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Cell Biology Emphysema Research Paper

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Emphysema

“Losing your Lungs”

by Anja Mareike Neumann

Cell Biology - Honors Component

Professor Dunphy

02/02/2013
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Emphysema

Losing Your Lungs

Emphysema, or the "slow killer" as it is often called, is currently affecting 4 to 5

million people in the United States alone. These numbers are staggering considering

the time in which we live. In a year that saw prices for tobacco rise considerably across

the board, the strengthening of smoking laws, as well as a steep advancement in health

consciousness of our society, it is hard to believe that this disease is still affecting so

many people. Additionally, despite the advancements in medicine and technology,

there is still a significant misunderstanding of the effects it has on the human body and

which treatment methods are most beneficial. According to the Center for Disease

Control (CDC), as of 2012 the number of deaths caused by emphysema specifically,

numbers over 10,000 people. What is important to note about emphysema is that there

is long-term treatment available for patients with the disease but currently no cure. With

up to 5 million incurable people affected and 10,000 of them dying each year,

emphysema certainly is posing a serious threat to the health of the world. This essay

will explain and discuss the disease, and its known effects on the organs, on a cellular

level, as well as the treatments that are available.

Humans have two lungs; a right lung that's divided into the three lobes of

superior, middle and inferior and a left lung that's divided into only two lobes, the upper

and the lower. In addition to only having two lobes, the left lung is also smaller, creating

a cavity for the heart. The way of the air into the lungs is going into a gradually more
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and more compressed area. While the diaphragm pulls downward when the body is

breathing in, air enters through the mouth and nose into the trachea. Cilia sit on the side

of the trachea trying to remove any harmful components in the air, but leaving the

oxygen component. Air moves further into the lungs into the bronchi, which are two

large tubes leading to each side of the lungs. The bronchi branch into smaller bronchi

and finally into very small bronchioles. At the terminal bronchioles, the end of these tiny

“twigs”, sit the alveoli. The alveoli are the minuscule balloon like structures that are the

actual part of the organ that do the work. They are used in the exchange of carbon

dioxide (CO2) and oxygen (O2) from the blood to the lungs. They expand while breathing

in and deflate when breathing out. They are surrounded by the blood vessels that

deliver the oxygen poor blood and pick up the oxygen enriched blood. The lungs contain

about 300-500 million alveoli in a healthy adult and have a surface area of about 70

square meters approximately.

Emphysema is a type of Chronic Obstructive Pulmonary Disease (short COPD).

In other words, emphysema is a disease in which airflow to the lungs is limited or

obstructed persistently. By destroying the tissue of the above described alveoli,

emphysema significantly and dramatically reduces the lungs surface areas. When the

tissue walls of the alveoli break down, an undersupply of oxygen in the body is created

and a constant shortness of breath is felt. After years of smoking the disease usually

ends up being fatal. As mentioned above, its affects can be slowed or diminished by

medication and other treatments but unfortunately cannot be reversed.

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An important question to ask in turn, is how does this process happen in the

body? We know that once the smoke of a cigarette or other polluted air is inhaled, our

body tries to fight it off. When the polluted air inevitably enters our body, the body can

and does react in many different ways. The reactions include running of the eyes and

nose, itching of the throat and coughing. Cilia, the small hair like structures in our

airways, try to protect the lungs by sweeping the throat of the micro particles that are

inhaled. However, tar along with other chemicals make cilia sticky and slow them down.

As a result, the cilia do not perform well anymore and the smoke along with the tar and

mucus are given a free ride right into the lungs. This breakdown of function leads to

inflammation, infection and disease of the lungs.

There is still a lot unknown about the disease and a large amount of research still

needs to be done. One area where many things are unknown is regarding what

happens after pollution enters the lungs and after many years of exposure to that

pollution. From work that has been done, we know the outcome of such exposure can

lead to A1AT in the body being destroyed, the creation of an antiprotease imbalance, a

VEGF reduction in the lungs, or apoptosis and senescence in lung cells is caused. What

each of these possible causes mean and what they are will be described in the

remainder of the essay.

Alpha-1 antitrypsin, or A1AT, is a naturally occurring enzyme in the body that

inhibits the enzyme neutrophil elastase from attacking the lungs. The neutrophil

elastase is created by white blood cells in response to irritants or infection of the lungs.

