Pathophsyiology Of Respiratiry Diseases

Question 1

What is copd

Answer 1

Chronic obstructive pulmonary disease (COPD) is a term to describe a mixture of chronic bronchitis
and emphysema that encompasses a long-term progressive and accelerated decline of respiratory
function. This statement suggests that respiratory health naturally declines with age.

Question 2

What happens to the ageing process of someone who eg smokes

Answer 2

However, this ageing process is
accelerated in individuals that aggravate the decline through lifestyle choice (e.g. smoking). Around
90% of COPD cases are associated with long-term exposure to tobacco smoke with 30% of long term
smokers developing COPD.

Question 3

What are other factors that can cause copd

Answer 3

There are other factors that can cause COPD including genetic causes 
(alpha-1 antitrypsin deficiency where lung tissue is destroyed) as well as exposure to other 
environmental hazards (e.g. chemical pollution).

Question 4

What causes acute damage to the respiratory tissue

Answer 4

There are a large number of harmful constituents (especially reactive oxygen species and noxious
chemicals) of tobacco smoke that cause acute damage to respiratory tissue generating an
inflammatory response.

Question 5

What happens with repeated exposure to tobacco smoke

Answer 5

With repeated exposure, the inflammation becomes pathological and
generates chronic and irreversible dysfunction.

Question 6

What inflammatory response takes place

Answer 6

The inflammatory response involves the

1. production of IL-8 and TNF-alpha
2. This attracts macrophages and activates and recruits neutrophils.
3. These immune cells secrete proteases including trypsin, elastase and metalloproteases that digest the
   damaged tissue.

Question 7

What problems does the inflammatory response have

Answer 7

However, this process takes a number of hours to complete by which time a person
has smoked more cigarettes that causes further damage.

Question 8

What can further damage after the inflammatory response initiate

Answer 8

This again initiates the inflammatory
response further and the cycle repeats. The result is increased protease burden where the number of
proteases secreted are so large that healthy tissue is now also digested.

Question 9

What enzymes are inhibited by tobacco smoke

Answer 9

The antiprotease enzymes v
that inactivate proteases are also inhibited by some of the constituents of tobacco smoke. In the long
term, there is now chronic and irreversible changes to the structure of the airways. This includes
impaired mucociliary function.

Question 10

Describe the functionality of the lungs ( mucous , cilia )

Answer 10

The airways are coated with a layer of mucous secreted by goblet
cells. This layer of mucous traps different particles including small particulate matter as well as
infectious organisms. Cilia then beat and move the mucous up the airways in one direction until the
mucous is eventually spat out or swallowed into the GI and prevented from gaining access to the
body.

Question 11

Describe mucous and cilia in patient with copd - and effect

Answer 11

Where there is damage to the airways in the case of COPD, hypersecretion of mucous occurs
due to toxic particles irritating structures of the airways that produce of mucous causing them to
secrete more mucous. Cilia function can also be damaged as well such that they cannot beat
effectively and perform their function. The effect is the build-up of mucous in the airways that traps
infectious organisms but facilitates an environment for them to live as the mucous is not removed.

Question 12

How is negative immune response promoted further in copd

Answer 12

This means impaired mucociliary clearance makes individuals more vulnerable to respiratory
infections. This stimulates the immune response further causes increased protease burden and more
tissue damage.

Question 13

What is tissue remodeling

Answer 13

What is tissue remodeling

Question 14

What are the different pathological features observed in patients suffering from copd

Answer 14

There are different pathological features observed in patients suffering from COPD. Within the
airways, there is damage to cilia preventing the effective clearance of mucous. There is also mucous
hypersecretion from goblet cells and increased mucous gland activation. This clogs the airways and
increases the difficulty of airflow. There is also inflammation and swelling of airway tissue as well as
oedema. The airway structure is weakened due to the breakdown of some of the structural proteins
of airways including elastin. Airway patency can be lost as a result as they just collapse. The result of
these pathological features include increased risk of infection, irritation of sensory neurons resulting
in coughing (triggered by smoke as well as mucous), as well as decreased luminal area that increases
airway resistance and obstruction.

Question 15

What are the pathological changes to the lungs in copd

Answer 15

COPD also causes pathological changes to the lungs. The predominant effect is the overall decrease
in lung surface area. There is an overall decrease in surface area of the lungs due to degradation of
proteins within it. A fusion of alveoli also occurs to cause airspace enlargement. There is also a
resulting decreased perfusion that decreases gas exchange efficiency due to degradation of the
vasculature and capillaries found in the lungs. The degradation of structural proteins in the lungs
include the degradation of elastin fibres that decrease recoil and therefore increase compliance. This
gets to a point such that respiratory muscles are eventually utilised to force the lungs to recoil and
close.

