brain occurs.
Information included on
Website
23
Tissue Plasminogen Activator
Early treatment can minimize symptoms in stroke patients
Diseases that Affect Blood Clotting
 Most of the blood clotting factors are synthesized in the liver,
and liver diseases such as hepatitis and cirrhosis can
negatively impact on the ability to form blood clots.
 A genetic disorder, hemophilia, also leaves an individual
incapable of forming blood clots. Hemophiliacs typically lack
Factor VIII. Almost all of the people who suffer from
hemophilia are male, as the defective gene is on the X
chromosome. It is very simple to treat hemophilia: all that is
necessary is to inject Factor VIII. In the past, this factor was
isolated from human blood, but today a geneticallyengineered form of this agent is given to hemophiliacs.
 A few individuals lack platelets, a condition called
thrombocytopenia. In most cases, it is completely unknown
why the patient cannot manufacture platelets.
The Respiratory System
 The most obvious function of the respiratory
system is to rid the body of CO2 and to acquire
O2.
 In order to do this, a moist and thin exchange
surface that lets the gases pass into and out of
the blood is needed. In terrestrial creatures
such as us, this presents a challenge: how do
you expose a moist surface to air without a
tremendous amount of fluid loss from the body.
 The problem is complicated further by the fact
that the gas exchange surface must be huge: in
humans, on the order of 75 m2 area (the size of
a racquetball court).
The Respiratory System
 We have selected to solve the problem of gas exchange by




placing the exchange surface inside of our body. This helps
to keep the surface warm and moist.
However, muscular pumps are then needed to pull air over
the exchange surface. The so-called respiratory muscles
accomplish this function.
Respiratory muscles are typical skeletal muscles, whose
motoneurons are located either in the brainstem or the spinal
cord.
To complicate matters further, the respiratory muscles have
additional functions to moving air over the exchange
surface, which makes controlling the process of ventilation
very difficult. In fact, the respiratory muscles are chiefly
involved in the most precise motor act that humans engage
in: speech.
Other functions of the respiratory muscles include posture
adjustments and protective responses such as coughing and
vomiting.
Functions of the Respiratory System
1. Exchange of gases between the
atmosphere and the blood
2. Homeostatic regulation of body pH
3. Protection of the respiratory membrane
from inhaled pathogens and irritating
substances
4. Specialized motor functions unrelated
to gas exchange
How Is Gas Exchange Accomplished?
1. Movement of air into and out of the lungs, in
a process called ventilation. Inspiration is the
movement of air into the lungs, whereas
expiration is the movement of air from the
lungs.
2. The exchange of oxygen and carbon dioxide
between the lungs and the blood
3. The transport of oxygen and carbon dioxide
by the blood
4. The exchange of gases between blood and
the cells
Structure of the Respiratory
System
 The Conduction System
 Air enters the upper respiratory tract and passes
into the pharynx, a common passageway for
both ingested materials and air. It then passes
through the larynx into the trachea, or windpipe.
Note that the larynx contains the vocal cords,
connective tissue bands which are tightened or
loosened by the actions of muscles to create
sound when air passes past them. The trachea
itself is a semi-flexible tube held open by Cshaped rings of cartilage. The trachea
subdivides into a pair of primary bronchi, one for
each lung. Like the trachea, the bronchi are
semi-rigid tubes supported by cartilage rings.
Structure of the Respiratory
System
 The Conduction System
 Within the lung, the bronchi branch to
become bronchioles, small collapsible
passageways with smooth muscle walls.
The bronchioles continue to branch until
they end at the exchange surface.
 The conducting system serves to moisten
and warm air that has been taken-in
and protect the lung from harmful
irritants and particles.
Structure of the Respiratory System
 The diameter of the airways becomes
progressively smaller as they branch, but cross
sectional area becomes larger. This is a similar
arrangement as with the cardiovascular system,
and the same rules (e.g., Ohm’s law) still apply.
Structure of the Respiratory System
• As noted above, the airway serves to warm
and moisturize air and to filter out foreign
particles.
in Chronic
Obstructive
• If allResults
of these things
do not occur,
then the
alveoli
would be damaged.
Pulmonary
Disease (COPD)
• The nasal passages are lined with mucus which
serves to warm and moisturize air before it
reaches the trachea.
• The trachea and bronchi serve to filter air.
These passageways are lined with mucuscovered cilia, which constantly move the
mucus towards the pharynx (a process called
the mucus elevator).
Destroyed by Smoking
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The Mucus Elevator
Structure of the
Respiratory System
๏ The alveoli, or exchange
๏
surface of the lungs, is
where oxygen and
carbon dioxide move
between the air and the
blood.
The bulk of lung tissue is
composed of alveoli.
Two types of alveolar
cells exist, in
approximately equal
numbers. Type I alveolar
cells are the thin gasexchange cells, whereas
Type 2 alveolar cells
synthesize a chemical
called surfactant.
Surfactant acts to ease
the expansion of the
lungs during inspiration.
Structure of the
Respiratory System
๏ Many connective tissue
๏
fibers, or elastin fibers,
exist between alveoli.
These fibers contribute
to elastic recoil when
lung tissue is stretched.
The surface of Type I
alveolar cells is covered
with blood vessels to
permit gas exchange.
Often these lung
epithelial cells adhere to
the capillary endothelial
cells, so that the
interstitial space is small.
