Respiratory Physiology and Disease (29/10/13 lecture)

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Pulmonary ventilation, surfactant and the Law of LaPlace, the gas exchange zone, Dalton's and Henry's Laws of gaseous exchance, transport and exchange of O2 and CO2, pathologies of the respiratory system, and nervous regulation of ventilation. From the 29/10/13 Human Physiology lecture.

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Respiratory physiology and disease (29/10/13 lecture) The function of the respiratory system is to supply the body with oxygen and dispose of carbon dioxide – it does this through four processes: pulmonary ventilation, external respiration, transport, internal respiration. Air flow (minimal airway resistance) and diffusion (maximal gaseous exchange) are required for overall lung function. The lungs are a compromise between wide airways and many alveoli. The work of the lungs is also a compromise: alveolar ventilation = frequency x depth of breaths. So low frequency/deep breaths have low resistance but must expand thorax far; whereas high frequency/shallow breaths require more work to overcome resistance, but the thorax is only expanded minimally. General function is a compromise of 12 breaths of 500ml (as we can hold 6L in total) to reduce overall work as much as possible. Resistance in the lungs is a result of airway radius and length – but length is constant, whereas radius can be altered. As with the vascular system, it is the medium-sized bronchi (such as the left primary bronchus) that offer the most resistance to air flow. Compliance is the ease with which the lungs can be expanded – the change in lung volume that occurs with a given change in transpulmonary pressure (which establishes a pressure gradient) i.e. stiffer lungs would require a larger pressure to push air through. This is determined by the distensibility of the lung tissue and thoracic cage, and the surface tension of the surfactant coating the inside of the alveoli. Smaller bubbles of surfactant in alveoli are ‘firmer’ than larger ones, as the radius is smaller so the pressure is bigger. The Law of LaPlace states that P = 2T/r, meaning that recoil pressure = 2 x surface tension / radius of the bubble of surfactant in the alveoli. Given that the pressure is higher in the smaller alveolus due to its smaller radius, there is a tendency for air to be forced from the smaller alveolus to the larger alveolus in an interconnection (which alveoli are) in order to prevent itself from collapsing. However, the presence of detergent-like surfactant produced by type II alveolar cells reduces the surface tension (more so in the smaller alveoli as there is more surfactant present) to prevent alveoli from collapsing, which keeps them in equilibrium so there is no air exchange between different sized alveoli. This also reduces the amount of work done to expand lungs and force alveoli to expand. The ‘dead space’ (non-exchange) of the upper respiratory tract stores ~150 mL of air. This means that at the end of inspiration, the dead space is storing 150mL of fresh air – which is the first to be exhaled. So during exhalation, one exhales only 350mL ‘stale’ air. This means in the next inspiration, the first 150 mL to be inhaled is the stale air from the dead space! So only 350mL is exchanged. Alveoli aren’t exactly ventilated, as, though the velocity of air is relatively high in the trachea, the division of the airways results in a larger cross-sectional area so the velocity of the air gets smaller to the point that the bulk flow is near zero at the alveoli. This helps keep the alveolar composition relatively constant and exchange with blood fairly constant in the face of intermittent breathing, as rapidly oscillating O2 levels would mean that blood concentration would change with each breath, rather than remain stable (homeostasis). External respiration occurs in the respiratory zone, which consists of terminal bronchioles, respiratory bronchioles, alveolar ducts, and clusters of alveoli, and is defined by the presence of alveoli. There are ~300 million alveoli which are 0.3mm in diameter, consist of a single squamous epithelial cell layer, and account for most of the lung volume. The respiratory membrane that the air must cross between the blood and the alveoli consists of: the alveolar epithelium, the capillary endothelium, and the fused basal laminas of both, making the diffusion distance ~1μm. Gaseous exchange across a respiratory membrane: D = (s / √MW) * ΔP * (A/d) (D = diffusion rate; s = solubility; MW = molecular weight; ΔP = partial pressure difference; A = diffusion area; d = diffusion distance) (d – distance