Question 16

Why is loss of airway patency a problem for a cops individual

Answer 16

The simultaneous loss of airway patency and elastic recoil is problematic in COPD. Airways are
connected to surrounding lung tissue and in healthy individuals, these connections are what
essentially keeps the airways open. During inspiration these airways are expanding due to
surrounding pressure and compressed slightly during expiration. In COPD however, the compression
during expiration causes them to compress too much and lose patency. The simultaneous loss of
elastic recoil means the lungs must be compressed harder during expiration. This increases the
pressure on airways further causing further obstruction. The net effect is ventilation is greatly
reduced.

Question 17

What is the damage caused by copd called

Answer 17

The damage COPD causes to the airways is generally termed chronic bronchitis whilst the damaged
caused to the lungs is generally termed emphysema.

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Question 18

What does chronic bronchitis cause

Answer 18

Chronic bronchitis causes airway obstruction

that decreases FEV1 and the FEV1/FVC ratio and causes wheezing.

Question 19

What does the obstruction of airways in chronic bronchitis lead to - and treatment

Answer 19

The obstruction of airways leads to

alveolar hypoxia, which is treated by oxygen therapy, as well carbon dioxide build-up in the body.

Question 20

What happens to mucous in chronic bronchitis

Answer 20

Chronic bronchitis also causes mucous hypersecretion that leads to productive cough and copious
sputum. The overall effect of airway obstruction and mucous hypersecretion is decreased ventilation.

Question 21

Key features of emphysema

Answer 21

Emphysema is characteristic with decreased elastic recoil of the lungs that increases lung compliance
and increases work involved during breathing. Emphysema can also cause destruction of the capillary
bed that decreases perfusion.

Question 22

What is alveolar detachment in emphysema and what does this cause

Answer 22

Alveolar detachment also occurs that traps air in the lungs on upon
expiration. This causes increased end expiratory volume and residual volume as well as decreased
vital capacity.

Question 23

What is the overall effect of emphysema

Answer 23

The overall effect of emphysema is increased expiratory effort/ COPD as a whole leads
to hypoxaemia and hypercapnia.

Question 24

How does exacerbations occur due to COPD

Answer 24

Although there is an overall accelerating decline in respiratory function during COPD, there are
temporary exacerbations caused by bacterial infections that drastically reduce lung function.

Question 25

WHAT MECHANISM does the lungs use to match perfusion with ventilation

Answer 25

One of the mechanisms that

healthy lungs use to match perfusion with ventilation is through hypoxic vasoconstriction.

Question 26

What is hypoxia vasoconstriction

Answer 26

This is a
regulatory reflex that in patients suffering from COPD, causes large scale pulmonary vasoconstriction
that greatly increases pulmonary vascular resistance.

Question 27

What happens when pulmonary vascular resistance is increased

Answer 27

This increases right ventricular afterload due to
pulmonary hypertension. This leads to right ventricular hypertrophy as the heart works harder and
this can eventually lead to heart failure.

Question 28

What is right sided heart failure associated with

Answer 28

Right sided heart failure is associated with fatigue, increased
peripheral venous pressure, ascites (accumulation of protein-containing fluid in the abdomen caused
by high venous pressure), enlarged liver and spleen, distended jugular veins (increased venous
pressure), anorexia and complaints of GI distress, weight gain and dependant oedema. Alveolar
hypoxia also leads to hypoxaemia, hypercapnia and acidaemia that decreases the body’s ability to do
exercise and increases fatigue. COPD decreases quality of life overall.

Question 29

What is an effective method of slowing decline in respiratory of copd patients

Answer 29

Smoking cessation is the most effective method of slowing the rate of decline of the respiratory
system in patients suffering from COPD. This however does not stop the decline as lung function is
not regenerated.

Question 30

How can the pathophysiology of copd be observed

Answer 30

The pathophysiology of COPD can be modelled in animals (e.g. mice) for research purposes. Mice are
first exposed to tobacco smoke (e.g. 2 times a day for 5 days a week for a year). At the end of this
time period, lung function is measured as well as airway resistance and lung compliance. The animals
can also be culled and bronchoalveolar and lung tissue samples can be taken. In these samples, the
cytokine and leukocyte levels can be measured. The histological changes can also be observed.
Histological changes can also be observed through bronchoalveolar lavage (BAL) where the animal is
injected with saline in its lungs and then removed via a syringe that will contain sample cells for
analysis. Resistance-compliance testing can be carried out to evaluate functional changes to the
airway. Here, the animal is intubated via its trachea and attached to a pressure transducer to detect
changes in airflow and pressure. An oesophageal tube is then used to measure intrapleural pressure
with a vacuum pup used to produce pressure changes moving air into and out of the lungs.

