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BMS12 - Respiratory System :wind_blowing_face: (Respiration II - Transport…

- - - - This part of the tract is responsible for filtration of large impurities in air via the nose-hairs, moistening and warming of air due to the special type of epithelium.
    - - The larynx is responsible for phonation (vocal sounds) and also houses the epiglottis, a sphincter responsible for allowing air down the trachea or food down the oesophagus.
      - The trachea is a long tube which at a point bifurcates into two primary bronchi which each supply a single lung.
        
        The trachea has a C-shaped rings of cartilage which prevents the collapse of the tube during inspiration and expiration. Contraction of the trachealis muscle, decreases the diameter but increases intrathoracic pressure assisting with forcing air in or out. Trachea histology
        
        The epithelium sits on a lamina propria which is rich in elastin. Beneath the lamina is a thick submucosal layer which contains many mucoserous glands which are usually found between cartilage rings.
      - Primary bronchi further subdivide into secondary bronchi which supply a lobe of the lung.
        
        The bronchi still have a respiratory epithelium with fewer goblet cells. They have plates of cartilage rather than rings. There is a layer of discontinuous muscle separating the lamina from the submucosa.
      - Secondary bronchi then also divide into tertiary bronchi which supply individual bronchopulmonary segments.
        
        Tertiary bronchi also have a respiratory epithelium but it has fewer goblet cells with less pseudostratification. There is a complete layer of smooth muscle beneath the lamina innervated by the PNS to contract and antagonised by the SNS. There is some cartilage but it is very irregular.
      - The smallest processes of the tertiary bronchi are called bronchioles. These then get smaller and divide and which supply alveolar ducts. These ducts then finally, supply air to the alveolar sacs which are the actual site of exchange.
        
        The bronchioles completely lack cartilage and submucosal glands. They have bits of discrete muscle which are responsible for asthma attacks. They also have a respiratory epithelium but the cells are more cuboidal than columnar.
        
        The bronchioles subdivide once more into terminal and respiratory bronchioles.
        
        The terminal bronchioles are the smallest part of the airways. They have a cuboidal ciliated epithelium with Clara cells rather than Goblet cells. Clara cells secrete surfactant, pump chloride ions and maybe stem cells.
        
        Terminal bronchioles terminate in at the respiratory bronchioles. These bronchioles have a single alveolus in their walls. These then continue into alveolar ducts.
        
        The alveolar ducts are made entirely of alveoli supported by collagen and elastin. These terminate in alveolar sacs.
        
        The alveoli are the site of gaseous exchange. They are either lined by Type 1 or Type 2 pneumocytes.
        
        Type 1 pneumocytes are squamous lining cells. These take up a majority of the surface area but less than half of the cellular abundance.
        
        Type 2 pneumocytes secrete surfactant, these are the most abundant cell type but barely cover much surface area.
        
        These cells contain lamellar bodies which secrete phospholipid and cholestrol. These bind to surfactant proteins to form a lipoprotein lattice - this overcomes a surface tension so that the alveolar walls can separate.
        
        The alveolar wall contains the capillary plexus. These share a lamina with the Type 1 pneumocytes - the diffusion distance is 0.2 micrometers.
  - - - The goblet cells produce mucus whilst sub-mucosal glands trap dust.
      - The cilia are able to propel mucus and dirt upward toward the pharynx. This is known as the muco-cillary escalator.
        
        Cilia are motile structures approx ~8nm long, constructed using 20 microtubules (a pair surrounded by nine pairs). It grows out of a basal body which is very similar to a centriole.
      - Sub-mucosal glands also produce a serous secretion which humidifies inspired air.
- - - - The alveolar sacs consist of many alveoli and are supplied by a respiratory bronchiole. The entire sac is highly vascularised, with a dense network of capillaries. The capillaries are fed deoxygenated blood via a branch of the pulmonary artery. Gaseous exchange occurs at this level.
  - - - The amount of air trapped in the conducting zone during breathing is known as anatomical dead space. This volume is approx. 150ml.
      - This means after every breath, 150ml of air will remain in the lung. Therefore, 350ml of every 500ml new breath will ventilate the alveoli alongside with a new 150ml becoming dead space after every inspiration. Alveolar ventilation is minute ventilation minus dead space ventilation. VA
      - Ventilation occurs due to a pressure gradient between atmospheric and alveolar pressures. Air flows from a region of high to low pressure. Flow is measured by the difference of pressure divided by resistance.
        
        Boyle's law explains the pressure differences in the lung and in a nutshell explains that volume and pressure are inversely proportional.
        
        At residual capacity (full expiration), the muscles are relaxed - this leads to a recoil of the lungs but this is balanced by an outward pressure of the chest wall. This generates a negative intrapleural pressure due to the serous fluid between membranes, this helps the alveoli inflate.
        
