This is for my personal use, though it should help anyone in a similar boat.
Since cutting out dairy and gluten four days ago the heavy breathing that I used to get in the mornings, afternoons and evenings has greatly subsided. However, it seems to have made a bit of a comeback today (Monday 11th January 2016) and yesterday (Sunday 10th January 2016). I also felt very tired earlier in the afternoon which is a symptom I haven't had in a month or so.
This may be due to a sensitivity to fried foods as I ate chips on Saturday and Sunday night. It may also be totally unrelated to food and just a part of recovering from fatigue. I shall see how I feel tomorrow and whether or not the heavy breathing is present then as today I will only be eating fruits, vegetables, noodles, meat and some herbal and fruit drinks.
Random Interests
Ad
Monday, 11 January 2016
Saturday, 13 June 2015
Question 5: How might a patient's white blood cell count be affected by a drug that reduces cell division, and how may this person be treated differently to compensate for this effect?
*These posts are from coursework answers for my degree, but the Figures that are referred to in the text didn't scan well and have already been handed in. These long posts would probably not interest most people but if you enjoy quite in-depth reading of scientific problems then this may be for you.
Question 5: If a patient with an inoperable cancer is treated using a drug that reduces the rate of cell division, how might the patient’s white blood cell count change? How might the patient’s environment be modified to compensate for the effects of these changes?
Answer:
Question 5: If a patient with an inoperable cancer is treated using a drug that reduces the rate of cell division, how might the patient’s white blood cell count change? How might the patient’s environment be modified to compensate for the effects of these changes?
Answer:
If a drug
that reduces the rate of cell division is given to a cancer patient, one would
expect a decrease in that person’s white blood cell count (Prinjha, and
Tarakhovsky, 2013).This is because not only would the cancer cells have their
rate of cell division stunted, but the immune cells would also.
A drug which
inhibits cancer cell growth and is given to a patient with an inoperable cancer
is likely to be a form of targeted therapy in regard to cancer treatment. These
drugs are more specialised in choosing cancer cells to exhibit their effects.
Older drugs find it harder to differentiate between healthy and cancerous
cells, and given that their effect usually increases depending on the rate of
cell reproduction (advantageous because cancer cells tend to rapidly
reproduce), these older drugs commonly cause much harm to fast-growing cells
such as the skin and digestive tract. However, targeted therapies still have
substantial side-effects, particularly fatigue, nausea, skin and clotting
problems as well as elevated blood pressure. These forms of drugs, however,
would have less effect upon the white blood cell count than ordinary drugs
(National Cancer Institute, 2014).
Chan, Koh
and Li (2012), state that cancerous cells are most vulnerable during mitosis
and that the use of drugs centred on cell division is therefore of high
importance to cancer treatment. They also state that drugs producing
antimitotic effects tend to be highly specific, but that the body reacts
unpredictably when exposed to them.
According to
Schmidt (2000 pp. 112-115), the production of thymidylate and dihydrofolate are
of substantial importance in the role of DNA synthesis. Given that cancer is
fundamentally a cellular error causing uncontrolled replication, the inhibition
of DNA synthesis plays a pivotal role in treating cancer. A compound called
5-fluorouridine bears strong similarity to the substrate acted upon by
thymidylate synthase, once it has been phosphorylated by a nucleoside kinase
(the only difference is that this product contains a fluorine where the natural
substrate, dUMP, contains hydrogen). However, once this end-product (called
5-fluorouridine monophosphate) binds with thymidylate synthase, the fluorine
stays bonded to the enzyme, causing it to no longer function. Since the 5-fluorouridine
monophosphate reacts with the enzyme, and the enzyme can no longer function
afterwards, it is called a “suicide substrate”. DNA necessary for cell division
can also be reduced by decreasing the reduction of dihydrofolate to
tetrahydrofolate. When N5,N10-methylene tetrahydrofolate
donates a methyl group to deoxy-UMP under the supervision of the thymidylate
synthase enzyme, thymidylate (deoxy-TMP) is formed. This reaction is
illustrated in figure 5.1.
Since the
tetrahydrofolate compound in this reaction is oxidised to dihydrofolate, the
converse of this (reduction of dihydrofolate by dihydrofolate reductase (DHFR)),
will consequently lead indirectly to thymidylate production. Thus, the
inhibition of DHFR will also reduce thymidylate production. Substrates which
are competitive inhibitors of folates are called folate antagonists, where an
antagonist is a substance that binds to a receptor, without producing the
receptor’s activity. Thus, a substance binding to a folate-receptor, may not
produce the same effect as a folate-containing substance binding to it. The antagonists
in this example will attempt to out-compete the folate substrates involved in
activating the DHFR enzymes, thus preventing the chemical reactions leading
initially to the reduction of dihydrofolate to tetrahydrofolate and eventually
to the production of thymidylate, which would increase DNA synthesis and allow
cell division to occur.
From Schmidt
(2000, p. 230), information is given about the G1 phase of cell division. This
particular phase is actually a point of non-division, in which various
biochemical reactions take place, but the cell does not actively divide. Many
animal cells can spend years in the G1 phase without dividing, which makes it
highly important in cancer treatment. If the G1 phase could be clearly
understood, then cells could be encouraged to remain within it, not dividing,
and consequently not resulting in cancer formation. An unfortunate consequence
of decreasing cell division non-specifically however, is that all cells in the
body which take in a particular drug that decreases cell division will have
their rate of replication decreased. This makes it more difficult for the body
to combat infections which are not affected by the drugs, given that the body
cells may be subjected to division-inhibition for many weeks or months before
encountering a new infection, its immune cells are likely to be lower in number
and therefore not be as capable of combating the threat.
If the
number of white blood cells that a patient has, decreases, then that person is
more susceptible to all possible infections as these cells fight them.
Among the
white blood cells or leukocytes, the form most important during consideration
of possible infections is the neutrophil. This is the type of white blood cell
most abundant in plasma, constituting roughly 54-62% of the overall number of
circulating leukocytes (Mescher 2013, p. 235). Neutrophils are relatively small
phagocytic immune cells that are produced in vast quantities every day (roughly
126 billion enter the digestive tract daily, according to Seeley, VanPutte,
Regan and Russo, 2011, p. 791), and are often the first of the immune cells to
reach infected regions in great numbers. Once at an infected site, neutrophils
are responsible for increasing immune cell activity and inflammation at this
area. This is brought about by their release of cytokines which encourage the
proliferation and differentiation of immune cells, and by chemotactic agents,
respectively (Seeley, VanPutte, Regan and Russo, 2011, p. 792).
The test for
abundance of circulating neutrophils is called the absolute neutrophil count
(ANC), and is considered the most important risk factor for both bacterial and
fungal infections, according to Johnston and Spence (eds, 2003, p. 253). The
diagnosis of neutropenia (a deficiency of neutrophils), is stated as an ANC of
less than 500 per millilitre of plasma, or expected to fall to this level
within the next 24 hours of being tested. These writers also state that risk
increases as neutrophil count decreases, and that the rate at which neutrophil
count is decreasing, as well as how long neutropenia has presented, also play a
pivotal role in contracting bacterial and fungal infections. The more rapidly
neutrophil count is falling, and the longer a person has had neutropenia, the
more likelihood there is of becoming infected, and the more severe the
infection is likely to be. Thus, it is highly important to consider
neutropenia, although B-cell and T-cell function is also compromised in cancer
treatment, usually due to chemotherapy, but further exacerbation can occur via
concomitant utilisation of steroids (Johnston and Spence, eds, 2003, p. 246).
These authors also explain that the use of catheters in immunocompromised
cancer patients poses a significant risk of subsequent infection, this is due
to the ease with which microbial colonies can form within the synthetic
catheter, possibly migrating into the host and causing infection. Therefore, it
is of the utmost importance that catheters be monitored and if possible,
sampled, in order to gauge microbial growth.
There are
many other types of immune cell that are important in the response to
infection. This first section deals with those cells which are an integral part
of the innate immune system, i.e. the branch of the immune system acts in a
non-specific manner:
Neutrophils
fall into this category but are explained in detail above.
Monocytes
are white blood cells that circulate the body and are enticed by
chemo-attractants to enter damaged tissue and differentiate into macrophages
which are important for consuming toxic substances and cells that may damage
the body, they may also stimulate B-cell and T-cell activity during infection (Seeley,
VanPutte, Regan and Russo, 2011, p. 791). Macrophages are roughly 5 times the
size of monocytes, and have additional lysozymes and mitochondria. They are
larger, longer-lasting, and are capable of engulfing larger particles than
neutrophils, though they appear at the site of infection a little later than
neutrophils. Thus, they are most used in the later stages of infection. Their
large size makes them ideal for engulfing cellular debris, and even whole
neutrophils which have died earlier on during the immune response. Macrophages
may also secrete various substances such as interferons, complement, and
prostaglandins. The roles of interferons and complement are discussed
elsewhere, but prostaglandins have a variety of actions, perhaps most
importantly of which are its function in increasing the permeability of blood
vessels (which can allow immune cells to permeate vascular and reach infected
or damaged tissue, and also in causing vasodilation, again allowing immune
cells to reach a particular site by aiding blood flow to the affected region.
This is shown by Seeley, VanPutte, Regan and Russo, 2011, pp. 789, 792.
Both
basophils (motile) and mast cells (nonmotile) are immune cells that promote
inflammation within tissues through the release of various chemicals, e.g.
leukotrienes and histamine. This inflammatory response can increase blood flow
to the area, signal other leukocytes to arrive on the scene, and encourage the
formation of either a platelet plug or clot to seal off the affected region to
further damage and/or infection. Conversely, eosinophils are motile immune
cells that enter tissues and inhibit the inflammatory response. They do this by
breaking down the substances secreted by the basophil and mast cells.
