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Samenvatting van alle colleges van MG endocrine system, digestive and respiratory tract
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MG: Endocrine system and digestive and respiratory tractLecture 1 Tractus respiratorius
31/08/2020 Reinoud Gosens
The respiratory tract starts in the nose and mouth cavity (at the nostrils). The function is to humidify
air and to facilitate the exchange of air at the blood-air interface in the alveoli. Here, oxygen is taken
up and CO2 is released. The anatomical structure of the different components of the airways vary. In
the nose there are the cavities (conducting function). The trachea (still extra-pulmonary) also mainly
has a conducting function. Then going into the thoracic cavity, the bronchi and bronchioles still have
conducting functions. Then in the alveoli the gas exchange takes place.
So the airways are anatomically and functionally distinct from the alveoli. The airways have a
conducting function. The gas exchange in the airways is really limited. There are around 23
generations (bifurcations/splits) of airways. The first generation is the trachea and then the mouth
and nasal cavity. The second are the main stem bronchi that split into lung lobes and then you get
further splits to in the end the alveolar ducts and sacs.
When comparing the large to the small airways there are a couple
anatomical differences. The large airways have airway smooth
muscle which is connected between cartilage segments which are U
shaped. The smooth muscle narrows the lumen of the large airways
by constricting and therefore allowing the cartilage to shrink. The
small airways cartilage is not present anymore as a U shaped ring
but rather as loose fragments. In between the islands are
fragments of smooth muscle that contract the smaller airways
resulting in a similar reduction in lumen size.
In general, airways are only referred to as bronchi or bronchiole, if there is smooth muscle present.
So in the alveoli the smooth muscle is absent.
Upper airways: from the nose down to the trachea and the
main bronchi. Epithelium covers the airways. The epithelium
mostly consists of ciliated cells as well as mucous producing
goblet cells. In addition to this layer of epithelium there are
glands present in the upper airway regions. These glands
produce mucous mostly in response to neuronal stimulation
by the parasympathetic nervous system. So nerves help to
promote mucous secretion into the lumen both in the nose
and upper airways. A defining feature of the upper airways
also is the presence of cartilage.
SMG = submucosal gland
Small airways: the cartilage is still there but now as islands.
The presence of glands is still there but much reduced. Also
the composition of the airway epithelium is different → there
is less involvement of the goblet cells. For the rest, the
morphology is similar to that of the upper airways.
1
,So the further you go down the more you lose the density of glands and of mucous producing goblet
cells. So in general mucous production is mainly a feature of the upper airways. This makes sense
because at some point the small airways are so small that if excessive mucous production would take
place it would obstruct the entire bronchiole. This will prevent you from breathing.
Distal lung (alveoli): gas exchange takes place here. The pulmonary
circulation is in close contact with the alveoli. There are alveolar epithelial
cells which cover the alveoli. Surrounding that are endothelial cells that make
up the pulmonary circulations (CO2 is exchanged for oxygen here).
There is a large degree of epithelial cell heterogeneity in the respiratory tract. So the type and
distribution of the epithelial cell subtypes that is present in the large airways is really different from
that in the smaller airways and even further different in the alveolar zone. In the large and small
airways the epithelial cells that are present are primarily:
1. Ciliated cells → express cilia and play a role in the clearance of the lungs from mucous. These
are more present in the large airways. The cilia all moves in the same direction, so there is
synchronized beating. They are moving mucous away from the lung into the oesophagus. If
this is not synchronised you have the disease primary ciliary dyskinesia.
2. Goblet cells → mucous producing cells. These are more present in the large airways. Mucosa
helps the airways to protect against particles or bacteria that may end up in the airways
when inhaled.
3. Basal cells → at the bottom of the epithelial cell layer. They function as progenitors such that
when there is damage, the basal cells will proliferate and will generate new epithelial cells.
So they repair the airways.
4. Club cells → secretory cell which produces a more fluid secretion than the goblet cell. These
are more present in the small airways.
Mucociliairy transport is regulated by the goblet cells in concerted action with the ciliated cells. So
the goblet cells produce the mucous and the ciliated cells produce water and electrolytes and ciliary
beating. All these things are necessary for appropriate mucociliairy transport, the cleaning system of
the lung. So the synchronized ciliary beating transports the mucous that is laying on top of it towards
the oesophagus. Goblet cells produce the muc proteins. But in addition, to achieve the right
consistency, it is very important that water and electrolytes are also secreted into the lumen. Sodium
and chloride are pumped across the membrane into the lumen and then water will follow the
chloride via passive osmosis. This liquifies the mucous. The protein that is involved in the
transmembrane transport of chloride across the plasma membrane in the ciliated cells is CFTR (cystic
fibrosis transmembrane conductance regulator). If this channel does not function, chloride will not
transport and water will not follow. This will result in very thick mucous which makes is hard to
adequately clear the mucous from the lungs → cystic fibrosis.
2
, Smoking also has an impact on the ciliary
clearance. Smoking causes destruction of
the cilia. So people who smoke have shorter
and less dense cilia, and as a result the
mucociliairy clearance is often impaired in
smokers. This leads to cough.