        Trans-pulmonary pressure is alveolar pressure minus intrapleural pressure.
        
        Inspiration and Expiration rely on changes in pressure and volumes.
        
        Nervous stimulation causes the chest cavity to expand. This causes a fall in intrapleural pressure. This increases transpulmonary pressure causing the volume of the alveoli to increase. Due to Boyle's law, alveolar pressure falls. As alveolar pressure falls below atmospheric, air flows into the lungs. Expiration is the opposite. Pressure relationships
  - - - Elasticity/ability to recoil should not be too high - too much resistance to recoil due to excess collagen, leads to fibrosis and low compliance. Not enough recoil leads to emphysema and a high compliance.
      - Compliance is useful clinically in checking disease states. Abnormally low compliance would suggest fibrotic lung whilst high compliance would show emphysema.
      - Increasing compliance is not good as it causes the lung to collapse and be unable to force air out of the alveoli. This would increase residual volume.
      - Alveoli have an air-fluid interface as they have a thin layer of serous fluid on their inner surface. Water molecules form intermolecular bonds and create a tension which is exerted over the entire fluid.
        
        Tension is fixed so only pressure and radius will vary. The relationship was describe by Laplace, pressure is equal to two multiplied by tension divided by radius. So, clearly - anatomically smaller alveoli will have large pressures.
        
        As alveoli vary in size, pressure differences will be established between adjacent alveoli. Air will flow from these smaller alveoli to larger alveoli with lower pressures.
        
        The smaller alveoli would then collapse and impair exchange. However, surfactant prevents collapse.
        
        Surfactant reduces surface tension. This will reduce the pressure in the smaller alveoli to a point where it is equal with the large alveoli. Therefore, air will not flow. Surfactant increases compliance.
        
        Surfactant
- - - - Partial pressures are a better indicator of how the gas will move from one compartment to another.
      - Concentration of gas dissolved in a liquid is dependent on solubility as well as partial pressure but talking about pressures is more simple. Concentration is solubility multiplied by partial pressure.
  - - - In reality, systemic PO2 is slightly lower than alveolar because:
        
        This is due to the mixing of deoxygenated and oxygenated blood which lowers the partial pressure of oxygen.
        
        There is an 'anatomical right to left' shunt in the bronchial artery which mixes deoxygenated blood with oxygenated blood from the pulmonary vein going to the left atrium.
        
        Also, part of the coronary venous blood drains directly into the oxygenated blood of the left ventricle. This mixing of blood lowers the partial pressure of oxygen.
  - - - Haemoglobin consists of four haem- groups (four protein sub-units). Each haemoglobin can bind to four molecules of oxygen. At the centre of each haem-group is an Fe2+ ion which is able to conjugate with a histidine residue and a molecule of oxygen.
      - When an oxygen binds this is called oxygenation not 'oxidation' because the ferrous ion does not change.
        
        Oxygenation in itself is regulated by haemoglobin's structural co-operativity and environmental factors e.g. PCO2, temperature and the concentration of 2,3 diphosphoglycerate.
        
        The oxygen-haemoglobin dissociation curve is a sigmoid. Co-operativity describes the increase in 'affinity' for oxygen after a molecule of oxygen has already bonded. It has an exponential phase (where small changes in PO2 cause large increases in saturation) and a plateau phase. Dissociation curve
        
        The Bohr effect describes that the dissociation curve will shift to the left or right depending on certain conditions.
        
        In the alveoli, PCO2 is low and this will cause a rise in PH. There will also be reduction in temperature due to evaporation and 2,3DPG will be in low concentration as it is a product on anaerobic respiration. This causes a leftward shift - this means haemoglobin will have a higher affinity for oxygen meaning O2 uptake is a lot faster.
        
        In the tissues, PCO2 will be high and PH as a result will be low. Metabolism is exothermic so raises temperature. 2,3DPG will also begin to accumulate in hypoxic conditions during anaerobic respiration. This causes a rightward shift; decreasing oxygen affinity meaning haemoglobin is more likely to release oxygen.
  - - - The equilibrium of the reversible reaction forming bicarbonate shifts to the right favouring the reaction thanks to - the buffering of protons due to deoxyhaemoglobin (Haldane effect) and the exchange of bicarbonate with chloride via an exchanger. Carbon dioxide transport as bicarb
      - The Haldane effect works in reverse in the lungs as bicarbonate will be converted back into CO2 and CO2 will be released from carbamino compounds which allows CO2 to be easily diffused out of the lung.
- - - - The main respiratory muscle is the diaphragm which is innervated by the Phrenic Nerve - this nerve stems from between cervical vertebrae C3-C5.
      - The intercostals are innervated by spinal nerves.
    - - These centres particularly the Pons and the medulla - help to form the medullary respiration centre.
        
