pulmonology1 Flashcards
Pleura
Movement of the lungs within the thoracic cavity during inspiration and expiration is facilitated by a space between the two structures, the pleural space. The pleural space is created by the apposition of the inner lining of the chest wall, the parietal pleura, and the outer lining of the lung, the visceral pleura. A thin film of fluid separates the visceral and parietal pleura and acts as a lubricant. Disruption of this space either by air (pneumothorax), fluid (pleural effusion), or scarring can impair lung function.
Conducting Airways
The airways are a series of dichotomously branching tubes (i.e. a ‘parent’ airway divides into two ‘offspring’ airways) starting with the trachea and ending at the terminal bronchioles (the last conducting airway). On average there are 23 generations of airways in humans (from trachea to the last respiratory bronchiole). The first 16 are the conducting airways because they form a conduit for gas transfer to and from the respiratory exchange units of the lung. The structure of the airway wall changes depending on the generation of the airway. The walls are made up of three principal structures: the inner mucosal surface (epithelial cells, cilia, and goblet cells), the smooth muscle layer, and the outer connective tissue layer. Alterations in any of these layers can have an impact on airway resistance. Morphology of the airway wall changes as generation increases. Note specifically that the loss of cartilage in the outer tissue layer represents the transition from bronchi to bronchioles. Hence disease such as bronchitis and bronchiectasis refer to airways with cartilage whereas bronchiolitis affects the bronchioles or non-cartilagenous airways. Since the conducting airways by definition do not exchange gas, they are known as “anatomic deadspace.” Deadspace refers to parts of the lung that do not exchange gas. It can be anatomically defined or physiologically defined.
Gas-Exchange Regions
This region must permit efficient diffusion of oxygen and carbon dioxide across alveolar and capillary walls. The gas-exchange region (the acinus) begins distal to the terminal bronchiole and includes the respiratory bronchiole, the alveolar ducts, and the alveoli. The simple epithelium of the bronchioles gives way to two different types of alveolar epithelial cells, squamous lining cells (type I cells or pneumocytes) and secretory cells (Type II cells). Type I cells account for 95% of the alveolar surface area and fuse with the capillary endothelium to create a sufficiently thin membrane for adequate gas transfer. These cells can be injured in many diseases [such as the acute respiratory distress syndrome (ARDS)] impairing gas-exchange. Type II cells have two primary functions: 1) to repair or replace injured Type I pneumocytes, and 2) to secrete surfactant, a substance which lowers alveolar surface tension. Other cells found in the acinus (alveolar macrophages). Note that in the lung the pulmonary arteries (and arterioles) run with the bronchi (and bronchioles). Gas-exchange occurs at the capillary-alveolar interface. The pulmonary veins do not run with the airways but are more peripheral. Lymphatics run near the pulmonary arteries and veins to help cope with extravascular lung water.
Development of the Lung
The lungs develop from the lung bud of the gut tube endoderm. This bud eventually branches multiple times into the mesenchyme. The pulmonary circulation develops from the surrounding mesenchyme. The overlapping stages in embryogenesis on the lung include this initial branching, called the embryonic phase (26 days to 6 weeks gestation), the pseudoglandular phase lasting through 16 weeks where 14 more rounds of branching to the terminal bronchioles occurs, and the cannicular phase where the terminal bronchioles branch into respiratory bronchioles (to age 28 weeks). At about 26 to 28 weeks, if a premature infant is born, it has a reasonable chance of survival owing to the production of surfactant that begins at the end of the canalicular stage. Between 28 and 36 weeks, during the saccular phase, the respiratory bronchioles branch into terminal sacs and after 36 weeks, the alveolar phase occurs with maturation of the alveoli, increased surfactant secretion, etc. The lung continues to grow after birth into childhood (with growth occurring with formation of terminal sacs and then alveolarization taking place). Understanding lung development helps us understand why infants born after 36 weeks rarely have respiratory distress due to prematurity
Embryonic stage of lung development
at around 26 days to 6 weeks. The foregut endoderm extends into surrounding mesenchyme and 3 rounds of branching establish lung lobes. Initially asymmetric branching then a dichotomous branching pattern. This forms the proximal structure of the tracheobronchial tree to the level of the subsegmental bronchii and begins to fill bilateral pleural cavaties. Branching pattern determined by mesoderm. At branch points epithelia cell division stopped and collagen is produced. At developing buds, growth factors are produced to induce epithelial mitosis. Other mesodermal and epithelial factors stabilize and develop airways.
Pseudoglandular stage of lung development
6 to 16 weeks. 14 rounds of branching form terminal bronchioles. There is differentiation of conducting airway epithelium. It has a glandular appearance surrounded by mesenchyme. Formation of conduction airways is completed at end of this stage. The presence of cartilage, smooth muscle cells and mucous glands develop from the splanchnic mesenchyme
Canclicular stage of lung development
16 to 28 weeks. Terminal bronchiole divides into 2+ respiratory bronchioles. Surfactant production begins and increases as weeks progress. This stage is characterized by formation of respiratory bronchioles with delineation of pulmonary acinus. Initial development of pulmonary capillary bed. Expansion of airspaces at expense of mesenchyme. Fetal breathing is detected. Epithelial cell differentian beings and it is possible to survive but with respiratory distress problems.
