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

2. 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 Anatomy

3. 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 O 2 / CO 2 and RBCs. The thin cell wall coupled with the extensive surface area of alveoli results in the rapid, bulk movement of gases. Respiratory Zone

4. Similar to blood, air move by bulk flow, such that it can be defined as: F =  P / R Air flow (F) is proportional to the change in pressure, and in this scenario we are thinking in terms of atmospheric pressure (P atm ) and alveolar pressure (P alv ): F =  P alv - P atm) / R During inspiration, P alv is less than P atm so the driving force is negative and air flow moves inward; the reverse occurs during expiration. To change P alv 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) Mechanics

5. Two factors determine lung volume: 1.The difference in pressure between the inside and outside of the lungs – the transpulmonary pressure (P tp ) 2.Lung compliance – the amount of expansion that they are capable of The pressure inside the lungs is equivalent to P alv while the pressure outside equals the pressure of the intrapleural fluid (P ip ). Therefore: P tp = P alv – P ip By taking advantage of Boyle’s law, air can flow into the alveoli as a result of decreasing P ip. This is achieved through the expansion of the chest wall, which as a result increases the volume of the intrapleural space. What happens? P ip decreases as a result, making P tp more positive making the lungs expand. This expansion results in decreasing P alv allowing air to flow inwards. Mechanics

7. 0mmHg -4mmHg -3mmHg -6mmHg +3mmHg -3mmHg

8. Diaphragm and inspiratory intercostal muscles contract Thorax Expands P ip becomes more negative Transpulmonary pressure increases Lungs expand P alv becomes more subatmospheric Air flows into alveoli Mechanics

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

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

11. Lung compliance: this can be thought of as the opposite of stiffness Compliance (C L ) is defined as the magnitude of change in lung volume (  V L ) produced by a given change in transpulmonary pressure (  P tp ): C L =  V L /  P tp Therefore – the greater the compliance, the easier it for the lungs to expand. If compliance is low, then a greater decrease in P ip 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. Mechanics

12. 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. Reduces attractive forces of hydrogen bonding by becoming interspersed between H 2 0 molecules. As alveoli radius decreases, surfactant’s ability to lower surface tension increases. Vitally important in premature neonates – infant respiratory distress syndrome Mechanics

13. 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 r 4   L8 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 (P alv - P atm ) during a normal breath? Resistance

14. 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 r 4   L8 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 (P alv - P atm ) during a normal breath? 1 mmHg Resistance

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

16. 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? Resistance - Pathologies

17. 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. Resistance - Pathologies

18. O 2 has to get from the alveoli into the capillaries, from there to metabolically active tissues, into the extracellular fluid & across the plasma membrane; CO 2 does it in reverse Generally speaking, in a steady state, the volume of O 2 added to the blood is the same as the volume of O 2 consumed by tissues, with the reverse being true for CO 2. 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 O 2 alone then we discuss it’s partial pressure. As oxygen makes up 21% of the atmosphere then it’s partial pressure (P O2 ) is 21% of 760mmHg = 160mmHg. Partial pressures are important for understanding the exchanges of gases Exchange of Gases

19. 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 P O2 = 105 mmHg and P CO2 = 40 mmHg, whereas the atmospheric partial pressures are 160 mmHg and 0 mmHg, respectively. What would lead to a drop in alveolar P AO2 ? Exchange of Gases

20. 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 P O2 = 105 mmHg and P CO2 = 40 mmHg, whereas the atmospheric partial pressures are 160 mmHg and 0 mmHg, respectively. What would lead to a drop in alveolar P AO2 ? High altitude = lower atmospheric P O2 Decreased ventilation Exercise - Increased demand for O 2 from tissues Exchange of Gases

21. Venous Blood AlveoliArterial Blood Atmosphere P O2 40 mmHg105 mmHg100 mmHg160 mmHg P CO2 46 mmHg40 mmHg 0.3 mmHg You should be able to recognise that as venous blood reaches the pulmonary capillaries, the differences in partial pressure for O 2 and CO 2 between the blood and alveoli will result in an exchange of both gases. Why isn’t all the CO 2 removed?

22. Review – Pulmonary I - Hypoxemia 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 P CO2 Diffusion Impairment: either a thickening of the alveolar cell well and / or a decrease in surface area leads to impairment of equilibria between arterial and alveolar P O2 Pa CO2 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 Pa CO2 is normal due to increased ventilation to counteract hypoxemia Ventilation-Perfusion Inequality: most common cause of hypoxemia – found in lung diseases such as COPD – ie. an increase in dead space. Ventilation is the same but perfusion (gas exchange) is impaired. Pa CO2 is increased or normal if increased ventilation is possible