Therefore, eosinophils are produced in larger quantities during immune
reactions where a large inflammatory response occurs, such as in allergies.
Additionally, eosinophils have the ability to kill some forms of parasites (Seeley,
VanPutte, Regan and Russo, 2011, pp. 791-793).
Finally, NK
(natural killer) cells are important in the attack on cancer cells. NK cells
contain enzymes that can chemically lyse or split tumour cells, preventing the
growth spread of cancer, one of their preferred mechanisms of actions is to
chemically lyse the plasma membrane of harmful cells (Seeley, VanPutte, Regan
and Russo, 2011, p. 791-792).
The adaptive
immune system then, deals with specific and personalised threats to the body. This
branch of the immune system is capable of responding to a specific substance,
called an antigen. These antigens may be produced by the body, for example, a tumour
cell (a self-antigen), or produced by a foreign invader or microbe which has
found its way into the body and may cause harm (a foreign antigen). Within the
umbrella term of adaptive immunity, there are two main categories of immune
response; cell-mediated immunity and antibody-mediated immunity.
Antibody-mediated immunity is brought about by the production of antibodies
(these are released by cells that result from the differentiation of B-cells)
that bind with antigens to form antigen-antibody complexes that inhibit the
actions of harmful cells. On the other hand, cell-mediated immunity arises from
the activity of T-cells, which can destroy whole cells instead of inhibiting
vital components. This is highly useful for infections from viruses, which essentially
‘hijack’ the biochemical reactions of a cell for their own needs (Seeley,
VanPutte, Regan and Russo, 2011, p. 794-806).
The adaptive
immune system almost entirely consists of B-cells and T-cells to combat
infection:
B-cells can
be stimulated by antigens on the cell surface membrane of a pathogen and
differentiate to produce either a plasma cell or memory B-cell. The plasma cell
in this scenario would produce antibodies complementary in shape to the harmful
antigen which would inhibit the effectiveness of the pathogen and signal for
its lytic destruction by neutrophils, eosinophils, macrophages or monocytes.
The memory B-cells formed by differentiated of B-cells can promote a rapid and
lasting immune reaction to a specific form of pathogen. If this pathogen were
to enter the body, memory B-cells would mass-produce antibodies that would
inhibit its actions. (Seeley, VanPutte, Regan and Russo, 2011, pp.791, 803).
There are
many types of T-cells; delayed hypersensitivity T-cells promote inflammation through
the release of cytokines, helper T-cells stimulate the activity of effector
T-cells and B-cells, Suppressor T-cells do the opposite, inhibiting the action
of both T-cells (effector forms) and B-cells, and lastly, memory T-cells are
similar to memory B-cells in their ability to maintain a lasting immunity
towards a particular antigen that has been previously encountered. (Seeley,
VanPutte, Regan and Russo, 2011, p. 791).
Finally,
dendritic cells activate both B-cells and T-cells after recognition of a harmful
antigen (Seeley, VanPutte, Regan and Russo, 2011, p. 791).
Another area
of concern is the mucous membrane throughout the digestive tract. This membrane
can become inflamed and mouth, stomach and other ulcers can result from the use
of both chemotherapy and radiotherapy (depending on where the latter is
targeted to), these ulcers and general damage to the mucous membrane can
facilitate the harbouring of pathogens which can infect the body (Johnston and
Spence, eds, 2003, p. 253). Further to this, though beyond the scope of this
essay, is the effect of the underlying cause or simultaneous condition with
regard to cancer. Chronic lung or liver diseases as well as AIDS, can
independently compromise immune function, which would only be worsened by cancer
treatment.
Care must be
taken to ensure proper health of skin, teeth and the general oral cavity.
Healthy skin and mucous membranes in the oral cavity produce secretions that
prevent bacterial infection. For example, skin secretes oils and has an acidic
pH due to the actions of sebaceous and sweat glands. Saliva in the oral cavity
contains many antimicrobial agents, including the protein lysozyme, which
destroys the cells walls of bacteria. These are some examples of nonspecific
barriers (methods that provide a broad-spectrum of defence not limited to a
single pathogen at a time). See Houghton Mifflin Harcourt (2014). Broken skin,
infected gums and rotting teeth can all harbour bacteria that can lead to an
infection the immunocompromised patient. Antibiotics may be taken to control
overall and in particular, digestive bacteria, lest these should turn
pathological.
According to
Pack (2001, pp. 210-212), there are three types of barrier preventing
infections to the body. These are the nonspecific barriers, the nonspecific
defences, and the specific defences of the body. Many of the nonspecific
barriers have already been covered, these are; skin, sweat, proteins such as
lysozyme, cilia, digestive juices, and commensals (symbiotic organisms exist in
and on the human body that can compete against harmful microbes). These
barriers prevent the inward movement of harmful substances and microbes into
the body.
The
nonspecific defences are responsible for nonspecific removal and destruction of
threats that have found their way into the body. Examples include phagocytes
(white blood cells that engulf and digest pathogens, neutrophils, eosinophils,
macrophages and monocytes are included in this category). Natural killer cells,
are also on the list, as well as interferons and a defensive chemical called
“complement”. Interferons are released by cells that are infected by viruses,
and help the immune system recognise when a viral infection has occurred. Interferon
is also aptly named for its ability to interfere with the production of viruses
(Seeley, VanPutte, Regan and Russo, 2011, p. 789). Complement is a compound
formed by roughly 20 proteins bonded together which attracts phagocytic immune
cells to the site of an infection, as well as lysing cells by its own actions
(Pack, 2001, p. 211).
The immune
system forms the specific defence system against foreign microbes (Pack, 2001,
p. 213). Some of the nonspecific defences such as natural killer cells and
phagocytes are used for specific defence, particularly when an antigen has become
part of an antigen-antibody complex and immune cells are signalled to engulf
it.
On page 254
(Johnston and Spence, eds, 2003), the authors make known the vices of surgical
removal of the human spleen, which can take place occasionally as part of cancer
treatment. They state that the spleen is necessary for removal of opsonized
pathogens (those bound by antibodies in the preparation of phagocytosis) and
erythrocytes which have been infected with parasites. Surgical removal of the
spleen also reduces the body’s ability to develop immune reactions to
previously unencountered antigens. According to Pack (2001, pp. 204-209), the
spleen is the largest organ in the lymphatic system. It contains two distinct
regions; the white pulp and the red pulp. The white pulp contains many
lymphocytes (T cells and B cells), as well as reticular fibres, whereas the red
pulp contains many venous sinuses that act as a reservoir of red blood cells.
The spleen has several main functions; filtering the blood of pathogens and debris
from dead and aged cells, the destruction of old erythrocytes and subsequent
recycling of organelles and nutrients, acting as a reserve for blood, and
providing a site of T cell and B proliferation (T cells reproduce before
returning to attack non-self cells and B cells produce antibodies and plasma
cells which go on to inactivate harmful antigens. Thus, its removal can have
dangerous consequences.
The above
effects combined produce a patient who is highly susceptible to infection. They
mention several bacteria whose infections are more commonly and severely
present in immunocompromised patients, there are; Streptococcus pnuemoniae, Capnocytophaga canimorsus and Babesia microti (a bacterium that
presents with malaria-like symptoms such as fever, chills, sweating, and head
and body aches information that is elaborated upon by the Centers for Disease
Control and Prevention, 2014a).
Wigglesworth
(2003) gives a lot of information on the use of environment changes for
immunosuppressed patients. If such patients are currently residing in a
hospital then they can be separated from the main hospital population and wads,
usually by keeping them in a single room. Hygiene is of particular importance
to ensure that no pathogens are transferred from care workers to the patient.
Hand-washing is a must in this scenario.
According to
the University of Utah Health Care (2003), proper hand-washing is the most
important action in the prevention of infectious diseases. The amount of
visitors that a person meets during the day and the foods that they eat must be
monitored to ensure there is little risk of infection. Certain foods are
considered high-risk when it comes to patients with a weakened immune system,
extra care must be taken to avoid these foods. Soft cheeses and anything made
with raw eggs are a hazard for such patients. Therefore, mayonnaise was also be
avoided.
Additionally,
the use of vaccinations before a person is likely to become immunocompromised
can decrease the likelihood of infection. This has been proposed as a strategy
for persons likely to exhibit lower immune function for a number of different
reasons including cancer and HIV (Tolan, et al, 2013).
The Centers
for Disease Control and Prevention recommend that any sign of fever in patients
receiving chemotherapy be treated as an emergency, even if it is the only
symptom (Centers for Disease Control and Prevention, 2014b). Further safety
precautions can be taken to reduce the chance of infection can be taken. One
can avoid sharing any personal items, such as cups or utensils or anything that
requires insertion into the mouth, e.g. toothbrushes. Daily washing should be
done with unscented lotions. Lotions which are scented can damage or dry the
skin, allowing pathogens to colonise or pass through this layer. Meat and eggs
must be cooked thoroughly, raw fruit and vegetables must be washed carefully,
gloves should be worn around pets and for gardening, and care must be taken to
avoid damaging the gums during tooth-brushing (thus a soft toothbrush is highly
recommended), see Centers for Disease Control and Prevention, 2014c. This same
source provides ample knowledge of the warning signs of infection in order to
warn immunocompromised patients. Some of the more noticeable signs are; a fever
of >38oC for over one hour, sore throat, burning or other pain
upon urination, shortness of breath, diarrhoea, vomiting and increased
urination.