Saccular stage of lung development
28 to 36 weeks. Respiratory bronchioles subdivide to produce terminal sacs (these continue to develop well into childhood. Distal growth and branching of terminal saccule with thinning interstitial space and decrease in cell proliferation. Now have type II and type I epithelial cells
Aveolar stage of lung development
36 weeks to early childhood (4 to 6 years). Lungs grows and alveoli mature: septea thin, single capillary network in alveolar wall, gas exchange unit established. Secondary septal formation. Presence of true alveoli. Type II cells proliferate and differentiate into type I cells. Lengthening and sprouting of capillary network. Fusion of the double capillary network and mature respiration surface for gas exchange.
Type I pneumocytes
90-95% by surface area but 33% by cell number (compared to Type II pneumocytes). Has a flat, thin squamous structure for gas diffusion. Poorly replicative. Form tight junctions with one another which prevent passage of large molecules
Type II pneumocytes
areclustered cuboidal cells that cover ~ 5% of the surface area of the lower area, but comprise ~ 2/3of all the cells in the lower airway(by cell number).Type II pneumocytes contain secretory cytoplasmic inclusions called lamellar bodies which secrete pulmonary surfactant. In addition to secreting surfactant,type II pneumocytes also act as stem cells. They are capable of mitotic division and replace damaged type I and II pneumocytes. The lower airway also contains several other cell types, including: Alveolar macrophages, Mast cells, Club cells (formerly known as Clara cells), and Lymphocytes. Neutrophilsare not normally found in the lower airway, but can be found in there in patients following anacute lung injury (ex: active smokers). In embryology, type II pneumocytes appear at 6 mongths
Surfactant
secreted by type II pneumocytes, acts to decrease alveolar surface tension, leading to an increase in compliance. Surfactants act to decrease surface tension in the alveoli, which ultimatelydecreases the work of inspiration (remember Laplace’s law). Surfactant synthesis does not begin until around week 26 of development. Mature levels of surfactant are not achieved until week 35 of development. Pulmonary surfactant is composed of dipalmitoyl phosphatidylcholine (a type of lecithin). A lecithin-sphingomyelin ratio of > 2.0 in amniotic fluid suggests that the fetal lungs are mature.
An acinus
refers to any cluster of cells that resembles a many-lobed berry, such as a raspberry (acinus is Latin for “berry”). The berry-shaped termination of an exocrine gland, where the secretion is produced, is acinar in form, as is the alveolar sac containing multiple alveoli in the lungs.
Lung embryology
Lung development begins in week 4 and continues until birth, with the majority of development takes place in the third trimester. The respiratory system arises from the embryonic endoderm in the pharyngeal and foregut region. Epithelial cells of primitive foregut invade the splanich mesenchyme. Primitive lung bud develops from an outpouching between the 4th and 6th brachial arches, called the laryngotracheal groove. The respiratory diverticulum is a ventral outgrowth of the foregut that grows anteriorly and inferiorly, developing into the: Trachea, Bronchi, and Bronchioles. Right and left lung bud push into primordial pleural cavity called the pericardioperitoneal. Portions of mesoderm from the paired pericardioperitoneal canals become the visceral and parietal pleura. As the lung buds develop, they push the visceral peritoneum outward expanding to meet the parietal peritoneum against the body wall, shrinking the pericardioperitoneal canals. As the lungs (and the heart) descend into the thorax, the pleuroperitoneal foramen closes. The downward growth of the lungs is halted from the liver. The lungs remain contained within the visceral peritoneum. The lungs develop through progressive division in a sequential order: Main bronchi, Bronchioles, Alveoli. The tracheoesophageal folds on either side of the respiratory diverticulum grow medially to become the tracheoesophageal septum, which separates the foregut into the laryngotracheal tube and the esophagus. The respiratory diverticulum maintains a small, superior communication with the distal pharynx, which will become the laryngeal inlet.
Pulmonary arteries
arise from the 6th aortic arch and muture into pulmonary arch. Pulmonary veins are out growths to left atrium.
General Overview of structure and Anatomical Terms of the Lungs
The lungs are contained within the pleural cavity and are connected via the trachea to the region of the larynx. The conduction system, beginning with the trachea, distributes air in up to about 20 generations of branching to the gas exchange system of the lung. Branching of the trachea to the left and right primary bronchi permits air to enter the left and right lungs, respectively. The primary bronchi branch to the secondary or lobar bronchi (three in the right lung, two in the left) that enter the five lobes of the lung (Upper right, middle right, and lower right, up- per and lower left). These then branch into segmental bronchi that respectively aerate individ- ual segments of the lung (10 in the right lung, 8 in the left). The medical relevance of segments is that each has its own air and blood supply and function as separate subunits. Should disease be restricted to one seg- ment, it can be surgically resected.
Pleura
The lung is contained in the pleural cavity and is covered by a thin elastic layer (the visceral pleura), which is com- prised of elastic fibrocol- lagenous tissue embed- ded with small amounts of smooth muscle, and contains nerves, lymphat- ics and blood vessels, covered by a surface layer of mesothelial cells.
