Pulmonary Pathophysiology Iain MacLeod, Ph.D imacleod@hsph.harvard

1. Pulmonary Pathophysiology Iain MacLeod, Ph.D imacleod@hsph.harvard.edu Iain MacLeod 2 November 2009

2. Anatomy Areas of the lungs: Conducting zones: upper airways, trachea, bronchi, bronchioles act to filter air of pathogens/dust and to humidify contains mucous glands, ciliated cells, smooth muscle and cartilage Transitional zone: respiratory bronchioles Respiratory zone: alveolar ducts and alveoli site of gas exchange synthesizes surfactant contains type I and II epithelial cells, macrophages and fibroblasts

3. Respiratory Zone Alveoli are small, hollow sacs that contain a cell wall that is usually one cell thick – made up of type I alveolar cells (flat epithelial cells) – a single cell wall can separate adjacent alveoli. In addition to type II alveolar cells, the cell wall can contain capillaries. A small volume of interstitial fluid can separate capillaries and the alveolar cell wall, but when fluid is absent, the capillary and cell wall can fuse – results in an extremely thin barrier between O2 / CO2 and RBCs. The thin cell wall coupled with the extensive surface area of alveoli results in the rapid, bulk movement of gases.

4. Mechanics Similar to blood, air move by bulk flow, such that it can be defined as: F = DP / R Air flow (F) is proportional to the change in pressure, and in this scenario we are thinking in terms of atmospheric pressure (Patm) and alveolar pressure (Palv): F = (Palv - Patm) / R Duringinspiration, Palv is less than Patm so the driving force is negative and air flow moves inward; the reverse occurs during expiration. To change Palv the body can vary the volume of the lungs, resulting in a change in pressure (Boyle’s law – pressure is inversely proportional to the volume)

5. Mechanics • Two factors determine lung volume: • The difference in pressure between the inside and outside of the lungs – the transpulmonary pressure (Ptp) • Lung compliance – the amount of expansion that they are capable of • The pressure inside the lungs is equivalent to Palv while the pressure outside equals the pressure of the intrapleural fluid (Pip). Therefore: Ptp = Palv – Pip • By taking advantage of Boyle’s law, air can flow into the alveoli as a result of decreasing Pip. This is achieved through the expansion of the chest wall, which as a result increases the volume of the intrapleural space. • What happens? Pip decreases as a result, making Ptp more positive making the lungs expand. This expansion results in decreasing Palv allowing air to flow inwards.

6. Mechanics Diaphragm and inspiratory intercostal muscles contract Thorax Expands Pip becomes more negative Transpulmonary pressure increases Lungs expand Palv becomes more subatmospheric Air flows into alveoli

7. Mechanics Diaphragm and inspiratory intercostal muscles stop contracting Chest wall recoils inwards (due to elasticity) Pip becomes more positive Transpulmonary pressure decreases back to preinspiration levels Lungs recoil - elasticity Palv becomes greater than Patm Air flows out of lungs

8. Mechanics Lung compliance: this can be thought of as the opposite of stiffness Compliance (CL) is defined as the magnitude of change in lung volume (DVL) produced by a given change in transpulmonary pressure (DPtp): CL = DVL / DPtp Therefore – the greater the compliance, the easier it for the lungs to expand. If compliance is low, then a greater decrease in Pip must occur so that the lungs can expand sufficiently. People with low lung compliance tend to have shallow, rapid breathing. What determines lung compliance?

9. Mechanics Lung compliance: this can be thought of as the opposite of stiffness Compliance (CL) is defined as the magnitude of change in lung volume (DVL) produced by a given change in transpulmonary pressure (DPtp): CL = DVL / DPtp Therefore – the greater the compliance, the easier it for the lungs to expand. If compliance is low, then a greater decrease in Pip must occur so that the lungs can expand sufficiently. People with low lung compliance tend to have shallow, rapid breathing. What determines lung compliance? Elasticity of the connective tissue and surface tension.

10. Mechanics Surface Tension: The surface of alveolar cells is moist creating surface tension (think of two glass slides with water in between them that are difficult to prise apart). If this attractive force wasn’t countered, it would require extreme effort to expand the lungs and the would collapse. Recall that type II alveolar cells are found in the cell wall – these cells release surfactant. This lipid / protein mixture vastly reduces the attractive forces and increases lung compliance. Vitally important in premature neonates – infant respiratory distress syndrome

11. Resistance Recall that flow is dependent not only on a change in pressure but also the resistance. Factors that determine resistance are similar to those of blood flow: tube length, radius and interactions between molecules. Like the circulatory system, airway resistance is inversely proportional to the radius (Poiseuille’s law): F = ∆P r4 p hL8 With the main point being that halving the radius results in 16-fold increase in resistance (decrease in flow). There is usually little airflow resistance such that small changes in pressure are the main driving force behind large flows of air - however, it has a detrimental effect when increased. what’s the average change in pressure (Palv - Patm) during a normal breath?

12. Resistance Recall that flow is dependent not only on a change in pressure but also the resistance. Factors that determine resistance are similar to those of blood flow: tube length, radius and interactions between molecules. Like the circulatory system, airway resistance is inversely proportional to the radius (Poiseuille’s law): F = ∆P r4 p hL8 With the main point being that halving the radius results in 16-fold increase in resistance (decrease in flow). There is usually little airflow resistance such that small changes in pressure are the main driving force behind large flows of air - however, it has a detrimental effect when increased. what’s the average change in pressure (Palv - Patm) during a normal breath? 1 mmHg

13. Resistance - Pathologies Asthma – how does this disease process help us understand the impact of resistance?

14. Resistance - Pathologies Asthma – how does this disease process help us understand the impact of resistance? A pathology that results from chronic inflammation of the bronchi. Inflammatory mediators stimulate bronchoconstriction – reduced tube radius = increased restriction. How is it treated?