This specialization
enhances gas
exchange between the
alveoli and the blood.
Structure of
the
Respiratory
System
 The size of the closed thoracic cavity can be altered by
the actions of the respiratory “pump” muscles. The
enlargement of the thoracic cavity increases negative
intrathoracic pressure, which “sucks” air into the lungs
(like a vacuum cleaner).
 The major inspiratory muscle is the diaphragm. When this
muscle contracts, the lungs are pulled downward.
Structure of
the
Respiratory
System
 During expiration, the muscle relaxes, and elastic recoil
causes air to be forced out of the lungs.
 During heavy breathing, additional force is required to
push air out of the lungs. This force is mainly supplied by
the abdominal muscles, which force the abdominal
contents up against the bottom of the diaphragm.
Structure of
the
Respiratory
System
 Muscles that move the ribcage also participate in
respiration. Expansion of the rib cage assists in generating
inspiration. The most important muscles for this purpose
are the external intercostal muscles. In addition, the
sternocleidomastoid, anterior serrati, and scaleni muscles
participate in expanding the ribcage and enhancing
negative intra-thoracic pressure.
Structure of
the
Respiratory
System
 The ribcage is compressed by the actions of the internal
intercostal muscles, which participate in expiration.
Structure of the Respiratory System
 Both the outer coverings of the lungs and the
walls of the thoracic cavity are composed of
pleura, or layers of elastic connective tissue
permeated with many capillaries.
 The pleural tissue is held together with pleural
fluid. This fluid provides a moist, slippery
surface so that the lungs can easily slip along
the walls of the thorax.
 Furthermore (and more importantly), the fluid
tends to hold the lungs against the thoracic
wall. This is important, as the lungs could
collapse without this support.
The Pulmonary Circulation
• The pulmonary circulation also has many
specializations.
• Cardiac output from the left and right
heart has to be matched,
so Q/A
the same
V=
amount of bloodVflows
through
the
lungs
= Velocity of Blood Flow
per minute as flows through the rest of
Q
=
Flow
Rate
the body!
A = Cross Sectional Are
• Since the cross sectional area of the
vessels in the lungs is much smaller than
in the rest of the body, the flow rate
through the lungs tends to be high.
The Pulmonary Circulation
 Another difference between the pulmonary
and systemic circulation is pressure.
Because the right ventricle does not contract
as powerfully as the left ventricle and
resistance in the pulmonary circulation is low,
pressure in the pulmonary circulation tends to
be low (25/8 mm Hg).
 As a result, the hydrostatic pressure in lung
capillaries is low, and little fluid tends to leave
the circulation in the lungs. This is a useful
adaptation, as a minimization of fluid in the
interstitial space acts to facilitate gas
exchange.
Physics of Gas Exchange
Dalton’s law
 Dalton’s law states that the total pressure of a
mixture of gases is the sum of the pressures of
the individual gases. Atmospheric pressure at
sea level is 760 mm Hg, so if nitrogen is 78% of
air, then the partial pressure exerted by
nitrogen is 760 * 0.78 =593 mm Hg. Oxygen
comprises 21% of air, so the partial pressure
exerted by oxygen is 0.21*760=160 mm Hg.
Physics of Gas Exchange
 Gases move from regions of high
pressure to regions of low pressure. This
applies to a mixed gas, and to a single
gas (that moves from a region of higher
partial pressure to a region of lower
partial pressure).
Physics of Gas Exchange
Boyle’s law
 If the volume of a container of gas changes,
the pressure of gas will change in an inverse
manner. In other words, if a sealed vessel
containing a fixed number of gas molecules
gets smaller, then the number of collisions of
gas molecules in that chamber will increase
and pressure will increase. If a gas is at a
pressure of 100 mm Hg, and the volume of
the container holding it doubles, then its
pressure will fall to 50 mm Hg.
Physics of Gas Exchange
 The amount of gas that will dissolve in a
liquid is determined by the partial
pressure of the gas, the solubility of the
gas, and the temperature. In general,
the latter variable can be ignored in
humans (T is always about constant).
Physics of Gas Exchange
 Air flow into the lungs is largely
explained by Boyle’s law and Ohm’s
law (Q = ∆P/R). As noted above, the
thoracic cavity and lung enlarges
during inspiration, so that a pressure
gradient exists between the
environment and the lung. As a result,
air moves down its pressure gradient
into the lung.
Lung Compliance
 Recall that Compliance (C) = ∆V/∆P. Thus, if lung
compliance is low, then it is difficult to increase lung
volume (∆V) at a particular distending pressure (∆P)
generated by the contraction of respiratory muscles.
 However, if lung compliance is high, it is easy to expand
the lung.
Lung Compliance
 The relationship between
distending pressure and
the corresponding change
in lung volume is depicted
by a pressure-volume
curve. The relationship is
dictated by lung
compliance.
 Note that compliance
changes as the lungs
inflate. At low lung volumes
the compliance is relatively
high. At high lung volumes,
the compliance is relatively
low. This is due to how the
elastic components of the
lungs respond to stretching.
Lung Compliance
 The pressure-volume curve
differs during inspiration
and expiration. There are
disagreements why this
occurs.
 Chest wall compliance is
additive with lung
compliance, and must also
be overcome to allow for
lung expansion and filling.