Finally, the
Centers for Disease Control and Prevention also note that white blood cell
usually drops to its lowest value as a result of chemotherapy around 7 to 12
days after the chemotherapy dose has finished, and from this point the low
count can last for around a week before increasing again. This lowest point is
when most vigilance is required in protecting oneself from infection, as the
immune system will be most weakened and unable to respond adequately (Centers
for Disease Control and Prevention, 2014d).
Question 5 References:
Centres for
Disease Control and Prevention, 2014a. Babesiosis
FAQs, [online] Available at: <http://www.cdc.gov/parasites/babesiosis/gen_info/faqs.html#symptoms> [Accessed 13 April 2015].
Centres for
Disease Control and Prevention, 2014b.Emergency
Room Personnel, [online] Available at: < http://www.cdc.gov/cancer/preventinfections/pdf/er_personnel_poster.pdf
> [Accessed 13 April 2015].
Centres for
Disease Control and Prevention, 2014c. How can I prevent an infection? [online] Available at: < http://www.cdc.gov/cancer/preventinfections/pdf/neutropenia.pdf
> [Accessed 13 April
2015].
Centres for
Disease Control and Prevention, 2014d. Protect:
Know the Signs and Symptoms of Infection, [online] Available at: <http://www.cdc.gov/cancer/preventinfections/symptoms.htm> [Accessed 13 April 2015].
Chan, K.S.,
Koh, C.G., and Li, H.Y., 2012. Mitosis-targeted
anti-cancer therapies: where they stand. [online] Available at: <http://www.nature.com/cddis/journal/v3/n10/full/cddis2012148a.html> [Accessed 7 April 2015].
Houghton
Mifflin Harcourt 2014. Nonspecific
Barriers, [online] Available at: <http://www.cliffsnotes.com/sciences/anatomy-and-physiology/the-immune-system-and-other-body-defenses/nonspecific-barriers> [Accessed 7 April 2015].
Johnston,
P.G., and Spence, R.A.J., eds. 2003, Oncologic
Emergencies. United States, New York: Oxford University Press Inc.
Mescher,
A.L., 2013. Junqueira’s Basic Histology
Text & Atlas, 13th ed. China: The McGraw-Hill Companies.
National
Cancer Institute, 2014. Targeted Cancer
Therapies, [online] Available at: <http://www.cancer.gov/cancertopics/treatment/types/targeted-therapies/targeted-therapies-fact-sheet> [Accessed 7 April 2015].
Pack, P.E.,
2001. Anatomy and Physiology, Hoboken, NJ: Wiley
Publishing, Inc.
Prinjha, R.,
and Tarahovsky, A., 2013. Chromatin
targeting drugs in cancer and immunity. [online] Available at: <http://genesdev.cshlp.org/content/27/16/1731.full> [Accessed 7 April 2015].
Schmidt, F.,
2000. Biochemistry II, New York, NY:
Wiley Publishing, Inc.
Tolan, R.W.,
Brook, I., Windle, M.L., Domachowske, J., Rauch, D., and Steele, R.W. 2013. Infections in the Immunocompromised Host, [online]
Available at: <http://emedicine.medscape.com/article/973120-overview> [Accessed 7 April 2015].
University
of Utah Health Care, 2003. Prevention of
Infectious Diseases, [online] Available at: < http://healthcare.utah.edu/healthlibrary/related/doc.php?type=85&id=P00644> [Accessed 7 April 2015].
Wigglesworth,
N., 2003. The use of protective isolation,
[online] Available at: <http://www.nursingtimes.net/nursing-practice/specialisms/infection-control/the-use-of-protective-isolation/205720.article> [Accessed 7 April 2015].
Question 4: Discuss causes, effects and treatments of atherosclerosis
*These posts are from coursework answers for my degree, but the Figures that are referred to in the text didn't scan well and have already been handed in. These long posts would probably not interest most people but if you enjoy quite in-depth reading of scientific problems then this may be for you.
Question 4: Atherosclerosis in the coronary circulation causes heart disease; discuss the causes of atherosclerosis and its effect on the cardiovascular system. How are stents used to treat atherosclerosis?
Answer:
Kumar V., Abbas A.K., and Fausto N., 2004. Robbins & Cotran Pathologic Basis of
Disease: With STUDENT CONSULT Online Access. 7th ed.
Philadelphia: Saunders.
National Centre for
Biotechnology Information, 2015. VCAM1 vascular
cell adhesion molecule 1 [Homo sapiens (human)]
[online] Available at: <http://www.ncbi.nlm.nih.gov/Structure/biosystems/docs/biosystems_publications.html> [Accessed 4 April 2015].
Question 4: Atherosclerosis in the coronary circulation causes heart disease; discuss the causes of atherosclerosis and its effect on the cardiovascular system. How are stents used to treat atherosclerosis?
Answer:
Atherosclerosis
is the build-up of plaque formed primarily by white blood cells and cholesterol
within the innermost membrane of an artery wall, called the tunica intima
(Seeley, VanPutte, Regan and Russo, 2011, p. 725). This accumulation of plaque
is a slow process, often taking years or decades to present with any symptoms,
if at all, to the person suffering from it. It is important to note that
oxidised low-density lipoproteins (ox-LDLs) are considered more atherogenic
than native LDLs. This is agreed upon in many works, for example; Samsioe
(1994), Panza, and Cannon, eds. (1999, pp. 89-92), and Kummerow, (2013). Dr. Kummerow,
in particular, gives much weight to the pathological effects of oxidised
cholesterols, known as oxysterols. He believes that the intake of oxysterols
via fried foods, excess vegetable oils (especially partially hydrogenated
vegetable oils) and cigarette smoking play a far greater role than simple
dietary cholesterol. This will be a part of the original thought later on in
this essay.
Schmidt
(2000, p. 38), explains that as cells take in LDL cholesterol to satisfy their
metabolic requirements, they begin to exhibit fewer cell membrane receptor
sites for LDLs. Therefore, if a high concentration of LDL cholesterol exists in
the bloodstream, then cells will take in as much as they need, down-regulate
their receptor sites, and the remaining cholesterol will be free to circulate
the body. This means that more of the cholesterol will be free to travel the
circulatory system and become deposited in walls of blood vessels, leading to
an increased risk of arterial diseases. The use of receptors on cell surface
membranes in order to take in a specific molecule or nutrient is an example of
receptor-mediated endocytosis (Pack, 2001, pp. 26-27). When this occurs, a
vesicle is formed as the cell membrane folds inwards around the substance being
received. Once the substance is safely inside of the cell, the vesicle can
break-down, releasing, in this case, the LDL.
The resultant problems associated with
atherosclerotic lesions are typically due to the narrowing of blood vessels
(stenosis), this decreases the available size of lumen for blood to travel
through, leading to a reduction in blood supply to tissues (ischemia). There
are many causes of atherosclerosis, these include: Hypercholesterolemia or
dyslipidemia (particularly increased LDL [low-density lipoprotein]
concentrations, but decreased levels of HDL [high-density lipoproteins that
appear to offer a protective effect against plaque build-up] are also a risk factor
[Carmena, Duriez and Fruchart, 2004]). Habitual cigarette smoking (Lin, et al,. 1992) has also been found
as a potential factor in disease progression. Mitchell, et al. (2007, p.345)
show that diabetes, elevated C-reactive protein in serum, growing older, male
gender, genetic faults that produce high levels of cholesterol and family
members who have suffered from atherosclerosis and its related cardiovascular
incidences (more detail further on in this essay), were more likely to get the
disease. Concomitant disorders also include obesity and insulin resistance (as
well as type 2 diabetes), as shown by Hotamisligil (2010).
The above
factors will be touched upon briefly, however a lot of this write-up will be
dedicated to biochemical pathways within the body that both decrease and
contribute to atherosclerosis, and how a down-regulation of antiatherogenic
chemicals can lead to this disease.
Some of the
more microscopic changes that occur to bring about atherosclerosis include but
are not limited to the following: Monocyte and macrophage adhesion to
endothelial cells, platelet aggregation, reduced endothelial nitric oxide
levels, high endothelial permeability increasing the migration of lipoproteins
into the walls of arteries, and increased vascular smooth muscle cell
proliferation, this rapid reproduction rate greatly speeds up the aging process
(Panza, and Cannon, eds., 1999, p. 44).
One of the
largest factors in the occurrence and progression of atherosclerosis is the
movement of lipoproteins, primarily LDLs, into the arterial wall, where they
can then deposit cholesterol which can become oxidised. HDL is considered
protective in this situation as it bonds to cholesterol and carries it to the
liver. This is one of the main reasons why proportions of varying types of
lipoproteins is an important study in these diseases, in particular, having low
HDL and high LDL is considered a strong factor in the onset of atherosclerosis
(American Heart Association, 2014a).
Mescher (2013, pp.
234-239) shows that the whole blood consists of approximately 1% leukocytes and
platelets combined (white blood cells) which are usually inactive while
circulating the body. Their activity is apparent however, when they are
signalled to sites of infection, inflammation or general damage. Here they will
migrate into tissues and exert (generally) appropriate action. In the case of
atherosclerosis, the prime white blood cell to be considered is the monocyte,
an agranulocytic blood cell that, among many other functions, modulates the
concentrations of LDLs in the arterial wall, it has this capability because it
is a precursor of the macrophage (an immune cell of the mononuclear [one
nucleus] phagocyte system, that engulfs cellular remnants and infectious
agents, among other substances and living matter). Whenever LDLs and
particularly oxidised LDLs are present in the arterial wall, monocytes (a form
of leukocyte) are coaxed into adherence to the endothelial cells by the
presence of a protein, VCAM-1 (vascular cell adhesion molecule 1 or vascular
cell adhesion protein 1, as shown by the National Center for Biotechnology
Information, 2015). Without this protein, the monocyte would
continue its journey around the body without stopping. Instead, the monocyte
will migrate into the endothelium experiencing LDL-induced inflammation and
will differentiate into a macrophage, in order to phagocytise the offending
molecule and carry it away.
