Medicine groups: endocrine system ad digestive and respiratory tract
Lecture 1: Respiratory tract part 1
04/07/2023, Gosens
Human airways
- 23 bifurcations (vertakkingen) = 2^23 airways.
• First generation nose/pharynx/larynx and trachea.
- Function humidify air and conduct air to the alveoli to facilitate gas exchange.
- Bronchi airways that still have cartilage.
Anatomy: upper airways
- Smooth muscle which is connected between cartilage segments with a horseshoe shape.
Smooth muscles can constrict to shrink the cartilage and narrow the airways.
- Double layer of epithelial cells consists of basal cells. they can differentiate in goblet
cells (produce mucus) or mucous producing cells.
- Glands present that produce mucous (mostly in response to parasympathetic NS) make
thicker mucous than goblet cells more in the nose and mouth and less in the airways.
Anatomy: small airways
- Cartilage is present as small segments. In between are fragments of smooth muscle that can
contract to narrow the airways.
- Less glands than the upper airways.
- Less goblet cells.
- More club cells secretion that is more watery and more protective. Against bacteria.
Anatomy: distal lung (alveoli)
- Type I cells 95% of surface, support gas exchange between O and CO 2 (flat and long).
- Type II cells produce surfactant that is anti-bacterial/fungi and prevent collapse of the
airsack by reducing surface tension, also can become type I cell when those are damaged
(more round).
Airway epithelial cells
- Ciliated cell: mucocialairy transport. Clearance mechanism of the lung.
• More present in the large airways.
• Have small motors that beat so the mucus is moved to the oesophagus and then
stomach.
- Goblet cell (in epithelial)/mucous cell (in gland) mucous production.
• More present in large airways.
• Produced goblet cell drops need to be diluted to function well.
- Basal cell stem cells, airway progenitors, repair.
• At the bottom of epithelial layer.
- Club cell secretory proteins, more fluid secretion than goblet cell
• More present in small airways.
Mucocialairy transport
Goblet cell produces mucous ciliated cell produced water and electrolytes and synchronized ciliary
beating mucous goes to oesophagus. Sodium and chloride are pumped into the airways across
the membrane and water will follow dilutes the mucous. CFTR (cystic fibrosis transmembrane
conductance regulator) pumps chloride across the membrane. If this does not function well thick
mucous hard to clear mucous from lungs cystic fibrosis.
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,Diseases of the respiratory tract Asthma, allergic rhinitis, cough, COPD, pulmonary fibrosis, cystic
fibrosis.
Asthma
- Definition heterogenous disease, usually characterized by chronic airway inflammation.
Symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over
time and in intensity, together with variable expiratory airflow limitation.
- Symptoms are a lot of the time seasonal. Can be related to pollen or house dust mite peaks.
- 70% of asthma is associated to allergies allergic asthma. 30% is non-allergic asthma
induced by cold air, exercise, air pollution etc most difficult to treat.
- In the last years there is an increase in the prevalence of allergies and asthma. This could be
due to the hygiene hypothesis grow up in clean environment less challenge to immune
system heavy reaction against harmless things.
- Asthma gender paradox in childhood boys have more asthma than girls. In adulthood
females have more asthma than men. May be due to change in hormones.
Airway hyperresponsiveness
- One of the main diagnostic features to diagnose asthma.
- FEV1 forced expiratory volume in 1 second. Amount of
air you can blow out in one second after full inspiration.
- Bronchoconstrictors will be given to a person and FEV1 will
be tested before and after.
• Healthy patients high dose will not even give a
20% drop in FEV1. Also plateau at end of curve.
• Asthma patients low dose already gives drop in
FEV1.
- PC20: the concentration when your lung function is
lowered by 20% the striped line.
Asthma can be due to genetic predisposition but usually this is not enough to develop asthma.
Transient airway hyperresponsiveness mainly driven by inflammation. Subsequent expose to
allergens, viruses or occupational sensitizers.
Permanent airway hyperresponsiveness structural changes (remodelling) that lead to e.g. more
mucous.
Inflammation allergic asthma
- Inhale antigen APC presents antigen to T cells activation of Th2 cells
• activation of B cells IgE antibodies.
• produce IL-4 activates B cells to produce IgE.
• Produce IL-5 and IL-13 activate eosinophils.
• Produce IL-13 mucous production.
- IgE will be loaded onto mast cells release histamine bronchoconstriction.
- Eosinophils will release proteases, cytokines (active Th2 again) etc.
- All leads to mucous hyper secretion and oedema airway limitation.
- Eosinophils typically in the second phase of the allergic response path.