Question 31

What is asthma

Answer 31

Asthma is a chronic, inflammatory and obstructive disease of the airways. The disease has an
inflammatory component that is initiated by a stimulus.

Question 32

What in asthma causes airway dysfunction

Answer 32

The inflammatory response leads on to the

airway dysfunction component of asthma.

Question 33

What causes inflammation in asthma

Answer 33

Inflammation is usually stimulated by allergic inhalation of
pollen or house dust mite (HDM), or by exercise and cold air exposure. It triggers the immune system
response that causes airway inflammation.

Question 34

What are symptoms of asthma

Answer 34

The resulting airway dysfunction causes symptoms like
wheezing, coughing and dyspnoea.

Asthma can have different causes and cause different
pathological changes between different patients afflicted with this disease. This lecture addresses
the most predominant subtype; allergic asthma.

Question 35

What is the aetiology of asthma

Answer 35

The aetiology involves genetic and environmental factors.

Question 36

How is asthma genetically linked

Answer 36

Genetically, there are genes that increase
susceptibility to asthma including ADAM33, GSTP1- and FcεRI-β, and there are asthma protective
genes that include GSPT1+. There is also clear heritability of this disease however, it is not purely a
genetic disease.

Question 37

What are other factors that can causes asthma

Answer 37

Other factors involved include immunological exposure and lifestyle. In terms of
immunological development, this is the type of infection the immune system is exposed to during
development.

Question 38

Where is asthma more predominant

Answer 38

Asthma is more predominant in infants with respiratory virus infection, new-borns
born by caesarean delivery and individuals who employ modern hygiene techniques. Asthma is less
predominant in individuals who are exposed to helminth infections, have healthy microbiota and
new-borns delivered by vaginal delivery. Lifestyle choices can also increase or decrease the likelihood
of development of asthma. Urban dwellings, pollution exposure, poor diet and obesity all increase
the likelihood of asthma whilst rural dwellings, lower-pollution environments and healthy diet all
decrease the likelihood of asthma development.

Question 39

What happens when the airways do not function correctly

Answer 39

If the airways do not function correctly, ventilation is hampered leading to problems like
hypoxaemia and hypercapnia.

Question 40

What is airflow through the airways proportional to

Answer 40

Airflow through airways is proportional to the level of airway
resistance that is mainly governed by the radius of the airway lumen and the patency of airflow to a
lesser extent.

Question 41

What is the main factor that determines the diameter of the airways

Answer 41

The predominant factor determining the diameter of airway lumens are the smooth
muscle surrounding the airways that decrease diameter when contracted and increase diameter
when relaxed.

Question 42

What happens in asthma to smooth muscle

Answer 42

In asthma particularly, the contraction of smooth muscle around the airway is what
causes asthma symptoms.

Question 43

What are the pathological features of asthma

Answer 43

Other pathological features in the airway further exacerbate the problem
including hypersecretion of mucus (clogs airways narrowing the airways further) and swelling of the
airways (oedema). Sensory neurons in airways are also irritated causing coughing. The overall effect
is a decrease in lumen size that increases airway resistance and therefore decreases airflow. This
leads to the general symptoms associated with asthma.

Question 44

What is the effect of turbulent air flow in the lungs on asthma

Answer 44

Airflow in the airways can also be
exacerbated by obstruction that causes turbulent airflow. This decreases the speed of airflow and
produces a noise characteristic with wheezing.

Question 45

What are the steps involved in the response to allergens

Answer 45

There are two steps involved in response to allergens. Upon initial exposure to the allergen, allergen
sensitization occurs where the allergen (e.g. HDM or pollen) is encountered and processed by the
adaptive immune system without it producing a response. This generates antibodies that can be
triggered upon subsequent exposure. Subsequent exposures are what causes the allergic response as
the antibodies recognise and bind to the allergen causing a series of downstream responses
including immune cell activation and inflammation that produce the allergic reaction symptoms.

