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Samenvatting - Medicines Group: Endocrine System and digestive and respiratory tract (WBFA033-05)
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MG: Endocrine System and Digestive and Respiratory TractLecture 1: Respiratory tract
The respiratory tract starts with the mouth cavity and nose and not the lung.
- Humidify air
- Facilitate the exchange of air at the blood-air interface in the alveoli (oxygen is taken
up and CO2 is released
We have no smooth muscles in the nose, but we have cavities with a conducting function.
Anatomy: 1) the internal ostium of the nose, 2) nasal cavities, 3) larynx, 4) trachea, 5)
intrapulmonary bronchus, 6) bronchioles.
The airways are anatomically and functionally distinct from the alveoli.
Airways: conducting function, gas exchange is limited
Large airways have airway smooth muscle which
is connected between cartilage segments which are
shaped like a U (hoefijzer). Contraction of the smooth
muscle causes the cartilage to shrink which will lead
to narrowing the lumen of the large airways.
Small airways hereby the cartilage is present as
loose fragments and between these fragments there
is smooth muscle. Also when these smooth muscles
will contract there is a narrowing of the lumen, but then of the small airways.
Intrapulmonary bronchi (small airways): there is more muscle than cartilage. Therefore there
is more bronchoconstriction.
Upper respiratory tract
Defence mechanism in upper airways
- Double layer of epithelium cells which mainly
consists of ciliated cells as well as goblet cells
that are responsible for mucous production.
- SMG = submucosal gland produce
mucous mostly in response to neural stimulation
by the parasympathetic nervous system.
- Presence of cartilage
- When you go more down into the body, there
will be less defence with mucus because if you
have small airways you don’t want to much
mucus that will block the air and cause
obstruction. So mostly mucus around the nose,
mouth and upper airways. Also the density of
glands is reduced lower in body.
Lower respiratory airways (small airways)
- Still cartilage but now in presence of cartilage
- Glands are still present but reduced
- Less involvement of goblet cells
Anatomy: distal lung (alveoli) GAS EXCHANGE
- Different structures
- Gas exchange unit must be very thin
- 2 cell types:
1
, Type 1 are flat thin cells: responsible for gas exchange with neighbouring pulmonary
microcirculation. Makes up 95% of the surface of the alveoli.
Type 2 is more bigger and more round: moisturizes airways, antibacterial properties
and produce surfactant which lowers the surface tension (so that the airways will not
stick together and will collapse). Surfactant is developing around 28 weeks in baby’s.
Lungs are one of the last organs that mature in babys, therefore surfactant is really
important for the survival of babys. Babys that are premature are given surfactant so
that the lung does not collapse, because they don’t have that capacity themselves.
When Type 1 cells are damaged: these cells will be replaced by Type 2 cells. Type 2
cells are progenitor cells for type 1 cells.
Airway epithelial cell heterogeneity
Ciliated cell: mucociliary transport (clearance of lungs from mucous) small motor units
that move mucus layer to oesophagus. More present in larger airways. If this moving of
mucous is not synchronised you have primary ciliary dyskinesia. Smoke you cough up the
mucus because ciliated cells are damaged.
Globet cell/ Mucous cell: mucus producing cells more present in larger airways. Protects
against bacteria or particles that are accidentally inhaled.
Basal cell: airway progenitor make mucus drops, need to be diluted otherwise you get dry
sticky mucus. They repair the airways so when there is damage, they will generate new
epithelial cells.
Club cell: secretory proteins, small airway progenitor larger in number when you go from
nose to distal lung. Produces a more fluid secretion than the goblet cells.
Mucociliary transport (important)
Diseases of respiratory tract
- Asthma
- Allergic Rhinitis
- Cough
- COPD
- Pulmonary fibrosis
- Cystic fibrosis
Asthma
Asthma is a heterogeneous 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.
- it can be seasonal
Majority (70%) of all asthma patients have allergic asthma. Not always the case and these
other part of 30% is harder to treat.
Prevalence: allergies & asthma most common chronic disease, but less severe than others like
diabetes, cancer, stroke. Though there are 250000 fatal cases but that has all to do with not
have access to the drugs. There is a rise in prevalence, particular in children. Theory of this is
high gene hypothesis: we are less exposed to things
because we live in cleaner environments and therefore
our immune system is also responding to harmless
elements.
Gender paradox: children has more asthma (presence
is twice as much) than adults. Children can grow out of
it.
2
, children: more common in males
adults: more common in females (can be
explained by change in hormones (estrogeen) , females have a better immune
system)
During puberty there is lung growth, which is bigger for boys than for girls, which may
increase presence of asthma in woman (adult).
Airway hyperresponsiveness in asthma is used
as a diagnostic. This is measured as a change in so-
called FEV1.