If this
process becomes chronic, i.e. many LDLs are constantly permeating the
endothelium and causing inflammation, then a high concentration of macrophages
will exist within the endothelium in order to try and remove these LDLs. This
accumulation of monocytes is called extravasation (Mescher, 2013, p. 245).
Unfortunately, the presence of so many macrophages and resultant inflammatory
response leads to disproportionate tissue damage within the artery. As the macrophages engulf lipoproteins they begin to change
size and shape, and are termed “foam cells” (Oh, et al., 2012). The change in
appearance is due to the high concentration of lipoproteins within the
macrophages. When this occurs, the atherosclerotic lesion begins to look like a
fatty streak. This point in the progression of atherosclerosis is usually not
severe enough to induce significantly restricted blood flow within the artery
to the point of producing symptoms, but the artery becomes more rigid and
susceptible to damage.
Thus, we can see that endothelial
permeability to low-density lipoproteins is a prime factor in atherosclerosis.
If the endothelium did not allow LDL to move into it, then there would be no
need for macrophages to enter either, possibly preventing atherosclerosis from
even beginning.
As time goes on, macrophages begin to die
and release chemicals that further exacerbate inflammation, leading to a
greater immune response within the area. This causes more monocytes to be
signalled to the vessel wall and differentiate into macrophages, furthering the
progression of plaque formation. This occurs primarily between the tunica
intima and tunica media (American Heart Association, 2014a). Also over time,
calcium deposits build up due to poor clearance of cellular debris from these
deceased cells. This is because the atherosclerotic plaque proves too great a
physical barrier to facilitate their removal. Further to this, if the
atherosclerotic plaque ruptures, possibly due to the high blood pressure in the
artery and weak structural strength of the plaque, then a clot may form. A clot
is the entrapment of blood cells, fluid and platelets by fibrin (a protein that
encourages clotting).
Another name for a blood clot is
coagulation, and the proteins involved in its production are called either coagulation
or clotting factors, which are contained in blood plasma. Under ordinary
conditions, these factors remain inactivated, however, when damage occurs to
tissue, such as a weakened blood vessel in our case of atherosclerosis, the
coagulation factors become more active. The initiation of clotting can occur
via an extrinsic or intrinsic pathway, though both link into a later route of
chemical reactions called the common pathway (Seeley, VanPutte, Regan and Russo, 2011, pp. 660-661).
The extrinsic pathway of clotting starts
due to the presence of chemicals that are not contained within the bloodstream.
This could be from the release of thromboplastin (other names for this chemical
are factor III or tissue factor) as a result of tissue damage. If calcium ions
react with thromboplastin, the result is a compound containing factor VII which
can react to activate another chemical called factor X. This is the point where
the common pathway begins at the end of the extrinsic pathway (Seeley, VanPutte, Regan and Russo,
2011, p. 661).
The
intrinsic pathway starts off differently, with chemicals that are contained
within the blood stream, such as collagen which can be exposed when blood
vessels are injured. Whenever a chemical called plasma factor XII reacts with
this collagen, the factor XII becomes active. Consequently, factor XI is
activated, leading to stimulation of factor IX, which binds with various other
molecules, such as factor VIII, phospholipids contained within platelets, and
positive calcium ions. The result of this is that factor X becomes acitivated,
and this is the point where the common pathway begins, just like at the end of
the extrinsic pathway (Seeley, VanPutte, Regan and Russo,
2011, pp. 661-662).
At the
beginning of the common pathway, prothrombinase is formed by the binding of
factors X and V, along with phospholipids from platelets, and calcium ions.
Prothrombinase is capable of converting a protein dissolved in plasma, called
prothrombin, into thrombin, an enzyme highly important in clot formation. This
enzyme produces a protein called fibrin from fibrinogen (another protein
dissolved in plasma). The fibrin formed is responsible for the entrapment of
platelets, blood cells and fluids that make up a blood clot. Blood clotting is
a relatively rare example of positive feedback in the human body, because its
presence can lead to the production of its own precursors (e.g. factor XI and
prothrombinase). Vitamin K is necessary for clot formation, and its deficiency
can lead to excessive bleeding (Seeley, VanPutte, Regan and Russo,
2011, p. 662).
When a clot is attached to an arterial
wall it is called a thrombus. After a clot has formed and attached itself, it
starts to become denser due to clot retraction. This occurs because platelets,
arranged as extensions to fibrinogen (which are bonded to fibrinogen receptors
on cells of the blood vessel wall), begin to contract through the use of actin
and myosin filaments, effectively pulling on the fibrinogen and drawing the
clot into a more compact structure. This process liberates serum (a fluid
similar to plasma, but which doesn’t contain some clotting factors, as well as
fibrinogen). As a result of this, the injured blood vessel is more tightly
sealed up, allowing it to recover more easily, and reducing the possibility of
infection (Seeley,
VanPutte, Regan and Russo, 2011, p. 663).
Figure 4.1 shows the development of
atherosclerotic plaque and subsequent clot formation. Here we see that the
plaque itself is enough to cause significant narrowing of the blood vessel,
however, due to rupture of plaque, a thrombus has started to form. This
thrombus is further restricting blood flow through the artery and will be
discussed further blow. The diagram also shows that the plaque is developing
between the tunica intima (innermost membrane of the artery, and one that
separates other tissue layers from the lumen) and the tunica media. (Seeley, VanPutte, Regan and Russo,
2011, p. 725).
A
fundamental chemical involved in atherosclerosis is nitric oxide. A reading of
the literature greatly brought up the antiatherogenic importance of this small,
highly-reactive free radical. Its production is decreased in atherosclerosis
(Panza, and Cannon, eds., 1999, p. 20) and this has a strong effect in the
progression of the disease, as will be elaborated on below.
It is
important to note before continuing that the following substances either
inhibit nitric oxide (NO) directly, either in production (which occurs via the
nitric oxide synthase enzyme), release or functional effect:
Endothelin-1,
abbreviated to ET-1. This is a petide composed of 21 amino acids that is
produced in the endothelium, one of its main effects is as a vasoconstrictor.
ET-1 has been shown to be elevated in atherosclerosis and likely contributes to
the disease. Its vasoconstriction effects are roughly a hundred times stronger
than noradrenaline per unit of concentration. Oxidised low-density lipoproteins
increase its release, explaining its increased production during
atherosclerosis. It also attracts monocytes to atherogenic lesions because it
has chemoattractant effects (Panza, and Cannon, eds., 1999, pp. 97-109).
Angiotensin
II or Ang II is also implicated in the development of atherosclerosis and
reduction of nitric oxide. This is a peptide hormone that also has
vasoconstrictive effects. Its administration has been shown to increase the size
of atherosclerotic lesions in mice deficient in apolipoprotein E (this is a
molecule that breaks down lipoproteins, and without it, mice as well as humans,
have a much greater risk of developing atherosclerosis, Daugherty,
A., Manning, M.W., and Cassis, L.A. 2000).
Nitric oxide also inhibits the effects of Ang II in the vasculature
(Toda, N., Ayajiki, K., and Okamura, T. 2007).
Asymmetrical
di-methylarginine (ADMA), this is a circulating amino acid that is similar in
structure to L-arginine. As l-arginine is a precursor to nitric oxide, ADMA is
able to interfere with this metabolic pathway, by interacting with its
components, namely the nitric oxide synthase enzyme (NOS).
NG-monomethyl-L-arginine
(L-NMMA) as well as L-nitroarginine methylester (L-NAME) share a similar
effect, by competing with L-arginine for the active site of the NOS enzyme
(Panza, and Cannon, eds., 1999, p. 165).
This occurs because the production of nitric oxide from L-arginine results from
the oxidation of the terminal containing a guanidine-nitrogen bond, which is
also contained within the inhibitors mentioned above.
Implicated
as well in the down-regulation of various aspects of nitric oxide are many
reactive oxygen species (ROS) including the superoxide anion (O2-)
and hydrogen peroxide (H2O2). This is due to the effect
of these species to rapidly and chemically alter nitric oxide. Panza, and
Cannon, eds. (1999, p. 134) show that the reaction between the superoxide anion
and nitric oxide produces the peroxynitrite anion, a relatively stable ion
compared to the particular radicals in this example of its creation. The
peroxynitrite anion loses many of the qualities of nitric oxide, but retains a
small ability to cause vasodilation, unfortunately it is also damaging to cells
and therefore needs to be detoxified (Panza, and Cannon, eds., 1999, p. 23).
The
following substances in some way enhance the effect, production or release of
NO:
Estrogen,
via its effect of up-regulating the eNOS enzyme (Chambliss, K.L., and Shaul,
P.W. 2013). Interestingly, estrogen has also been shown to alter lipid profile
in humans. Specifically, estrogen has been shown to reduce both total and
LDL-cholesterol levels while raising HDL. Evidence is currently gathering which
points towards an additional antiatherosclerotic effect of estrogen, namely in
the inhibition of lipid oxidation, this is based on an overall review of the
literature by Samsioe, 1994. As mentioned above, oxidised lipids are considered
more important in the onset and progression of atherosclerosis.
L-arginine
is also important (as mentioned above, L-arginine is a precursor for NO).
The
peroxynitrite anion (the actual formation of this anion actually greatly
reduces the effect of NO because it is formed via the reaction of nitric oxide
with the superoxide anion and attenuates the vasodilatory effects of NO,
however, the presence of the peroxynitrite anion itself still contributes to
some of NO’s effects, this information is referenced above in the text about
reactive oxygen species).