        The respiration centre receives inputs from higher brain centres and lung receptors:
        
        The Limbic system mediates responses in response to emotion. Emotion can lead to hyperventilation/hypoventilation in extreme cases.
        
        Voluntary control of breathing can override the respiratory centre thanks to the cerebral cortex. The cortex has motor neurons which directly innervate respiratory muscles via the pyramidal tract.
        
        The hypothalamus has thermoreceptors which can alter breathing rate.
        
        The lung has stretch receptors in bronchial smooth muscle which is innervated by the vagus nerve. The vagus nerve sends impulses to the DRG to inhibit inspiratory neurons and thus inspiratory muscles. This inhibits inspiration by giving expiration time to occur. This has negative feedback on this reflex.
        
        The Hering-Bruer reflex is used during heavy breathing to ensure that the lungs are not over stretched,
        
        The lung has irritant receptors. There are nerve endings in-between epithelial cells - once exposed to irritants (smoke, dust etc.). The vagus nerve sends impulses to the medulla to trigger the coughing reflex (to remove irritants), bronchoconstriction (prevents irritants reaching the alveoli), surfactant release and deep breaths (prevents lung collapse).
      - The respiration centre consists of the dorsal respiratory group (DRG) and the ventral respiratory group (VRG). Overview
        
        The DRG contains inspiratory neurones. These are rhythmic in nature and innervate inspiratory muscles. The DRG also receives inputs from receptors via the vagus nerve.
        
        The VRG contains both inspiratory and expiratory neurones. The neurones do have a degree of spontaneous pacemaker rhythmicity. It receieves additional inputs from chemoreceptors and the DRG.
        
        During normal breathing, the inspiratory muscles tend to be more stimulated than the expiratory. Expiration is mostly by elastic recoil so requires little neural input.
        
        During exercise, your breathing is heavier. This leads to the expiratory muscles being innervated as well via other inputs.
        
        Inspiratory neurones and expiratory neurones inhibit eachother. This mutual inhibition leads to 'alternate stimulation' of the different muscle groups.
      - Two regions from the Pons receives inputs from the cerebrum and hypothalamus and then feed these forward to the respiration centre in the medulla oblongata.
        
        The Pneumotaxic centre inhibits the DRG to promote expiration thus affecting breathing rate by changing the space between breaths.
        
        The Apneustic Centre stimulates the DRG to promote inspiration this increases the duration of a single breath.
        
        The pneumotaxic and apneustic centres of the Pons inhibit eachother and allow a fine-tuning of the basic rhythmicity established in the medulla.
  - - - Low PCO2 in the brain causes cerebral vasoconstriction leading to cerebral hypoxia and dizziness.
    - - Hypercapnia can adversely affect the CNS which is potentially fatal. Hypoventilation lowers PO2, causing hypoxia.
    - - Increasing alveolar PCO2 leads to a direct increase in ventilation. Small changes in PCO2 lead to large changes in ventilation. Alveolar PCO2 graph
      - Top of the curve decreases as there is excessive hypercapnia - there is no point of increasing ventilation. Near bottom of the curve is the basal rate of ventilation.
      - PCO2 directly affects pH balance but protons can be generated or lost from other chemical reactions/processes (metabolic acidosis/alkalosis). For example:
        
        Diabetes Mellitus causes the build up of ketone bodies, one of these is acidic causing an aggregation of H+.
        
        Kidney disease and diarrhoea can both lead to a loss of bicarbonate causing the gain of protons and drop in pH.
        
        Physical exercise also contributes by lactic acid production but this is usually normal and transient. All the above contribute to Metabolic acidosis.
        
        Metabolic alkalosis on the other hand could be caused by a loss of H+ e.g. by vomiting or by excessive use of diuretics which causes a loss of water but high retention of bicarbonate raising pH.
        
        Chemoreceptors detect changes in PCO2, PO2 and pH. The most important are the central chemoreceptors in the medulla (80% - PCO2 and H+) and the others are peripheral; they are present in the aortic and carotid bodies (20% - responsible for PO2, PCO2 and H+).
        
        The central chemoreceptors are bathed in cerebrospinal fluid and sense the pH of the fluid.
        
        These indirectly measure PCO2. As protons cannot pass through the blood-brain barrier - H+ and bicarbonate must from CO2 and water. CO2 can diffuse through the barrier and then reforms protons which are then detected by the medulla.This means that H+ is directly proportional to PCO2.
        
        The peripheral chemoreceptors send impulses to the medulla via the vagus and glossopharyngeal nerves.
        
        Most important of the peripheral receptors is the carotid bodies. These are at the bifurcation of the common carotid artery. The body contains two types of cell:
        
        Glomus cells respond to decrease in PO2 and increases in PCO2 and H+. These are the main O2 sensing cells and they release dopamine at the nerve junction. The body also contains sheath cells.
        