between erythrocyte and air, can be as little as 0.5 microns; A = 70m2 over which a monolayer of 100ml of blood is distributed Dalton’s law of partial pressures states that the total pressure exerted by a mixture of gases is the sum of that exerted independently by each gas in the mixture (its partial pressure). The partial pressure of the gas is proportional to its percentage in the mixture. Gases diffuse independently down their partial pressure gradients, regardless of other gases present, but these are not reflective of concentration gradients so it is not correct to think of them in this way. Henry’s Law states that when a liquid is exposed to a mixture of gases, each gas dissolves in proportion to its partial pressure. The amount of gas dissolved depends on its solubility. So the partial pressures of the gases will be equal in and out of the liquid at an interface, but the concentrations may or may not be equal. PCO2 = 5mmHg: 45mmHg in venous blood vs 40 mmHg in alveoli – CO2 is very soluble in plasma but the gradient is sufficient to exchange the CO2. PO2 = 64mmHg: 40mmHg in venous blood vs 104mmHg in alveoli – O2 is much less soluble in plasma than CO2. Its diffusing capacity is ~21ml O2/min/mmHg, so given that its average partial pressure gradient is 11 mmHg, the diffusing capacity of the respiratory membrane for O2 is ~230ml/min at rest. The diffusing capacity can be increased by: increasing perfusion of under-perfused parts of the lungs, and increasing the cardiac output. The latter may seem counterintuitive, but only 1/3 of the time an erythrocyte spends travelling through a capillary is spent oxygenating, so pushing through 3x faster is not detrimental. Ventilation and perfusion are coupled, with a ratio usually around 0.85 (ventilation capacity: 6L/min, cardiac output: 5L/min). If there is low [CO2] in the alveoli, constriction of bronchioles results so ventilation is reduced and excess work not put in to ventilate lung tissue with little CO2. If there is low [O2] in alveoli, there is constriction of arterioles so lung tissue with little O2 to pick up is not perfused. CO2 is removed from the plasma and erythrocytes by: That dissolved in plasma diffuses across the respiratory membrane into the alveoli. That contained in HCO3- ions in plasma, is converted: HCO3- + H+ → H2CO3 → H2O + CO2 (slow) which diffuses. That combined with haemoglobin (carbaminohaemoglobin) dissociates then diffuses through plasma. The majority dissociates from H2CO3 catalysed by carbonic anhydrase to speed it up: HCO3- + H+ → H2CO3 (CA) → H2O + CO2. The chloride shift in erythrocytes exchanges HCO3- in for Cl- out. O2 is delivered to the plasma and erythrocytes by: Diffusion into the plasma, which it then dissolves in. Binding to haemoglobin: O2 + HHb → HbO2 + H+. The movements of these gases are driven by partial pressure differences, between the tissues and the blood, the blood and the alveoli, and the alveoli and the atmosphere. Haemoglobin’s affinity for oxygen allows for a greater volume of O2 to be carried in the blood. O2’s solubility is 3mL/L of blood, but haemoglobin increases the amount carried to 200mL/L of blood. Further, haemoglobin’s O2 affinity acts as a buffer, as even if there is a 4x reduction in O2 available, haemoglobin will be ½ saturated. As PO2 increases, Hb saturates further with O2, plateauing at 98% saturated at 100mmHg O2 in alveoli. The plateau prevents desaturation even if PO2 falls. Low PO2 allows for both loading and unloading of O2 to Hb, depending on the pressure gradient. Hb has 4 binding sites per molecule as it is an aggregate of 4 subunits. The binding of O2 causes a conformational change which increases the affinity of other subunits for O2, whereas the dissociation of O2 from Hb reduces the affinity of other subunits for O2 (unloading). O2 CO2 2% carried dissolved in plasma 7% carried dissolved in plasma 98% carried by haemoglobin (oxyhaemoglobin) 23% carried by haemoglobin (carbaminohaemoglobin) Hb holds O2 reserve: 21ml O2/100ml blood – same as atmosphere 70% carried as HCO3- in the plasma During HHb + O2 → HbO2 + H+, an H+ ion is produced, which is then recycled to get rid of CO2: H+ + HCO3- → H2CO3 → H2O + CO2. If the pH is more alkaline (i.e. less CO2: PCO2 20mmHg, pH 7.6) the blood has an increased capacity to carry O2 even at the same PO2, whereas if pH is more acidic (i.e. more CO2: PCO2 80mmHg, pH 7.2) the blood has a decreased capacity to carry O2 even at the same PO2. Normal is: PCO2 40mmHg, pH 7.4, HbO2 98%. Pathologies Any factor involved in oxygen transport can be varied in pathology: composition of transpired air; alveolar ventilation (rate and depth of breathing; airway