Question 46

Outline the initial part of sensitization

Answer 46

The initial part of sensitisation involves the individual encountering the allergen. This is inhaled to
enter airway tissue where it is lodged and gains access to some of the tissue within the airway.
Healthy individuals would not recognise this allergen as dangerous and therefore would not trigger
their immune response. In individuals suffering from asthma, the allergen does trigger the immune
response. Antigen-presenting cells (most likely to be dendritic cells) encounter this allergen, engulf
and digests the allergen before presenting part of the allergen (antigen) on its surface to be
recognised by naïve helper T cells. These T cells have particular T cell receptors that recognise that
particular antigen and these bind to the antigen. This interaction activates the naïve helper T cells
(CD4+ T cells) to mature into Th2 cells. These Th2 cells coordinate the immune response through
antibody production as well as the activation and proliferation of other immune cells. One example
of the response coordinated is that Th2 cells secrete IL-5 that interact with receptors in eosinophils to
activate them, cause them to proliferate, and direct migration to different structures in the airways.
Th2 also interact with B cells displaying the antigen of the allergen. This interacting is direct and also
through IL-4 with the result being the maturation and proliferation of these B cells. The maturation
of the B cells allows them to produce antibodies with IgE being produced in this case. IgE antibodies
bind to mast cells (granulocytes) at IgE receptors with the antigen sites on IgE antibodies exposed to
enable them to interact with the allergen. The interacting of IgE with mast cells causes them to
degranulate releasing toxic material into the airways. This is a normal response to parasitic infections
however, this response is also triggered in allergic reaction. The result of sensitisation is the
production of these IgE antibodies that are bound to mast cells and recognise the allergen making
the immune system primed for further exposures to that particular allergen.

Question 47

What happens when the immune system encounters the allergen again

Answer 47

When the immune system does encounter this allergen again through IgE antibodies, degranulation
and airway inflammation occurs. The granules in the mast cells contain inflammatory mediators that
spread around the airways including prostaglandins, leukotrienes and chemokines. These different
mediators bind to specific receptors on smooth muscle that generates the symptoms. These
symptoms include the contraction of smooth muscle, the activation of goblet cells to hyper secrete
mucous and the activation of sensory neurons to induce coughing. The inflammatory mediators also
attract other cells to the airways including more Th2 cells and eosinophils.

Question 48

What do eosinophils do in the case of asthma

Answer 48

The eosinophils take
several hours to migrate to the airways where they release further
inflammatory mediators as well as reactive oxygen species (e.g.
ROS) that are usually used to kill pathogen. These radicals will
cause further symptoms causing a second round of them (not in all
asthma attacks) several hours after the first. The initial exposure
causes an immediate worsening in airway function (FEV1 drops
rapidly by around 25%) with recovery following this. The late
response is more gradual and takes place over a number of hours
(worsened by the fact the airways are already in an inflamed state;
hypersensitivity).

Question 49

How can the changes to asthma on respiratory function be quantified

Answer 49

The changes asthma has on respiratory function can be quantified using spirometry. Since asthma is
an obstructive airway disease, it causes a decrease in FEV1 without changing FVC. The result is the
FEV1/FVC ratio also decreases (under 70%).

Question 50

What is permanent damage of airways overtime called

Answer 50

The response to the allergen discussed above concerns a single asthma attack. Asthma is however a
chronic disease that permanently damages airway structure over time. This permanent irreversible
damage is known as airway remodelling.

Question 51

What happens when the smooth muscle is constantly contracted over time

Answer 51

The constant working of the airway smooth muscle causes
hypertrophy where it grows in size and it is more likely to contract harder when contracted. There is
also an increase in the number of goblet cells and activated mucous glands producing more mucous.

Question 52

What increases when an asthma attack occurs

Answer 52

Immune cell proliferation and infiltration will also increase within the airways. The epithelium itself is
disrupted and is unable to keep out antigens from airway tissue. Extracellular matrix deposition also
increases as well as fibrosis. The basement membrane also thickens.

Question 53

What are the pharmacological treatments for asthma

Answer 53

There are a number of different pharmacological treatments of asthma that impact some of the
different pathophysiological symptoms in different ways (the different drugs to be discussed in detail
next lecture). The drugs that are most effective are beta-2 agonists (salbutamol) and corticosteroids
as they work on symptoms that are shared between most asthma patients. The type of asthma
discussed above does not encompass all types of asthma. Some patients do not have Th2 cells, mast
cells, eosinophils or granulocytes involved in their allergic reactions but still experience the
symptoms. One of the main areas of current medical research is to discover new underlying causes
of asthma.