The
cysteine-containing NO donor SPM-5185, as demonstrated in (Panza, and Cannon, eds.,
1999, p. 22).
Finally,
antioxidants such as vitamin C (in some trials), and the enzyme superoxide
dismutase (SOD) as shown in (Panza, and Cannon, eds., 1999, p. 135).
When talking
about nitric oxide in relation to atherosclerosis, the endothelium of arteries
is the primary point of interest. Thus, the notation eNO (for endothelial
nitric oxide) and eNOS (short for endothelial nitric oxide synthase) can be
used interchangeably with NO and NOS for this topic.
eNO is
highly important in alleviating and preventing atherosclerosis because it first
of all decreases endothelial permeability. As covered previously, when the
endothelium is highly permeable, more low-density lipoproteins are allowed to
pass through it into the arterial wall, and this is what requires macrophage
activity. In decreasing endothelial permeability, the whole onset of
atherosclerosis could be abated. Much of the information regarding nitric oxide
as shown above is available in the works of Panza, and Cannon, (1999) where it
is backed up by hundreds of in-text citations.
The eNO
radical also reduces monocyte adhesion to cells of the endothelium, seemingly
by inhibiting the expression of VCAM-1. This would prevent the influx of
monocytes and subsequent differentiation into macrophages, thus inhibiting foam
cell occurrence. eNO also attenuates platelet aggregability, as shown by Panza,
and Cannon, eds. (1999, pp. 120-122). The cohesion of platelets at the site of
inflammation of endothelium can lead to a thrombosis (a clot attached to a
blood vessel) that starves cells and tissue further down the vessel of oxygen.
If the cells further downstream of the thrombosis are cardiac muscle cells
(myocardium) then the result can range from angina to a heart attack.
This next
section details the possible adverse effects associated with atherosclerosis.
It is important to note that each issue may occur as both a result of the build
of plaque directly, but also indirectly, as plaque formation can lead to blood
clots that cause and/or exacerbate many cardiovascular incidents. As plaque
builds up between the tunica intima and the lumen there is a possibility of
plaque rupture. This is shown on the atherosclerosis webpage of the American
Heart Association (2014b). The subsequent effect of this is that a stationary
clot (thrombus) in the wall of the affected blood vessel may further reduce the
size of the lumen and ability of blood to through the vessel. This can cause or
contribute to all of the problems shown below, for the same reason as a gradual
build-up of plaque, for it limits the blood flow to areas of the body
downstream from the affected blood vessel.
Alternatively,
the blood clot formed at the rupture site of plaque can dislodge from the
arterial wall and become free-floating. In this case it is called an embolus
and can cause an embolism (a substance that produces obstruction within a blood
vessel). This can cause the same effect as a thrombus, but the embolism can
float around and block a vessel located in the distal systemic circulation (Kumar, Abbas, and Fausto, 2004). This is also briefly pointed
out in the work of Seeley,
VanPutte, Regan and Russo, 2011, p. 663.
Angina
pectoris usually presents as a pain in the chest, though it may also appear in
the lower jaw, neck and possibly also the left arm or shoulder. It is caused by
anaerobic respiration in the heart. It can arise from atherosclerosis due to
narrowing of blood vessels within the coronary circulation. This causes
restricted blood and oxygen flow to the cardiac muscle. Unable to respire
aerobically but still requiring energy, the cardiac muscle cells must survive
on anaerobic respiration due to hypoxic conditions. Unfortunately, this
respiratory pathway causes a build-up of acidic by-products that raise acidity
(and lower pH) in the affected area. This causes a pain response to be
stimulated. This situation is exacerbated by any process demanding additional
cardiac output, for example physical and mental stress. On the other hand,
relaxation would have the opposite effect by reducing cardiac exertion.
Vasodilation via chemical intervention (nitro-glycerine or free radical NO) or
placement of a stent can increase the blood flow through the affected artery
and improve oxygen of the cardiac muscle as well as improving the removal rate
of acidic by-products of respiration. A clot could also cause this issue as a
result of atherosclerotic plaque rupture. The formation of a clot in a blood
vessel in this situation would further restrict blood flow through the vessel,
provided that the clot doesn’t cause severe obstruction. Angina pectoris is a
relatively minor condition, provided that it is only short-lasting. Normally if
the blood flow is restored, there is only mild permanent damage to cardiac
tissue.
Myocardial
infarction (heart attack), is caused by a more lengthened condition of hypoxia
(or even anoxia). In this circumstance, instead of just pain, the cardiac cells
may die in large numbers in affected areas. Atherosclerosis increases the
possibility of myocardial infarction because the resultant lesions can greatly
reduce the size of the lumen of coronary arteries, thus increasing blood
pressure and possible clot formation (thrombus). This thrombus further narrows
the blood vessel and exacerbates cell hypoxia, perhaps leading to total anoxia
in some areas, depending on severity. This leads to cell death in the cardiac
tissue. The above information on angina pectoris and myocardial infarction can
be found in the work of Seeley, VanPutte, Regan and Russo (2011), p. 686.
Stenosis can
also lead to enlargement of certain regions of the heart, such as the left
ventricle. Because the left ventricle is required to pump blood around the
whole body via the aorta, if there is stenosis in the aorta as a result of
atherosclerotic plaque, then there is increased resistance to the contraction
of the left ventricle. This means that the left ventricle must work harder in
order to overcome the resistance, otherwise the whole body will become affected
by hypoxia due to decreased blood supply. This can lead to hypertrophy of the
left ventricle, an increase in size of the muscles located here. The ventricular
hypertrophy allows the left ventricle to have more contractile force and push
more red blood cells through the stenosed aorta and into the systemic
circulation. It was mentioned in question 2 that the arterial stenosis causes
an increase in ventricular afterload which the left ventricle must overcome
(Jardins, 2008, p. 210). The increased force through the aorta increases
systolic pressure. This information was found from Seeley, VanPutte, Regan and
Russo, 2011, Appendix G, A-34 9 a-f.
A stent can
be used to treat atherosclerosis. In this case, the stent is typically made of
metal and is transported into the artery which is clogged with atherosclerotic
plaque. This occurs during a procedure called angioplasty in which an empty
balloon is inserted via catheter into the blood vessel which has narrowed. Once
inside the vessel, the balloon is inflated in order to open it up and reduce
stenosis. This occurs because the pressure of the balloon is both able to
forcibly widen the blood vessel and also in squeezing the atherosclerotic
plaque so that it takes up less space within the lumen of the blood vessel. At
this point, if the catheter also contains a stent, as it would in the case of
atherosclerosis, then this stent can hold the vessel open to the extent that
the balloon did. Thus, even when the inflating balloon has left the blood
vessel, it stays open to the same extent via the stent. Therefore, the stent
provides a more long-term ability to reduce stenosis. This has the same effect
as a vasodilator in holding the blood vessel open. So far, only the mechanical
properties of the stent have been touched upon. However, a stent can also
produce pharmacological effects as well. This is achieved by coating the outer
surface of a stent with medication which slowly releases into the arterial wall
and/or blood stream. Stents that have this capacity are called
drug-eluting-stents (DES). Blood which would ordinarily be forced through a
narrower space in the vessel, possibly leading to a blood clot or greatly
increased blood turbulence, is now free to travel through at the normal speed
and pressure. This can decrease the likelihood of cardiovascular incidences,
such as those covered above. Additional
lifestyle measures must also be taken however, as over time the stent itself
can become clogged if the underlying cause of arterial stenosis is not removed.
This process of repeated narrowing of the blood vessels after a measure has
been taken to reduce it is called restenosis. This information is shown clearly
on the stent webpage of the American Heart Association (2014c). Figure 4.2
shows the placement of a stent in the coronary artery. As can be seen from this
diagram, the stent is made of a metal mesh and is pressing against the
atherosclerotic plaque, thus opening up the lumen of this blood vessel. Once
the stent has been placed via the catheter, both it and the guide wire are
removed, leaving the stent to hold the artery open.
This portion
of the essay is dedicated to thought not seen in work by other sources on
atherosclerosis. Any relation to previous work done by any author on this topic
is purely coincidental.
It is
possible that some of the development of atherosclerosis is due to increased
ventilation and oxidative stress during mental stress. Granted modern society
has many problems when it comes to eating nutrient-depleted, high-fat foods and
breathing indoor air, but with many economic factors causing significant stress
and subsequent increases in respiration occurring as part of the
fight-or-flight reaction, various bodily changes are likely to occur. For
example, it is possible that prolonged mental stress and resultant
over-breathing reduce the bodily carbon dioxide levels and inhibit the Bohr
Effect, leading to an increased need for erythrocytes and a permanent shifting
towards elevated ventilation. This would also increase the level of oxygen
dissolved in blood plasma, as a result of air pressure within the lung during
inspiration. From this, more oxygen would travel through the bloodstream, and
cause oxidative stress throughout the body. This would exacerbate the
peroxidation of lipoproteins and oxysterol production, thus contributing
towards atherosclerosis.
Another
possible related mechanism for atherosclerosis is mouth-breathing. Because
nitric oxide is also produced within the nose, nose-breathing may also allow
significant quantities of nitric oxide to diffuse into the blood stream, which
may perhaps be unlikely given that it is a highly-reactive free radical, but it
could bind to haemoglobin, as opposed to travelling freely, see Seeley,
VanPutte, Regan and Russo, (2011) p. 653. The aforementioned reaction between
the superoxide anion and nitric oxide would readily result, decreasing the
amount of oxygen available for lipid peroxidation and subsequent atherosclerotic
plaque formation in blood vessels. Research
into the use of cancer cell growth inhibitors brought up the topic of
iron-mediated reactive oxygen species production (Galaris, and Pantopoulos,
2008). This abstract points towards iron accumulation as being a cause of
reactive oxygen species formation with toxic effects. It is possible that this
could further add to lipid peroxidation, with formation of oxidised LDLs
capable of atherogenesis.