The neutrophils are attracted to the lungs by smoke. They freely destroy elastin of the

alveoli if not inhibited. A1AT is produced and released by the liver once inflammation is
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detected in the body. It therefore can be seen as a protector against harmful proteins

attacking the body. Traveling through the bloodstream, A1AT covalently binds elastase

to its active site; a confirmation change then occurs and inactivates elastase. As a

result, the A1AT has kept the elastase from degrading the elastin of the alveoli.

An A1AT deficiency can take place if the enzymes are misshapen in the liver. If

they are misshapen they cannot cross the membrane of the liver cells and therefore

can't leave the liver in order to protect the lungs. If not enough A1AT is created, or none

at all, A1AD (A1AT deficiency) occurs in the body. The lungs will be destroyed by the

elastase because of the lack of A1AT protection. This destruction causes the alveoli to

become less elastic and the lungs won't be able to efficiently clear out oxygen anymore

during breathing. This leads to the oxygen staying in the alveoli, eventually depleting

and then followed by CO2 build up. After some time the CO2 is turned into carbonic acid

while still in the alveoli. Carbonic acid hurts the lungs and can potentially build scar

tissue. Fortunately, A1AD only effects 2% of emphysema patients because the

deficiency isn’t very common due to it being a strictly inherited deficiency. For the 2% of

emphysema patients who also have A1AD, medication can relieve symptoms. The

A1AD symptoms can of course develop faster in people who smoke or have heavy

exposure to second hand smoke or pollution.

The "Inflammation-Protease/ Antiprotease Imbalance Hypothesis" is widely

accepted as the leading cause for emphysema. It is believed that the toxins that get into

the lungs as described above attract white blood cells and macrophages. These

inflammatory cells then make the elastase. From that point forward, the process in the

IPAI is the same as the process in A1AD. Elastases chew up septa (the cell walls
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dividing the alveoli), ultimately destroying elastin and causing the creation of one or

multiple large alveoli instead of many small ones. These large alveoli are called bullae.

Alveoli are called bullae if they are at least 1cm large and if their wall is less than 1mm

thick. The creation of these bullae significantly decreases the surface area needed for

the gas exchange discussed above between the lungs and the blood vessels.

Another leading cause for emphysema is a reduction in Vascular Endothelial

Growth Factors, or VEGF. VEGF usually bind to receptors on the cell membrane and

dictate the cell to grow and divide. These VEGF, and even their receptors (VEGFR), are

known to be expressed in reduced numbers in emphysematous lungs. If there are less,

or a lack thereof, receptors and their ligands the signal to keep the cell alive (the cell

continuing to grow and divide) won't reach the cell and instead will eventually die. If

such a process takes place in lung cells, the lungs will slowly decrease their size, which

can then turn into apoptosis.

Apoptosis can be simply described as cell suicide. A cell is said to "kill itself" if

there is no growth or division because of reasons as named above. The body tries to

make up for apoptosis by making new cells, which is called "proliferation". During

proliferation, for each cell that dies a new one is created. Because of proliferation, it

would then be considered by most that apoptosis would lead to no issues in the body.

However, where apoptosis becomes a problem lies in the fact that proliferation has a

limit to its ability. Cells have a limit of 50-75 cell divisions. Once that limit is reached,

senescence in the cell sets in. Senescence is yet another contributing factor to

emphysema.
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Senescence is easier described as "replication fatigue" in the cell and occurs

after a cells telomere shortens due that cell replicating itself. If a telomere shortens 50 to

75 times, at some point a loss of function of this telomere sets in. DNA damaged

proteins can bind to the now unprotected end of the telomere because the telomere has

shortened so much that no "junk DNA" will protect the telomeres ends anymore. This so

called "junk DNA" is not what its name suggests however. Instead they are pieces of

DNA sequences that can protect sequences of more important DNA, interact with other

proteins and can overall control cell proliferation and death. We can consider them to be

"buffer zones" of a sort, and if they are missing the telomere has shortened so much

that it won't make the cell divide any longer and ultimately apoptosis will begin to occur.

This will mean that lung structure will be decreased.

Emphysema can be classified specifically by the location of the lung it appears

in. There is centrilobular (or centriacinar) and panlobular (or panacinar) emphysema.

While most people have either or, others have both classifications overlapping.

Centrilobular generally only affects the upper panels of the lungs. This location of the

lungs is mostly affected in patients with destroyed bronchial mucus membranes

because of chronic bronchitis caused by smoking frequently, for an extended period of

time or being subjected to second hand smoke extensively. Therefore centrilobular

spreading of the disease is more often found in older adults.