In the alveoli, all of the previously mentioned epithelial cell types are
not present. Here there are the type I cell and the type II cell. The type I
cell makes up 95% of the surface of the alveoli. This is a flat, thin cell
that facilitates gas exchange with neighbouring pulmonary
microcirculation. So this cell has a structural support and functions in
O2/CO2 transport. The type II cell is bigger and has two important
functions. It produces surfactant which lowers the surface tension. This
is to ensure that the lung will not collapse upon exhalation and is able to
expand again upon inhalation. In addition to this function, when type I
cells would be damaged type II cells are needed to replace the damaged
type I cells. So they are progenitor cells for type I cells. Surfactant is produces
relatively late during lung development, so only at around week 28. As a result,
prematurely born neonates require surfactant support in combination with
mechanical ventilation in order to support gas exchange.
Important: know function of mucociliairy transport and the role of goblet and ciliated cells. And know
the function of the type I and II cell.
Asthma is a heterogeneous disease (not every asthmatic person has the same underlying mechanism
of disease), usually characterized by chronic airway inflammation. It is defined by the history of
respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over
time and in intensity, together with variable expiratory airflow limitation. Asthma symptoms are
usually seasonal. They may be related to pollen or house dust mite peaks.
Around 70% of all asthma patients have allergic asthma. This has created a lot of focus on allergic
asthma in the development of drugs. But there also is a large group of patients (30%) with non-
allergic asthma. This type of asthma is induced by things as cold air, exercise, air pollution.
Allergy & asthma are the two most common chronic diseases in the western world. The prevalence
has substantially increased over time. This may be because of increased hygiene → less challenge of
the immune system so the immune system will respond to harmless elements. Asthma has a
prevalence of 4-6% in adults and 8-15% in children. The prevalence varies per country. In particular
Australia and New Zealand have a much higher prevalence.
Another important feature in asthma is the gender paradox. This is not really well understood.
Asthma is more prevalent in children than in adults. In the group of children, more men have asthma
than women. In the group of adults, more women have asthma than men. There are several
explanations for why this may be. With respect to the adult situation it has been suggested that the
change in hormones may contribute to an increase in asthma in woman. During puberty there is lung
growth, which is bigger for boys than for girls, which may increase the prevalence of asthma in
women. But this does not explain why boys have more asthma than girls in childhood.
3
, Airway hyperresponsiveness is one of the main diagnostic features that is used by the GP to
diagnose asthma. It is an exaggerated response by inhaled bronchoconstrictors. This is measured as a
change in so-called FEV1. This is the Forced Expiratory Volume in 1 second. This is the amount of air
that you can exhale in 1 second upon full inspiration. When people receive a bronchoconstrictor, the
FEV1 will drop because of airflow obstruction by narrowing. In normal individuals, the drop may not
even be 20% even after a very high dose. However in
patients who have asthma, the drop in lung function (drop
in FEV1) will already start at much lower doses. If you did
not reach a 20% drop at a dose of 32 mg/ml, you are
considered healthy. Also, in the normal patient you see a
plateau at the end of the curve. In asthmatic patients, the
curve will not reach a plateau but it will keep increasing. So
giving really high doses to asthmatic patients can be life
threatening. This is also the reason why asthmatic patient
end up in emergency rooms → because of acute asthma
attacks.
Airway hyperresponsiveness has its origin in a number of features which are very specific for asthma.
There is a genetic predisposition that can make you more suspected to asthma. But this is usually not
sufficient to also actually develop asthma. For this you need subsequent exposure to environmental
triggers (allergens, viruses or occupational sensitizers). Then there is transient airway
hyperresponsiveness which is mainly driven by inflammation. The inflammation is usually the result
of the environmental triggers. In patients who have chronic asthma disease, a repeated exposure to
the triggers (and therefore a persistent presence of inflammation) may result in airway remodelling.
The structural changes are basically like a fibrotic process associated with airway wall thickening
leading to permanent airway hyperresponsiveness.
Most people with severe asthma have a permanent
component of airway hyperresponsiveness. And on
top of that the transient component which is
dependent on the degree of airway inflammation
present at different times. This has important
consequences, because drugs that function to
inhibit the inflammatory response can treat the
transient component but usually do very little to
the permanent response. So severe asthma is
something that stays with you for a long period in
life despite of treatment. The more severe the
asthma is, the less likely you will grow out of it.
Inflammatory response:
In allergic asthma, the allergen is picked up by an antigen presenting cell (dendritic cell or
macrophage). The allergen is then presented in the lymph node to naïve T cells that will mature into
CD4+ T cells which can differentiate into Th2 cells. Th2 cells produce IL-4 which activates B cells to
produce IgE. Th2 will also produce IL-5 and IL-13 which will activate eosinophils. The IgE antibodies
are loaded upon mast cells. So the mast cells are covered with IgE antibodies that are against a
certain antigen to which the patient has developed an allergy. Upon encounter of that antigen, the
mast cells will release histamine and proteases that will lead to bronchoconstriction. Eosinophils will
typically release proteases, cytokines, etc. This will all contribute to mucous hyper secretion and
oedema. This will all lead to airflow limitation. So in an allergic asthma patients there is an antibody
response that drives the reaction.
4
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