resistance; lung compliance); O2 diffusion between alveoli and blood (surface area; diffusion distance – membrane thickness; amount of interstitial fluid); adequate perfusion of alveoli) } PO2 of plasma. Also: % saturation of Hb (pH; temperature; 2,3-diphosphoglycerate – glycolytic intermediate that decreases affinity of Hb for O2); and total number of binding sites (Hb content per RBC; number of RBCs) } O2 bound to Hb. Emphysema – destruction of alveoli by inflammation and tissue breakdown as a result of (often) tobacco smoking. Reduces total surface area for gas exchange. Results in constant shortness of breath. PO2 in alveoli normal or low. PO2 in blood low. Fibrotic lung disease – thickened alveolar membrane (as a result of autoimmune disease or exposure to harmful agents such as asbestos) slows gas exchange and loss of lung compliance may decrease alveolar ventilation. PO2 in alveoli normal or low. PO2 in blood low. Pulmonary oedema – fluid in interstitial space (e.g. in heart failure) increases diffusion distance. PO2 in alveoli normal. PO2 in blood low. PCO2 in blood may be normal due to higher CO2 solubility. Asthma – increased airway resistance as a result of inflammation decreases airway ventilation. Bronchioles are constricted so alveolar PO2 is low, resulting in low arterial PO2. Regulation of ventilation – a central pattern generator integrates input from the cortex, limbic system and chemoreceptors. This then drives the rhythmic contractions of skeletal muscles driving ventilation. These contractions are a result of reciprocal inhibition of neuronal networks in the pons/medulla: In the pons, continuous inhibitory signals travel from the pneumotaxic centre to the apneustic centre and the dorsal respiratory group in the medulla. Continuous stimulatory signals travel from the apneustic centre in the pons to the dorsal respiratory group in the medulla, and from there to the ventral respiratory group in the medulla. The ventral and dorsal respiratory groups then send stimulatory impulses to the internal intercostals, and to the external intercostals and diaphragm, respectively, causing contraction in opposition (i.e. VRG stimulation of internal intercostals for expiration). During inspiration, the activity of inspiratory neurons increases steadily, apparently through a positive feedback mechanism. At the end of inspiration, the activity shuts off abruptly and expiration takes place through recoil of elastic lung tissue. Chemoreceptors – Peripheral chemoreceptors include those in the carotid and aortic bodies, which contain O2, CO2 and H+ receptors, and consist of glomus cells. Central chemoreceptors include the medullary CO2 receptors. Glomus cell in carotid body Central chemoreceptor in medulla Low [O2], high [CO2], and high [H+] lead to increased ventilation. Low PO2 diffuses from the blood to the glomus cell, causing K+ channels to close. This depolarises the cell, causing voltage-gated Ca2+ channels to open. Ca2+ entry to the glomus cell causes exocytosis of dopamine-containing vesicles, and the dopamine activates a receptor in a sensory neuron which signals to the medullary centres (DRG and VRG) to increase ventilation. Increased PCO2 in cerebral capillaries increases the PCO2 in the cerebrospinal fluid (the other side of the blood brain barrier, which H+ molecules can’t cross). This CO2: CO2 + H2O → H2CO3 → H+ + HCO3-. Since H+ ions can’t cross the BBB, those from increased PCO2 are the only ones that activate the central chemoreceptor, resulting in sensory input to the respiratory control centres in the medulla, which increases ventilation. In both cases, the increase in PO2 and the decrease in PCO2 result in less sensory stimulation of the respiratory centres, and a reduction in the rate of ventilation via a negative feedback mechanism. Other receptors exist in: pain/emotional stimuli acting through the hypothalamus; stretch and irritant receptors in the lungs; voluntary control over breathing in cerebral cortex; and receptors in muscles and joints. Adjustments to ventilation are made in exercise, so it increases in rate up to 20x, and becomes deeper and more vigorous. Levels of PCO2, PO2 and pH remain surprisingly constant during exercise so it is not these which prompts the ventilation adjustment, but neural factors including psychological aspects, cortical motor activation, and excitatory impulses from proprioceptors in muscles. As exercise begins, ventilation increases abruptly, rises slowly, and reaches a steady state. Correspondingly, when exercise stops, ventilation declines suddenly, then gradually decreases to normal.

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