23. Primary determinant of partial pressure of arterial CO 2 (P a CO 2 ) is alveolar CO 2 partial pressure (P A CO 2 ), which in turn is determined by alveolar ventilation. It should be obvious that alveolar ventilation (V A ) is dependent on how much we breathe – how much we breathe per minute (V E ) will rely on the size of the breath (V T ) and the number of breaths/min (f): V E = V T x f Review – Pulmonary I - Hypercarbia

24. Primary determinant of partial pressure of arterial CO 2 (P a CO 2 ) is alveolar CO 2 partial pressure (P A CO 2 ), which in turn is determined by alveolar ventilation. It should be obvious that alveolar ventilation (V A ) is dependent on how much we breathe – how much we breathe per minute (V E ) will rely on the size of the breath (V T ) and the number of breaths/min (f): V E = V T x f But not all of the air we breathe reaches the gas exchange regions of our lungs, so the dead space (V D ) has to be taken into account when determining V A : V A = (V T - V D ) x f It is important to realize that P a CO 2 = P A CO 2 thus something that could affect alveolar ventilation will have a knock-off effect on arterial CO 2 levels by altering P A CO 2, with the primary determinant of hypercarbia being hypoventilation. Review – Pulmonary I - Hypercarbia

25. What can cause hypoventilation? (Discuss) Review – Pulmonary I - Hypercarbia

26. What can cause hypoventilation? (Discuss) 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 P CO2 Remember: you can still have a high minute ventilation (= tidal volume x freq.) but still be hypoventilating if the dead space has increased  overall this serves to decrease alveolar ventilation What can cause an increase in dead space? (Discuss) Review – Pulmonary I - Hypercarbia

27. What can cause hypoventilation? (Discuss) 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 P CO2 Remember: you can still have a high minute ventilation (= tidal volume x freq.) but still be hypoventilating if the dead space has increased  overall this serves to decrease alveolar ventilation What can cause an increase in dead space? (Discuss) Breathing through a tube Pulmonary embolus Disease (such as?) Review – Pulmonary I - Hypercarbia

28. Review – Pulmonary II – Lung Volume FRC: functional residual capacity TLC: total lung capacity VC: vital capacity RV: residual volume V T : tidal volume FRC The FRC is the volume in your lungs at the end of a breath when you are completely relaxed. It is the point at which the tendency of the chest wall to recoil outwards exactly matches the inward recoil of the lungs. TLC The TLC is the total amount of air in your lungs at the end of a maximal inspiratory effort. It’s a measure of the overall size of the lungs. TLC increases in emphysema and sometimes in asthma. RV RV is the volume of air in your lungs at the end of a maximal expiratory effort. In diseases such as asthma and emphysema, the airways close at low lung volumes. Air is trapped behind these closed airways and so RV increases. VC Vital Capacity is the difference between TLC and RV. It’s primarily determined by overall thoracic size and is influenced by height, age, and gender. It will change whenever RV or TLC changes due to disease.

29. Review – Pulmonary II - Obstruction Should be a well-understood concept that when an airway narrows its resistance greatly increases Airway resistance, and thus obstruction, can be easily measured by determining the FEV 1 / FVC ratio - forced expiratory volume in one second (FEV 1 ) and the forced vital capacity (FVC). The FVC is measured by having a person take in as much air as they possibly can and then breathe out as much as they can into a spirometer, until no more air will come out. The total amount of air that they breathe out is the FVC. The FEV 1 is the amount of air that comes out in the first second. The technique has the advantage of being mostly effort independent. A value less than 80% indicates that an airway obstruction may be present

30. Review – Pulmonary II - Asthma

31. FEV 1 /FVC is greatly reduced during an attack – why ?

32. Review – Pulmonary II - Asthma FEV 1 /FVC is greatly reduced during an attack – why ? Bronchoconstriction - Airway hyperresponsiveness: increased airway narrowing in response to contractile agonists that have little if any effect in normal subjects histamine, methacholine, leukotrienes – can be diagnostic using the PD 20 (provocative dose)

33. Review – Pulmonary II - Asthma FEV 1 /FVC is greatly reduced during an attack – why ? Bronchoconstriction - Airway hyperresponsiveness: increased airway narrowing in response to contractile agonists that have little if any effect in normal subjects histamine, methacholine, leukotrienes – can be diagnostic using the PD 20 (provocative dose) Inflammation - Mediated mainly by lymphocytes (CD4 and CD8 T cells) and eosinophils. IL-5 Granules IgE Diffusion & Contraction Allergy

34. Review – Pulmonary II – Asthma & Allergy IgE – important in inducing an inflammatory state in response to allergens. Like all antibodies, IgE is produced by B cells, which in turn are stimulated by T cells One region of the IgE molecule will bind to mast cells, while another region will recognize a specific allergen. This causes mast cells to degranulate rapidly – contain preformed inflammatory mediators such as histamine. Strong correlation between IgE titer and asthma severity Biphasic response to allergens – immediate and late (why?)