- FEV1: forced expiratory volume in 1 second (%
change). This is the amount of air that you can
exhale in 1 second upon full inspiration.
When receiving a bronchoconstrictor: the
FEV1 will drop because of airflow obstruction
by narrowing
the higher this number the more
obstructive you become. Healthy person will
never have a 20% drop. So if you did not
reach a drop of 20% at a dose of 32 mg/ml, you are considered to be healthy.
- Reversibility is also used as a diagnostic
In a normal patient you see a plateau at the end of the curve. Asthma patients are more
sensitive, so a by a lower concentration there is already a high FEV1. By asthmatic patient
(severe cases) there is no plateau, the curve keeps increasing. Asthmatic patient can react to
stimuli were a normal person never will react to (cold air, parfums, smoke).
Lower PC20 more severe the asthma. (point were lung capacity drops to 20%)
- Starts with inducers/inciters (transient) allergens, virus, exercise, cold air variable,
usually compared with inflammation.
- Structural changes (permanent) more muscle, more mucus
- Genetic predisposition
interaction of environmental things and your genes
Inflammation (allergic asthma)
Allergen is picked up by an antigen presenting cell (dendritic cell or macrophage). The
allergen is then presented to naïve t cells that can mature into CD4 T cells which can
differentiate to th2 cells. These Th2 cells produce:
- IL-4 which activates B cells to produce IgE (mast cells are covered with these IgE
antibodies: when antigen meets this antibody histamine and protease release which causes
bronchoconstriction)
- IL-5 and IL-13 which activates eosinophils (release protease and cytokines which will
contribute to mucous hyper secretion and oedema)
Allergic to grass. At a time in your life you are getting exposed with grass. Allergen is
presented by antigen. T cel can bind (CD4)
there is memory, you don’t have to do this mechanism all over all the time
this is you first phase (sensitization)
Second exposure will cause your mast cells to secrete histamine.
In non-allergic mast-cell response will be triggered. Thus release of histamine from mast
cells doesn’t always have to be triggered by an allergen, in this case the mast cell granules
are triggered by for example cold air. mast cells and eosinophils are still involved.
3
, Another kind of response that is mostly important in patient with non-allergic asthma involves
alarmins. The particle that is exposed to the patient causes micro injuries in the airway
epithelium. These injuries causes the epithelium to secrete cytokines that are also called
alarmins: IL-33, IL-25 and TSLP. These alarmins will activate the immune system and will
activate innate lymphoid cell type 2 (ILC2) which have similar functions to the Th2 cell, like
producing IL-5, IL-4 and IL-13. This means that the end response is really similar (same
symptoms) but the origin of the response is different.
- Th2 important antigen in asthmas
- Alarmins important role in non-allergic asthma
Glucocorticosteroids is used in asthma treatment to repress the inflammatory response.
They inhibit cytokine production by Th2 cells. Antibodies can now also be used against these
cytokines to support the anti-inflammatory treatment of asthma
Mucous hypersecretion (persistent variations in the number of goblet cells), fibrosis of the
airway wall, and a rise in muscle mass are all characteristics of asthma. The lumen will
become constricted and hypersensitive due to all of these characteristics. Remodelling cannot
yet be treated. Only inflammation can be managed.
Airway structure (remodelling)
Inflammation and damage to the airway wall are both closely connected to the mechanisms
that cause remodelling. Exposure to environmental irritants repeatedly will result in repeated
injuries. This will trigger the inflammatory response and an attempt to airway repair. Once the
cycle of airway healing is over, everything should return to normal. However, if the airway is
not fully healed or has already sustained damage again during the healing cycle, this might
trigger the production of growth factors (TGF) and proteases, which will result in
remodelling.
There have been no effective attempts to suppress the growth factors and
therefore remodelling . Because normal wound healing also depends on the same
growth factors, which is harmful.
Smaller lumen are for example caused by: more muscle, fibrosis
How are remodelling and inflammation linked?
Inflammation causes growth factors that causes fibroblasts
In allergic asthma there is a early and a late response
Early: Late:
- bronchoconstriction - inflammatory response,
- mast cell dependent oedema, mucus
- igE- dependent - t cell dependent, associated
smooth muscle/ with accumulation of
bronchospasm eosinophils
b agonist sensitive -IgE-dependent
inflammation
corticosteroid sensitive
- Early response: primarily driven by mast cells which will lead to bronchoconstriction
- Late response: causes an inflammatory
response, driven by T cells and eosinophils. This
can cause oedema and mucous hypersecretion
Both responses are IgE dependent
The late response drop can be a larger drop than the
early response (more intens). This can be very
problematic and it is harder to treat acutely:
4
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