In comparison to centrilobular emphysema, panlobular emphysema spreads

throughout the whole lung with an emphasis to the lower parts. Patients with inherited

A1AD, and sometimes smokers, are affected by that classification of emphysema.

Panlobular emphysema is also characterized by the destruction of alveoli by

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inflammation or A1AD more than in the centrilobular case. Because of that, panlobular

cases are more often found in young adults.

Another less common case of emphysema is Congenital Lobar Emphysema (or

CLE). CLE causes the pulmonary lobe to over expand and therefore not leave enough

space for the other lobes of the lung. In addition to that, bronchial cartilage might be

softened and weakened due to an overly large pulmonary artery. CLE is caused due to

stress in newborns and can potentially be reversed although might sometimes be fatal.

One big piece that is still missing, from the puzzle that is emphysema, is a cure

for the disease. While there still isn't a cure to be found researchers have discovered

various approaches that have been edging closer towards a cure over the years. One

big keyword in connection to emphysema seems to be Vitamin A. In 2003 the Journal of

Nutrition (JN) published a study made in Kansas regarding how Vitamin A deficiency is

directly connected to emphysema. While it was previously known that Vitamin A's role in

the lungs is mainly "lung maturation, development and maintenance" (Journal of

Nutrition), they wanted to find out if smoking induces Vitamin A deficiency and if this

deficiency could lead to emphysema. There was also knowledge that all-trans-retinoic

acid (the acid form of Vitamin A) injected rats had a reverse effect on elastase

deficiency induced emphysema and that it stimulated the production if alveoli. In this

study they exposed rats to cigarette smoke in the capacity of 20 cigarettes a day for 6

weeks straight. What resulted was a rather shocking outcome. After exposing the rats

they tested, Vitamin A levels in the lungs, in the serum and in the liver, since it is the

main storage area for Vitamin A. While a test group of rats that were kept in the same

conditions but without the cigarette smoke had no change in the Vitamin A levels, the
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group of rats that were exposed to the pollution had decreased levels of Vitamin A in

lungs, serum and liver. They also found less elastin in the rats' lungs and as expected

inflammation. With these results the group of scientists was confident to support their

thesis that smoking induces a Vitamin A deficiency in rats.

In looking at another study that has been published a year later in "Thorax - An

International Journal of Respiratory Medicine", their thesis failed to stand up to further

testings’ that Vitamin A could actually reverse emphysema. While this study was

conducted on mice instead of rats and was therefore harder to compare, the results only

show how we are still at the very beginning of finding a cure. After 12 days of injecting

emphysematous mice with all-trans-retinoic acid, no positive results could be found.

Alveolar destruction couldn't be stopped and therefore the group supported their thesis

that while a positive effect of Vitamin A might be species specific, it can't be said that

Vitamin A reduces the impacts of emphysema. After not finding any cure after

significant research, it should be noted however that 16 of 17 other studies on Vitamin A

effects have also been inconclusive.

Since it seems like research needs a little more time in order to find a cure for

emphysema, I believe that the immediate focus should be made on moving on to life-

prolonging methods. One of these methods is the Lung Volume Reduction Surgery

(LVRS), which has been performed at Columbia University Medical Center since 1994.

In this procedure emphysema damaged tissue is removed and the leftover tissue of the

lungs stays behind. The leftover tissue ends up working more efficiently because 20%

to 35% of the lung is actually removed and the leftover tissue including its muscles can

expand and work better. This procedure unfortunately doesn't cure the disease but does
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fortunately prolong a patient’s life and can make breathing easier, which is a great factor

towards leading a normal life. There is also a very freshman life prolonging procedure

that is currently being tested at Columbia. This method uses mesh wire stents that

bypass damaged tissues and allow airflow through a sort of artificial air passage.

Research is still being done on this method however and the surgery has not been

approved yet.

As a conclusion, I can say that in doing research of this horrible disease the fact

that very little has been discovered about emphysema became very clear to me. It's a

rather depressing reality because of the fact that emphysema will most likely lead to a

slow and painful death for more than 10,000 people in the upcoming months of 2013.

Public awareness of emphysema absolutely needs to be increased. What seems to be

a common misunderstanding, or non-understanding, is that smoking is one of the

leading man-made causes of the disease. If more people would learn more about

emphysema and how it is directly correlated to smoking, it would likely become less of a

threat to the world’s health. More money should be spent on finding a cure, especially

since it seems like that goal is so close to being reached.

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