15. Resistance - Pathologies Asthma – how does this disease process help us understand the impact of resistance? A pathology that results from chronic inflammation of the bronchi. Inflammatory mediators stimulate bronchoconstriction – reduced tube radius = increased restriction. How is it treated? Chronic Obstructive Pulmonary Disease – emphysema and chronic bronchitis Both diseases have the same etiology – they are caused by smoking. Chronic bronchitis is characterized by excessive mucus production and chronic inflammation of the bronchi. Emphysema is characterized by an increase in pulmonary compliance – why would this be an issue? Similar to chronic bronchitis, toxin-induced inflammation, this time in the alveoli, leads to cell death.

16. Exchange of Gases O2 has to get from the alveoli into the capillaries, from there to metabolically active tissues, into the extracellular fluid & across the plasma membrane; CO2 does it in reverse Generally speaking, in a steady state, the volume of O2 added to the blood is the same as the volume of O2 consumed by tissues, with the reverse being true for CO2. Gases are usually discussed in terms of partial pressure. For example: at sea level, atmospheric pressure is 760mmHg, but this accounts for all the gases found in the atmosphere. If we wish to think about O2 alone then we discuss it’s partial pressure. As oxygen makes up 21% of the atmosphere then it’s partial pressure (PO2) is 21% of 760mmHg = 160mmHg. Partial pressures are important for understanding the exchanges of gases

17. Exchange of Gases Similar to the bulk movement of air from high to low pressure, dissolved gases in a liquid behave in a similar manner. Alveolar gas pressures are PO2 = 105 mmHg and PCO2 = 40 mmHg, whereas the atmospheric partial pressures are 160 mmHg and 0 mmHg, respectively. What would lead to a drop in alveolar PO2?

18. Exchange of Gases Similar to the bulk movement of air from high to low pressure, dissolved gases in a liquid behave in a similar manner. Alveolar gas pressures are PO2 = 105 mmHg and PCO2 = 40 mmHg, whereas the atmospheric partial pressures are 160 mmHg and 0 mmHg, respectively. What would lead to a drop in alveolar PO2? High altitude = lower atmospheric PO2 Decreased ventilation Exercise - Increased demand for O2 from tissues

19. Exchange of Gases You should be able to recognise that as venous blood reaches the pulmonary capillaries, the differences in partial pressure for O2 and CO2 between the blood and alveoli will result in an exchange of both gases. Why isn’t all the CO2removed?

20. Hypoxemia – decreased arterial PO2 Hypoventilation: can result from a defect anywhere in the stimulation of respiratory muscles, from the controlling centres of the medulla down to the muscles themselves. occlusion of the upper airway / thoracic cages injuries hypoxemia by hypoventilation is accompanied by a rise in arterial PCO2

21. Hypoxemia – decreased arterial PO2 Hypoventilation: can result from a defect anywhere in the stimulation of respiratory muscles, from the controlling centres of the medulla down to the muscles themselves. occlusion of the upper airway / thoracic cages injuries hypoxemia by hypoventilation is accompanied by a rise in arterial PCO2 Diffusion Impairment: either a thickening of the alveolar cell well and / or a decrease in surface are leads to impairment of equilibria between arterial and alveolar PO2 PaCO2 is either normal or reduced (if ventilation is increased to offset hypoxemia)

22. Hypoxemia – decreased arterial PO2 Hypoventilation: can result from a defect anywhere in the stimulation of respiratory muscles, from the controlling centres of the medulla down to the muscles themselves. occlusion of the upper airway / thoracic cages injuries hypoxemia by hypoventilation is accompanied by a rise in arterial PCO2 Diffusion Impairment: either a thickening of the alveolar cell well and / or a decrease in surface are leads to impairment of equilibria between arterial and alveolar PO2 PaCO2 is either normal or reduced (if ventilation is increased to offset hypoxemia) Shunt: an anatomical abnormality that allowed mixed venous blood to by-pass ventilation and enter arterial blood. can also occur when blood passes through alveoli that are unventilated thus the blood in the capillaries does not become perfused PaCO2 is normal due to increased ventilation to counteract hypoxemia

23. Hypoxemia – decreased arterial PO2 Hypoventilation: can result from a defect anywhere in the stimulation of respiratory muscles, from the controlling centres of the medulla down to the muscles themselves. occlusion of the upper airway / thoracic cages injuries hypoxemia by hypoventilation is accompanied by a rise in arterial PCO2 Diffusion Impairment: either a thickening of the alveolar cell well and / or a decrease in surface are leads to impairment of equilibria between arterial and alveolar PO2 PaCO2 is either normal or reduced (if ventilation is increased to offset hypoxemia) Shunt: an anatomical abnormality that allowed mixed venous blood to by-pass ventilation and enter arterial blood. can also occur when blood passes through alveoli that are unventilated thus the blood in the capillaries does not become perfused PaCO2 is normal due to increased ventilation to counteract hypoxemia Ventilation-Perfusion most common cause of hypoxemia – found in lung diseases such as COPD – ie. an increase Inequality: in dead space. Ventilation is the same but perfusion (gas exchange) is impaired. PaCO2 is increased or normal if increased ventilation is possible