Question 4 References:
American
Heart Association, 2014a. Cholesterol and
CAD. [online] Available at: <http://watchlearnlive.heart.org/CVML_Player.php?moduleSelect=chlcad> [Accessed 4 April 2015].
American
Heart Association, 2014b. Atherosclerosis.
[online] Available at:
<http://watchlearnlive.heart.org/CVML_Player.php?moduleSelect=athero>
[Accessed 4 April 2015].
American
Heart Association, 2014c. Stent.
[online] Available at: <http://watchlearnlive.heart.org/CVML_Player.php?moduleSelect=cstent>
[Accessed 4 April 2015].
Carmena, R., Duriez, P., and
Fruchart, J.C., 2004. Atherosclerosis: Evolving Vascular Biology and Clinical
Implications, Cicrulation, [online]
Available at: <http://circ.ahajournals.org/content/109/23_suppl_1/III-2.long>
[Accessed 1 April 2015].
Chambliss,
K.L., and Shaul, P.W., 2013. Estrogen Modulation of Endothelial Nitric Oxide
Synthase. Endocrine Reviews. [online]
Available at: <http://press.endocrine.org/doi/full/10.1210/er.2001-0045> [Accessed 4 April 2015].
Daugherty,
A., Manning, M.W., and Cassis, L.A., 2000. Angiotensin II promotes
atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. The Journal of Clinical Investigation. [online]
Available at: <http://www.jci.org/articles/view/7818> [Accessed 4 April 2015].
Galaris, D., and Pantopoulos, K., 2008. Oxidative Stress and Iron
Homeostasis: Mechanistic and Health Aspects. Critical Reviews in Clinical Laboratory Sciences. [e-journal]
45(1), pp.1-23, Abstract only. Available through: Informa Healthcare website <http://informahealthcare.com/doi/abs/10.1080/10408360701713104%20> [Accessed 7 April 2015].
Hotamisligil, G.S., 2010. Endoplasmic
reticulum stress and atherosclerosis. Nature
Medicine [online] Available at: <http://www.nature.com/nm/journal/v16/n4/full/nm0410-396.html>
[Accessed 4 April 2015].
Kumar V., Abbas A.K., and Fausto N., 2004. Robbins & Cotran Pathologic Basis of
Disease: With STUDENT CONSULT Online Access. 7th ed.
Philadelphia: Saunders.
Kummerow,
F.A., 2013. Clinical Lipidology. Future
Medicine. [online] Available at: <http://www.futuremedicine.com/doi/full/10.2217/clp.13.34> [Accessed 4 April 2015].
Lin S.J., Hong C.Y., Chang M.S., Chiang
B.N. and Chien S., 1992. Long-term nicotine exposure increases aortic
endothelial cell death and enhances transendothelial macromolecular transport
in rats. Arteriosclerosis, Thrombosis, and Vascular Biology [online]. Available at: <http://atvb.ahajournals.org/content/12/11/1305.abstract?ijkey=c10d4e3980453f42073aa6bb15326ceda162adc3&keytype2=tf_ipsecsha> [Accessed 1
April 2015].
Mescher,
A.L., 2013. Junqueira’s Basic Histology
Text & Atlas, 13th ed. China: The McGraw-Hill Companies.
Mitchell, R.S., Kumar, V., Abbas,
A.K., and Fausto, N., 2007. Robbins
Basic Pathology: With STUDENT CONSULT Online Access. 8th ed. Philadelphia:
Saunders.
National Centre for
Biotechnology Information, 2015. VCAM1 vascular
cell adhesion molecule 1 [Homo sapiens (human)]
[online] Available at: <http://www.ncbi.nlm.nih.gov/Structure/biosystems/docs/biosystems_publications.html> [Accessed 4 April 2015].
Oh,
J., Riek, A.E., Weng, S., Petty, M., Kim, D., Colonna, M., Cella, M. and
Mizrachi, C.B., 2012. Endoplasmic Reticulum Stress Controls M2 Macrophage
Differentiation and Foam Cell Formation. The
Journal of Biological Chemistry, [online] Available at: <http://www.jbc.org/content/287/15/11629.long> [Accessed 4 April 2015].
Pack, P.E.,
2001. Anatomy and Physiology, Hoboken, NJ: Wiley
Publishing, Inc.
Panza,
J.A. and Cannon, R.O., eds., 1999. Endothelium, Nitric Oxide, and
Atherosclerosis. Armonk, NY: Futura Publishing Company, Inc.
Samsioe, G.,
1994. Cardioprotection by estrogens: mechanisms of action—the lipids. [online]
Available at: <http://www.ncbi.nlm.nih.gov/pubmed/8199640> [Accessed 4 April 2015].
Seeley, R.R,
VanPutte, C.L., Regan, J. and Russo, A.F., 2011. Seeley’s Anatomy & Physiology, 9th ed. New York, NY:
McGraw-Hill.
Schmidt, F.,
2000. Biochemistry II, New York, NY:
Wiley Publishing, Inc.
Toda, N.,
Ayajiki, K., and Okamura, T. 2007. Interaction of Endothelial Nitric Oxide and
Angiotensin in the Circulation. Pharmacological
Reviews. [online] Available at: <http://pharmrev.aspetjournals.org/content/59/1/54.abstract> [Accessed 4 April 2015].
Question 3: Multiple questions on a patient with chronic lung disease and shortness of breath
*These posts are from coursework answers for my degree, but the Figures that are referred to in the text didn't scan well and have already been handed in. These long posts would probably not interest most people but if you enjoy quite in-depth reading of scientific problems then this may be for you.
Question 3: Davy Smith is a 65-year-old male with a 50-year history of smoking 2 packets of cigarettes a day. Over the past 5 years, he has become increasingly short of breath. At first, he noticed this only when exercising, but now he is even short of breath at rest. Over the past two years, he has had several bouts of lower respiratory tract infection treated successfully with antibiotics. His shortness of breath hasn't subsided, and his breathing is assisted by use of his accessory muscles of respiration. Pulmonary function testing revealed the graph below:
Question 3: Davy Smith is a 65-year-old male with a 50-year history of smoking 2 packets of cigarettes a day. Over the past 5 years, he has become increasingly short of breath. At first, he noticed this only when exercising, but now he is even short of breath at rest. Over the past two years, he has had several bouts of lower respiratory tract infection treated successfully with antibiotics. His shortness of breath hasn't subsided, and his breathing is assisted by use of his accessory muscles of respiration. Pulmonary function testing revealed the graph below:
a.
Based
on the graph, fill in the following data:
The tidal volume:
____________
The inspiratory reserve volume: ______________
The expiratory reserve volume: _______________
The forced vital capacity: ______________
The inspiratory reserve volume: ______________
The expiratory reserve volume: _______________
The forced vital capacity: ______________
b.
Describe
the microscopic changes that are occurring in Davy's lungs. What effect do these
microscopic changes have on Davy’s ability to transfer oxygen and carbon
dioxide in the lungs?
c.
Blood testing showed Davy’s hematocrit to be 59%
(normal = 42-50%). Why was his hematocrit so high?
d.
Why is Davy susceptible to lower respiratory tract
infections?
Answer:
Part a:
Each box on
the graph is roughly 125 cc of volume.
The tidal
volume is the amount of air breathed in during a relax breath. On the graph
this is roughly 4 boxes in height. 4x125
= 500 cc.
Therefore,
the tidal volume is 500 cc in volume.
The
inspiratory reserve volume is the extra air that can be inhaled after a relaxed
inhalation. Thus it is the difference between the height of the forced
inhalation and that of the normal inhalation on the graph. This is
approximately 14 boxes in height. 14x125 = 1750 cc.
Therefore,
the inspiratory reserve volume is 1750 cc in volume.
The
expiratory reserve volume is the extra air that can be exhaled after a relaxed
exhalation. So it is the difference between the height of the forced exhalation
and that of the normal exhalation on the graph. This is approximately 3.5 boxes
in height. 3.5x125= 437.5 cc.
Therefore,
the expiratory reserve volume is 437.5 cc in volume.
The forced
vital capacity is the total volume of air which can be exhaled after a full
inhalation. This is can calculated as either the difference between the highest
and lowest points of the graph, or by adding up the tidal volume, inspiratory
reserve volume and expiratory reserve volume. This is roughly 21.5 boxes in
height. 21.5x125 = 2687.5 cc
Therefore,
the forced vital capacity is 2687.5 cc in volume.
(Bass, 1974
p.7).
The work of
Bass showed how to calculate volumes from a lung function graph, however much
of its other work may be outdated so it was only used for this initial piece of
work.