35. Review – Pulmonary II – Asthma Treatment What do each of these do ? Corticosteroids  -agonists Leukotriene Synthesis Inhibitors Omalizumab

36. Review – Pulmonary II – Asthma - Influencing Factors Nature vs. Nurture - genetic factors involved in IgE synthesis - exposure to viruses / allergens / cigarette smoke Why is asthma on the increase? - hygiene hypothesis - obesity - allergens - pollution

37. Review – Pulmonary II - COPD Emphysema and Chronic Bronchitis

38. Review – Pulmonary II - COPD Emphysema and Chronic Bronchitis destruction of alveolar wall and capillary bed but without obvious scarring (fibrosis). enlarged air spaces small airways are narrowed, thin walled, may be reduced in number pan acinar - central part of acinus (respiratory bronchioles mainly affected) pan lobular ‑ whole acinus afflicted apex of lung most often affected first increased pulmonary compliance (elastase) hypertrophy of mucus glands goblet cell metaplasia inflammation in small airways and in glands mucus in airways, sometimes occluding airway lumen airway wall edema thickened epithelium

39. Review – Pulmonary II – COPD - Emphysema Inhaled toxins trigger local inflammation in alveoli Inflammatory mediators cause the destruction of alveolar septum – decrease in surface area available for gas exchange Additional destruction of capillaries that serve alveoli. Ventilation/ Perfusion inequality – some areas of the lung could receive large quantities of air but have insufficient blood flow (or vice versa). Lower PaO 2 but normal PaCO 2 (although PaCO 2 will rise once disease becomes extensive)

40. Review – Pulmonary II – COPD - Emphysema How does emphysema lead to pulmonary hypertension ? - as disease progresses and high enough PaO 2 cannot be reached, the body compensates through vasoconstriction. - the heart tries to provide more blood to the lungs in order for PaO 2 to increase, leading to thickening of the heart muscle. Eventual heart failure ensues. What role does  1 anti-trypsin play? (Discuss)

41. Review – Restrictive Lung Diseases Lung recoil: The pressure required to fill an air filled lung is much greater than the pressure required to fill a fluid filled lung At the air/liquid interface, attractive forces between water molecules resist lung expansion Surfactant, a combination of proteins and phospholipids synthesized in Type II epithelial cells, reduces surface tension by interposing itself between water molecules With surfactant, pressure required to inflate the lung is still greater than it would be if you were filling it with liquid, but much less than if there was no surfactant Pulmonary Edema: Most fluid that gets out of the circulation into the interstitial space is collected into lymphatics and taken back to the circulation. If the fluid flow becomes greater than the lymphatics can handle, it first goes to spaces around the large airways and blood vessels, and then starts accumulating in the interstitial spaces. The epithelium is normally extremely impermeable to water, but if the fluid accumulation in the interstitial spaces gets big enough, it will start to leak across into alveoli. Fluid in the alveolar spaces impairs diffusion across the alveolar capillary membrane. If severe, it can fill up these spaces and form a shunt. Fluid in the airspaces can also interfere with surfactant function and impair lung inflation.

42. Review – Restrictive Lung Diseases Heart Disease  left atrial pressure   pressure in pulmonary vein   Pcap   fluid flux across the endothelium Self-limiting - fluid accumulation in the interstitial space causes the pressure in the intersitial space to rise. As fluid leaks out, the proteins in the capillary become more concentrated, there is an increase in the oncotic pressure, and fluid tends to get pulled back into the capillary.

43. Review – Restrictive Lung Diseases Heart Disease  left atrial pressure   pressure in pulmonary vein   Pcap   fluid flux across the endothelium Self-limiting - fluid accumulation in the interstitial space causes the pressure in the intersitial space to rise. As fluid leaks out, the proteins in the capillary become more concentrated, there is an increase in the oncotic pressure, and fluid tends to get pulled back into the capillary. Increased capillary permeability Toxins - eg: chlorine, nitrogen oxides, SO 2, endotoxin, radiation, bacterial or viral pathogens, high O 2 concentrations over long periods of time. Integrity of the endothelial barrier is destroyed, and proteins start leaking into the interstitial space; capillary oncotic pressure decreases resulting in increased leak of fluid into the interstitial space. Is not a self limiting process; the fluid that comes out has protein in it, so the oncotic pressure of the interstitium starts to increase, further increasing fluid flux. This kind of edema is extremely dangerous.

44. Review – Restrictive Lung Diseases If only interstitial edema is present, there is little change in P a O 2. Even though the barrier to diffusion is increased, at rest, O 2 uptake across the alveolar-capillary barrier is still complete. If alveolar edema is present, there is a decrease in P a O 2, mainly because of blood flow to fluid filled alveoli that are not being ventilated (shunt). P a CO 2 stays normal or even low, because the patients increase their ventilation. The reason for the increased ventilation may be the low P a O 2, or stimulation of lung receptors by high transpulmonary pressures (lung is stiffer, so it requires greater pressures for ventilation).