Inflammation non-allergic asthma
- Not regulated by the adaptive immune system (antibodies).
- Exposure to pollutant / microbed glycolipids etc. microinjuries in epithelium epithelium
secretes alarmin cytokines (IL-33, IL-25 and TSLP) activate ILC2 (innate lymphoid cell type
2) similar function to Th2 cell.
- Response is quite the same but origin is different.
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,Remodelling
Repeated exposure to environmental insults causes repeated injuries inflammatory response
triggered and attempt to airway repair. If airway repair not completed or re-injured during repair
activate production of growth factors (TGB-beta) and proteases remodelling (fibrosis).
Early and late response
- Early response
• Driven by mast cells degranulated histamine bronchoconstriction.
• Bronchoconstriction.
• IgE dependent.
- Late response
• Driven by second wave of eosinophils and T cells.
• Inflammatory response, oedema, mucus.
• IgE dependent.
• More difficult to treat because it if driven by inflammation and thus not responsive
to acute bronchodilators.
Bronchoconstriction
- Mast cells can secrete prestored histamine, cytokines and lipid mediators. This will be
released when there is an increase in intracellular calcium in the mast cell. Calcium comes in
via extracellular sources and via IP3 mediated release from the ER. PKA is also required to
release histamine.
- Parasympathetic nervous system are attached to the SMC of the lung with an Ach receptor
that can lead to SMC contraction.
- Reflex system activation of the cholinergic pathway. An afferent reflex nerve (from the
CNS to the lung SMC) is activated by a sensory nerve (from the lung SMC to the CNS). Also
leads to mucous production.
Muscarinic receptors in the lung
- M1 connecting pre-ganglionic nerves to post-ganglionic nerves.
• Blockage is difficult because drugs needs to pas BBB.
- M2 function in negative feedback on Ach release. Located on SMC.
• In asthma dysfunction. eosinophils secrete MBP (major basic protein) that is a M2
antagonist (block).
• Avoid blocking!! Block more Ach more constriction.
- M3 controls bronchoconstriction. Located on SMC.
• Want to block!!
• Atropine can clock M3.
Neurokinin/tachikins (eNANC) regulation of bronchoconstriction and oedema
- Sensory nerves have two functions cause reflex bronchoconstriction and secrete
neuropeptides (eNANC)
- NKA (neurokinin A) NK2 receptors activation on SMC induces bronchoconstriction.
- SP (substance P) activated NK1 receptors oedema and mucous secretion.
VIP, NO (iNANC) inhibition of bronchoconstriction
- Preventing bronchoconstriction.
- VIP (vasoactive intestinal peptide) on receptors on SMC relaxation.
- NO produced by nerves and epithelial cells promotes cGMP relaxation. activated
granulo cyclase
• NO is made out of L-arginine by eNOS (endothelial) and nNOS (nerve).
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, • In asthma NO is deficient. Because IL-4 and IL-13 increase arginase converts
arginine to other products less arginine available less NO less relaxation.
- NANC = non adrenergic non cholinergic.
- NMB blocks the uptake of L-arginine into the epithelial cells drop in NO.
Adrenergic inhibition of bronchoconstriction
All stimuli that lead to bronchoconstriction activate the Gq pathway. This is targeted by activating the
beta-receptor functional antagonist. This way, relaxation can be induced irrespective to the origin
of the bronchodilation.
Both cAMP (activated by adrenaline on beta-receptor, VIP and PGE) and cGMP (activated by NO) will
lead to relaxation.
Asthma pharmacotherapy
Current therapy is aimed at:
- Bronchoprotection (SMC relaxation)
- Inhibition of inflammation bronchoprotection, inhibition of airway hypersensitivity, and
inhibition of airway remodelling.
Types:
- Bronchodilators B2-adrenergic agonists, theophylline (PDE inhibitors), and
anticholinergics.
- Anti-inflammatories GCS, and antileukotrienes.
- Anti-allergics cromones, anti-IgE.
- Combination therapy.
Bronchodilators
1. B2-agonists
- B2-agonists produces cAMP in SMC which leads to relaxation,and inhibit mast cell and
lymphocyte activation a little bit.
- Overtime adrenaline, isoprenaline (synthetic), orciprenaline (orally stable), terbutaline
(first inhaled, also b2-selective).
• The first 3 were also blocking beta1 receptor cardiovascular side effects.
- Salbutamol and Funoterol short acting (1-2 hours).
- Formoterol and salmeterol long acting (12 hours).
- Side effects tremor, increased heart rate, lower diastolic BP
- Desensitation is possible.
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