Part b:
It is likely
that Mr. Smith is suffering from chronic obstructive pulmonary disease. This is
a chronic lung disease that is usually caused by cigarette smoking. Given that
Mr. Smith has a history of 100 pack-years of cigarette smoking (packets of
cigarettes per day multiplied by years of duration, i.e. 2 packets daily x 50
years = 100 pack-years) this particular pulmonary condition is highly likely. It
encompasses other respiratory diseases such as chronic bronchitis, emphysema
and possibly also chronic obstructive airways disease. The repeated lower
respiratory tract infections also point to this diagnosis so Mr. Smith is
certainly at risk of the disease and he has the decreased lung function test to
match. With regard to the microscopic changes occurring in Davy’s lungs, there
is probably dilation and enlargement of the bronchioles, which is only
partially reversible, i.e. much of the damage at this stage of illness is
likely to be permanent (Mescher, 2013 p. 361). Alveoli are also enlarged in
this condition as shown in Figure 3.1. This is due to the walls separating each
alveolus gradually being destroyed over the years. Alveolar enlargement can
occur because cigarette smoking provokes an inflammatory immune response which
causes the release of various proteases (enzymes
that break-down proteins, in this case these enzymes are mostly elastase and
trypsin, and the immune cells they are most associated with are neutrophils,
however macrophages are also involved in alveolar destruction), in the lungs
from immune cells (Davies and Moore, 2003 pp. 26-28). This can break down the
elastic protein in alveoli (called elastin) and render them inflexible (Seeley,
VanPutte, Regan, and Russo, 2011, pp. 830-862). In healthy persons the use of these enzymes is
inhibited by a chemical called alpha-1-antitrypsin. This stops the immune
cell-induced damage from continuing. However, in smokers and persons with a
genetic fault causing an alpha-1-antitrypsin deficiency, the damage goes
largely unchecked and pulmonary destruction ensues. In smokers the lack of
alpha-1-antitrypsin activity is attributed to its reaction with free radicals
in cigarette smoke, rendering it ineffective. What can then result from this is
that instead of having very many alveoli, the alveoli can break down their
walls to the extent that they form one larger air sac (Mayo Foundation for
Medical Education and Research, 2015a). This results in a much lowered surface
area for the diffusion of gases both into and out of the lungs which causes
many of the reduced volumes seen on the lung function test (Mayo Foundation for
Medical Education and Research, 2015b). Chronic bronchitis obstructs the larger
airways of the respiratory tract while emphysema causes the same effect in
small airways, as well as air-trapping in the alveoli (The McGraw-Hill
Companies, 2000). The differences between healthy alveoli and those affected by
emphysema are shown in Figure 3.2. Initially, the damage will reduce the amount
of oxygen diffusing into the bloodstream, leading to an increase in
ventilation. This hyperventilation lowers the concentration of carbon dioxide
in the blood, while attempting to compensate for lowered oxygen. Usually, there
is still some decrease in blood oxygen levels despite the hyperventilation. As
the damage progresses however, there comes a point when the respiratory tract
is so compromised that eventually carbon dioxide will accumulate in the
bloodstream because it cannot diffuse out of the lungs at this stage and oxygen
in the blood becomes significantly more decreased as well. The conditions of
elevated carbon dioxide and decreased oxygen in the blood are termed
hypercapnia and hypoxemia respectively (University of Maryland Medical Center,
2013). The inability to adequately
remove air from the lungs explains the elevated residual volume in Mr. Smith’s
lungs. The use of accessory muscles of respiration helps to create more
pressure in the lungs to expel air during expiration.
One
beneficial effect of the elevated level of carbon dioxide in the blood is that
oxygen is unloaded more readily from haemoglobin. This is known as the Bohr
Effect and may occur due to the conversion of carbon dioxide to carbonic acid
with simultaneous release of a hydrogen ion which reduces the blood pH. This
effect is very useful during exercise because the increased carbon dioxide
concentrations in the blood cause subsequent reduction in pH (which also occurs
via other metabolic by-products, e.g. lactic acid) will cause preferential
off-loading of oxygen to cells that are respiring more vigorously. This allows
cells that are under the heaviest workload to receive adequate amounts of
oxygen from haemoglobin (Razani, B., 2014). This means that in the case of Mr.
Smith, his body actually requires less oxygen to reach his erythrocytes, (i.e.
not as high an oxygen saturation in the blood is required) because it is
off-loaded to other cells and tissue within his body more readily. A similar
effect also occurs as the concentration of a substance called 2,
3-Diphosphoglycerate (2,3-DPG)
increases. This is a compound that is formed as a result of anaerobic
glycolysis, therefore its production increases under hypoxic / hypoxemic
conditions. It is important to note that hypoxia and hypoxemia are not
equivalents. Rather, hypoxemia is the state of reduced oxygen content in the
blood stream of arteries (or a pathologically low arterial oxygen tension),
whereas hypoxia is a condition in which too little oxygen is delivered to
tissues. It can therefore be possible, though unlikely, that hypoxemia may
exist in a patient, but compensatory mechanisms may be sufficient to encourage
oxygen dissociation from haemoglobin in order to oxygenate tissues adequately.
The aforementioned 2, 3-DPG however, increases under hypoxic conditions (given
its production occurs under anaerobic conditions), and consequently, increases
tissue oxygenation in a similar way to the Bohr Effect (Jardins, 2008, p.236).
Figure 3.3
shows the oxygen-haemoglobin dissociation curve. Note that when exercising,
erythrocytes will off-load oxygen more readily to respiring tissue (possibly
due to any number of reasons, for example, increased CO2 or 2, 3-DPG
production as well as increase in temperature) which explains the point
labelled deoxygenated blood on the graph. At rest, tissues respire more slowly,
and produce less CO2, 2, 3-DPG, heat and other metabolic by-products
that encourage the dissociation of oxygen from haemoglobin. The dashed curve to
the right of the continuously drawn curve shows what would happen if any or all
of the following components were increased: CO2, 2, 3-DPG, acidity,
and temperature, though more possibilities exist. This produces an effect known
as a “right-shift”, which means that a higher pressure of oxygen is required to
produce the same oxygen saturation percentage compared to normal conditions.
This means that under right-shift conditions, haemoglobin loses oxygen more
readily, and consequently, respiring tissue receives oxygen in greater amounts.
Figure 3.4
shows the diffusion of carbon dioxide and oxygen into and out of an alveolus.
This forms a diagrammatic representation for the equation of Fick’s Law of
diffusion, which is also shown in this figure. Relating this to the case at
hand, the reduced ability to both remove carbon dioxide from and deliver oxygen
to the alveoli in Mr. Smith’s lungs results in a higher partial pressure of
carbon dioxide and lower partial pressure of oxygen in these air sacs. A
consequence of this is that less carbon dioxide will diffuse out of the
bloodstream and into each alveolus, while less oxygen will diffuse from the
atmosphere into the same region. This is because the difference in partial
pressure between the blood stream and alveoli, relating to carbon dioxide, is
smaller for Mr. Smith than a regular person. Similarly, the partial pressure
difference of oxygen between the atmosphere and the diseased alveoli will be
smaller as well. Thus, less carbon dioxide is encouraged to diffuse into the
alveoli and be removed from the lungs in expiration, and less oxygen will diffuse
into the lungs during inspiration (Jardins, 2008, p. 139). This explains why
Mr. Smith is forced to use his accessory muscles of respiration.
The use of
accessory muscles of respiration can improve the delivery of gases both from
the atmosphere to the lungs and vice versa. Firstly, the accessory muscles of
inspiration must be considered. The largest muscles of this category are the
scalenus, sternocleidomastoid, pectoralis major, trapezius, and external
intercostal muscles. Without getting into excessive detail, the
overall function of these muscles is to help decrease the pressure within the
lungs to such a level below atmospheric pressure that gases flow more readily
into the alveoli, diffusing via a pressure and concentration gradient. As the
concentration of any gas increases in a given area, so also does its tension.
Therefore, the fact that Mr. Smith is having difficulty ventilating his lungs,
means that the concentration of oxygen normally extracted from the alveoli into
the blood stream has decreased (therefore, both alveolar partial pressure and
concentration of oxygen have decreased) and Mr. Smith’s blood carbon dioxide
levels have increased (regarding both partial pressure and concentration of
arterial carbon dioxide). Thus, for inspiration, the lower the pressure inside
the lungs, relative to the surrounding atmosphere, the greater the diffusion
gradient for gases moving from the atmosphere into the lungs (and consequently
alveoli). Therefore, the result of using the accessory muscles of inspiration
is to increase oxygen supply to the blood stream. A person who is using their
accessory muscles of inspiration while breathing will be quite noticeable, with
much of their upper chest expanding and elevating during each inhale and some
shrugging occurring also (Jardins, 2008, pp. 54-58). Conversely, the accessory
muscles of expiration will increase the pressure within the lungs, relative to
that of the surrounding atmosphere. This helps compensate for airway
resistance, such as that seen in COPD. The primary accessory muscles of
expiration are the rectus and transversus abdominis muscles, the external and
internal abdominis obliquus muscles and the internal intercostal muscles. The
basic movement of these muscles during expiration is of compression. The
abdomen becomes compressed, and the diaphragm is pushed into the thoracic cage,
increasing the pressure in the lungs well above atmospheric pressure and
causing a diffusion of gases out of the alveoli into the surrounding
environment (Jardins, 2008, pp. 59-61).
Part c:
Haematocrit
is the proportionate measure of red blood cells compared to the overall blood
volume (Seeley, VanPutte, Regan, and Russo, 2011, p 668).Thus, if Davy’s
haematocrit was 59% then this is the percentage of his blood which was composed
of red blood cells.
Red blood
cells are used strongly in the transfer of various gases both to and from the
lungs, and from and to cells. Therefore, an elevated level of red blood cells
would occur in an individual who had trouble dealing with both the build-up of
gases, and the inadequate diffusion of gases into the blood. In the case of
Davy, he is suffering from both hypoxemia and hypercapnia. Therefore, he will
need additional red blood cells to carry oxygen from his lungs. This sets up a
steeper concentration gradient between the alveoli of the lungs and the
bloodstream, thus allowing more oxygen to diffuse into the blood and be carried
to various cells. Approximately 98.5% of the oxygen in our blood is bonded to
haemoglobin to form oxyhaemoglobin, the remainder is dissolved in plasma
(Seeley, VanPutte, Regan, and Russo, 2011, p 652) and tends to be ignored in
calculations of arterial oxygen content.