        The aortic bodies are found on the aortic arch.
      - pH directly affects the PCO2-ventilation relationship. A low pH/increase in H+ causes a left-ward shift; enhancing the effect of PCO2 on ventilation. Whilst a high pH/decrease in H+ causes a right-ward shift; suppressing the effect on PCO2 on ventilation. pH on curve
      - The PO2-ventilation relationship is more a curved relationship, PO2 does not really effect ventilation until PO2 drops below 8kPa as a hypoxic response. As PO2 decreases, there will be an exponential rise in ventilation.
        
        The hypoxic response of PO2 (<7kPa) and the hypercapnic response from PCO2 act synergistically. When a person is hypoxic, ventilation becomes more sensitive to small changes in PCO2.
- - - - The asthmatic response is triggered by an allergen binding to immunoglobulin-E receptors on a mast cell which activates the cell. Once activated, the mast cell will secrete histamine, prostaglandins, leukotrienes and cytokines. These have a strong broncho-constrictive effect causing inflammation, oedema and mucus with inflammation due to the aggregation of white blood cells.
      - An asthma attack occurs in phases.
        
        The immediate phase is the initial response to the allergen which only takes a few minutes. The mast cells release a number of mediators and cause a strong broncho-spasm thus reducing respiratory ability.
        
        The delayed phase happens over hours. This occurs due to a narrowing of the airways by oedema, inflammation and high mucus production as a result of all the recruited cells releasing various mediators.
        
        The last phase is a 'hyper-responsiveness' of the airways to any inhaled irritants which can cause sudden broncho-constriction. This sort of response takes days to occur and does not occur all the time.
      - The drugs used to help treat asthma are broncho-dilators or anti-inflammatory agents.
        
        Beta 2 adrenergic- agonists are used in the immediate treatment of asthmatic symptoms due their dilative effect of the airways. Examples are: Salbutamol (short-acting) and Salmeterol (long-lasting). Theophylline is also used in prophylaxis but is not a B2-agonist. B2 agonist action
        
        These drugs work by a GPCR (Gs). The drug binds and causes a conformational change to activate the receptor. Adenylyl cyclase converts ATP into Cyclic AMP - this then activates Protein Kinase A to activate Myosin light chain kinase (MLCK) to become phosphorylated. This form of MLCK causes the relaxation of the muscle.
        
        Theophylline is a Xanthine which acts to inhibit Cyclic AMP Phosphodiesterase (isoform 3). This forces the reaction process forward which promotes the relaxation of the muscle. It's structure is very similar to that of Caffeine.
        
        Beta 2 drugs are chemically/structurally similar to endogenous B2 - agonists e.g. adrenaline. They cause a relaxation of the muscle and inhibit degranulation of mast cells.
        
        Muscarinic antagonists also cause a relaxing/dilative effect by preventing the contraction of smooth muscle in the airways. There are M2 (pre-synaptic) receptors and M3 receptors on the muscle fibres which are inhibited to prevent contraction.
        
        These are used mostly in treating chronic obstructive pulmonary disease. The main two inhibitors are: ipratropium bromide and tiotropium bromide which differ by how long-acting they are.
        
        The main type of anti-inflammatory drugs used are Glucocorticosteroids. Other examples of anti-inflammatory drugs are: Theophylline, Leukotriene antagonists, Anti-Immunoglobin E and Cromones.
        
        Glucocorticosteroids are lipophilic so are able to diffuse through the membrane with ease. They then bind to a receptor which is bound to a protein called HSP90 (heat shock protein). HSP90 helps to transport the steroid into the nucleus of the cell. The steroid then binds to a specific gene and thus affects protein synthesis.
        
        This can either be tran-repression (preventing the synthesis of certain proteins) of chemical mediators e.g. prostaglandins or trans-activation (encouraging the production of certain proteins) of proteins with a broncho-dilative effect e.g. annexin (lipocortin), mitogen kinase phosphatase 1 (inhibits MAP kinase) prevents oxidative stress or enhancing B2 receptors.
        
        These drugs are anti-oedema, inhibit the recruitment of inflammatory cells (mast cells, eosinophils, white blood cells etc.) and increase B2 receptor function.
        
        These drugs have a number of side effects. Possible effects are oral candidiasis and osteoporosis etc.
        
        Leukotriene antagonists work as a result of taking glucocorticosteroids. They produce annexin (lipocortin) which inhibits Phospholipase A2. This prevents the formation of Leukotrienes which cause a number of effects such as: broncho-constriction, oedema and mucus production.
        
        Cromones reduce inflammatory cell recruitment but are not as effective as steroids e.g. Sodium Cromoglicate.
        
        Anti-immunoglobulin E drugs bind to free igE, this reduces the activation of mast cells and the recruitment of inflammatory cells. This means that, there will be reduced secretion of chemical mediators thus reducing the asthmatic reaction. The example drug is Omalizumab.