There are
numerous equations for approximating oxygen delivery and content within the
body. Shown below is an equation for oxygen content in arteries (Gutierrez, and
Theodorou, 2009).
CaO2,
shorthand for the content or amount of oxygen in the arterial blood, is
calculated by the following equation:
CaO2
~ [Hb](SO2)x1.34
Where ~
means roughly equal to (because here we are neglecting the amount of dissolved
oxygen within plasma [roughly 1.5 to 2%], and instead focusing entirely on
oxygen bonded to haemoglobin), [Hb] is the concentration of haemoglobin in the
blood, and SO2 is the fractional oxygen saturation of haemoglobin.
Thus, we can
see that the oxygen content of arterial blood is proportional to the
concentration of haemoglobin, and also to the fractional oxygen saturation of
haemoglobin. This means that if either haemoglobin concentration or oxygen
saturation increases while the other remains the same, then oxygen content of
arterial blood will also increase. Also, if CaO2 remains
the same value, then [Hb] and SO2 are inversely proportional to each
other. This means that as one quantity increases, the other will decrease in
order to achieve the same result for CaO2. Therefore, if
we assume CaO2 to be an unchanging quantity, then we can
clearly see that if oxygen saturation of haemoglobin decreases, then the
concentration of haemoglobin must increase.
In the case
of Davy Smith, his ability to extract oxygen from alveoli has greatly
decreased. Even with a normal tidal volume of 500 cc, his blood is still not
receiving an adequate supply of oxygen. This means that in our equation SO2
has decreased. Mr Smith’s body will still need to utilise roughly the same
amount of oxygen, provided that compensatory mechanisms are not in place to
reduce overall metabolic rate. Thus, the concentration of haemoglobin (also
known as the haematocrit) will have to increase in order to supply to the same
demand for oxygen content. This particular form of increased erythrocyte
production (i.e. from hypoxic lung disease) is called either secondary
erythrocytosis or secondary polycthemia (Seeley, VanPutte, Regan, and Russo,
2011, p. 669). This means that if Davy Smith was to somehow have his lung
condition cured, then his haematocrit would drop to normal levels. However,
while his condition remains, his kidneys will secrete more erythropoietin in
response to decreased oxygen delivery.
Carbon
dioxide is also a highly important consideration in this situation. As Davy
Smith’s lung function deteriorates, his carbon dioxide levels will continue to
increase. This accumulation of carbon dioxide must be dealt with. The body will
naturally convert much of its extracellular carbon dioxide into bicarbonate
ions (roughly 66% takes this form). Of the remaining 34%, 7% will be dissolved
in plasma and the remaining 27% will bind to haemoglobin. The formed complex is
called the carbaminohemoglobin molecule (Mescher, 2013, p. 236). Thus, elevated
carbon dioxide levels will cause increased erythrocyte concentrations in order
to bond the plasma carbon dioxide and transport it away from cells.
A more
serious gas in the body that requires an elevated haematocrit level is carbon
monoxide. Carbon monoxide is a poisonous gas found in cigarette smoke among
other sources, especially those involving combustion of carbon-containing
compounds in a region of inadequate oxygen (incomplete combustion) which has a
very high affinity for haemoglobin and bonds to form carboxyhaemoglobin. Once
carboxyhaemoglobin has formed, it is unlikely that the carbon monoxide will
dissociate again in the lifespan of the red blood cell, usually it stays bonded
until the red blood cell is broken down by the body. During this time the
haemoglobin is unable to bind to oxygen or carbon dioxide molecules, or
anything else for that matter. Thus, carbon monoxide essentially disables the
effect of haemoglobin towards other molecules and requires increased red blood
cell concentrations. It has been found that the blood of chronic smokers
contains between 5 and 15% carboxyhaemoglobin. This alone provides a strong
reason for the elevated red blood cell concentration found in Davy Smith
(Seeley, VanPutte, Regan, and Russo, 2011, pp 653-655).
Part d:
Davy is
susceptible to lower respiratory tract infections. This could be due to the act
of smoking tobacco which has been reported to damage cilia in the lungs
(Mueller, 1997). Cilia are microscopic projections that protrude from cells and
sweep away various substances and microbes that can damage the body. When these
are damaged, various toxins and microbes can enter the lower respiratory tract
in greater numbers, requiring a stronger immune system to combat it.
Further to
this, differences in bacterial populations within regions of the respiratory
tract between smokers and non-smokers have been found. The exact location of
these bacterial colonies is unlikely to be of concern, considering that as long
as they are present somewhere in the respiratory tract, they may allow
pathological microbes to travel past them into lower regions, whereas bacterial
populations in healthy non-smokers would have some sort of inhibitory effect.
Brook, and Gober (2005) found that the nasopharyngeal flora of smokers
contained more potential pathogens than non0smokers, as well as fewer
beneficial bacteria which might inhibit their growth and harm. Fujimori, et al.
(1995) also found that healthy smokers had higher levels of Streptococcus
Aureus (S. Aureus) and lower levels of alpha-streptococci (the forms which
inhibit S. Aureus), as compared to healthy non-smokers. Forms of
alpha-streptococci that inhibit another potential pathogen called S. pyogenes
were similar in both healthy smokers and non-smokers. This indicates that
smokers are more susceptible to infections via Streptococcus Aureus.
A review of
many studies by Arcavi, and Benowitz (2004) revealed some interesting data
about smokers. Several studies that were examined showed decreases of 10-20% in
serum Immunoglobulins IgA, IgG and IgM. These are all vital antibodies that
play a major role in the response against infection. These same authors also
found that specific antibody responses to influenza (both as an unaltered virus
and as vaccine) and Aspergillus fumigatus
were decreased in smokers.
Additionally,
the act of smoking can cause excessive mucus production and due to the impaired
function of the damaged cilia in the respiratory tract, this mucus can build up
without being removed. Mr. Smith likely has a “smoker’s cough”, a heavy cough
which attempts to dislodge and remove this built-up mucus. Unfortunately, this
accumulating mucus in the bronchial tree provides vital nutrients for
pathological microbes that take up residence in the lungs. Thus, Mr. Smith is
more susceptible to lower respiratory tract infections. Antibiotics are likely
only to act as a short-term aid, with recurrent infections being a part of his
life in the long-term (The McGraw-Hill Companies, 2000).
Question 3 References:
Arcavi, L.,
and Benowitz, N.L., 2004. Cigarette
Smoking and Infection. [online] Available at: <http://archinte.jamanetwork.com/article.aspx?articleid=217624> [Accessed 6 April 2015].
Bass, B.H.,
1974. Lung Function Tests An
introduction. 4th ed. London: H.K. Lewis & Co. Ltd.
Brook, I.,
and Gober, A.E., 2005. Recovery of
potential pathogens and interfering bacteria in the nasopharynx of smokers and
nonsmokers. [online] Available at: <http://www.ncbi.nlm.nih.gov/pubmed/15947322/> [Accessed 6 April 2015].
Davies,
A., and Moore, C., 2003 The Respiratory
System. Spain: Churchill Livingstone.
Fujimori I.,
Goto R., Kikushima K., Ogino J., Hisamatsu K., Murakami Y., and Yamada T. 1995.
Isolation of alpha-streptococci with
inhibitory activity against pathogens, in the oral cavity and the effect of
tobacco and gargling on oral flora. [online] Available at: <http://www.ncbi.nlm.nih.gov/pubmed/7745286/> [Accessed 6 April 2015].
Gutierrez,
J.A., and Theodorou, A.A, 2009. Oxygen
Delivery and Oxygen Consumption in Pediatric Critical Care, [online]
Available at: <http://www.springer.com/cda/content/document/cda_downloaddocument/9780857299222-c1.pdf?SGWID=0-0-45-1328038-p174130681> [Accessed 6 April 2015].
Jardins,
T.D., 2008. Cardiopulmonary Anatomy &
Physiology Essentials of Respiratory Care, 5th ed. Delmar, USA: Nelson
Education, Ltd.
Mayo
Foundation for Medical Education and Research, 2015a. Diseases and Conditions Emphysema. [online] Available at: <http://www.mayoclinic.org/diseases-conditions/emphysema/basics/definition/con-20014218> [Accessed 6 April 2015].
Mayo
Foundation for Medical Education and Research, 2015b. Diseases and Conditions Emphysema. [online] Available at: <http://www.mayoclinic.org/diseases-conditions/emphysema/multimedia/emphysema/img-20007614> [Accessed 6 April 2015].
Mescher,
A.L., 2013. Junqueira’s Basic Histology
Text & Atlas, 13th ed. China: The McGraw-Hill Companies.
Mueller,
D.M., 1997. Smoking Any Substance Raises
Risk of Lung Infections, [online] Available at: <http://archives.drugabuse.gov/NIDA_Notes/NNVol12N1/Smoking.html> [Accessed 6 April 2015].
Razani, B.,
2014. Bohr Effect. [online] Available
at: <http://www.pathwaymedicine.org/bohr-effect> [Accessed 6 April 2015].
Seeley, R.R,
VanPutte, C.L., Regan, J. and Russo, A.F., 2011. Seeley’s Anatomy & Physiology, 9th ed. New York, USA:
McGraw-Hill.
The
McGraw-Hill Companies, 2000. Case History
13: Restrictive and Obstructive Lung Disease, [online] Available at: <http://www.mhhe.com/biosci/ap/ap_casestudies/cases/ap_case13.html> [Accessed 7 April 2015].
University
of Maryland Medical Center, 2013. Chronic
obstructive pulmonary disease. [online] Available at: <http://umm.edu/health/medical/reports/articles/chronic-obstructive-pulmonary-disease> [Accessed 6 April 2015].
Subscribe to:
Posts (Atom)