The parietal pleura
lies against connective tissue that is continuous with the periosteum of the ribs and connective tissue of the intercostal muscles. The potential space between the pleural linings is normally negative in pressure relative to the atmosphere, hence, a puncture of the pleural cavity can lead to partial collapse of the lung.
Conduction System of the Lungs
The segmental bronchi further branch, giving rise to smaller bronchi, then to the bronchioles, which can further branch to terminal bronchioles which connect with the respiratory bronchioles of the exchange system.
Histology of the trachea and bronchi
The trachea contains about 20 “c-shaped” cartilagenous rings along its length, connected posteriorly by the trachealis muscle, whereas primary bronchi have segmented cartilagenous plates around their entire diameter. They are similar in their histologic structure, having an inner pseudostratified epithelial layer and a lamina propria that comprise the mucosa, an underlying submucosa of connective tissue, the cartilagenous layer and an adventitia connecting them to surrounding tissues. Larger bronchi contain a circumferential layer of smooth muscle, the muscularis, between the epithelial layer and the submucosa, which is not continuous in smaller bronchi or in the trachea. The tracheal and bronchial epithelium is similar. It is primarily comprised of ciliated epithelial cells, goblet cells, and basal cells. Also present are neuroendocrine cells, albeit in less abundance. The submucosae of the trachea and bronchi contain glands that contribute mucous and serous secretions to the mucosal surface.
Neuroendocrine cells
have small granules and secrete serotonin, bombesin, and other regulatory peptides. They sometimes cluster near nerve terminals and are thought to play roles in reflexive control of vascular or airway diameter.
Goblet cells
secrete mucins and other proteins which accumulate on the surface of the epithelium. A major proportion of incoming particulates bind to the sticky surface of the mucous layer, which therefore serves as the first line of defense against infection and congestion. The degree of hydration of the mucous layer is regulated by ionic channels. The ciliated cells contain 100-200 cilia which move in synchrony, the wave-like action continually pushing the mucous layer, in conveyor-belt fashion, toward the esophagus where it is swallowed. The basal cells are progenitor cells for the goblet and ciliated cells.
Mucosal associated lymphoid tissue
In addition, nodes of lymphocytes (mucosal-associated lymphoid tissue, or MALT) are present in the submucosa and serve as a second line of defense against infectious agents which might have obtained a “foothold” on the epithelial lining.
Bronchioles
Branching of bronchi leads to smaller air- ways which, when the diameter is about 1 mm, no longer have cartilage or glands, called bronchioles. Bronchioles have smooth muscle underlying the lamina pro- pria. They have ciliated cells and goblet cells in the epithelial layer and actively move mucous toward the larger bronchi. As bronchioles branch they give rise to a terminal bronchiole which leads to the ex- change system. Toward the exchange sys- tem, the terminal bronchiole epithelium contains comparatively more club cells, which secrete surface-active substances.
Cystic fibrosis
a chronic congestive disease associated with a defect in control of chloride transport in epithelial cells. Patients are homozygous recessive for the disease which results in a more viscous mucous which is less easily removed. It results in chronic infections and respiratory failure, usually resulting in early death.
Kartagener’s syndrome
a severe genetic defect characterized by chronic respiratory congestion and infections. It results from immotile cilia, usually due to defects in dynein arms. iii. Excessive smoking and/or air pollution leads to a progressive loss of ciliated cells, starting with a loss in synchrony of the cilia “wave”. Ciliated cells become gradually replaced with squamous cells as chronic coughing is used to clear congestion.
The Distal Tract
The terminal bronchioles lead to respiratory bronchioles which begin to open into individual alveoli. They are still primarily bronchioles, containing a smooth muscle layer and an epithelial layer primarily comprised of club cells. These branch giving rise to alveolar ducts which are really alveolar-bounded channels that permit penetration of air into the outermost regions of the lung. Most of the gaseous exchange occurs in the alveolar saccules, which are dead-end, grape-like clusters of alveoli. Pores between alveoli also permit air equilibration be- tween them. This is believed to be important in permitting oxygenation of adjacent regions should individual respiratory bronchioles become blocked.
The Alveoli
The estimated number of alveoli is between 500 million to 1 billion giving rise to about 75 square meters of surface area for exchange. Individual alveoli are small chambers separated by interalveolar septa which are comprised of fibroelastic basal laminae and cells. Interpenetrating the interalveolar septa is an extensive network of capillaries, which approach the number present in the rest of the body.
The two main types of pneumocytes
Two main types of cells, the type I and type II pneumocytes, are found on the side of the alveolar septa that faces the air supply. They are present in roughly equal numbers, but the flat, thin type I cells cover 90% of the surface directly next to the air supply. Type II cells are rounded. Capillary endothelial cells are also very thin in regions of gas exchange, and are tightly apposed to the same basal lamina to which type I cells are bound. The passage of dissolved gases occurs through the air-blood barrier which consists of the surfactant layer, the plasma membranes and cytoplasm of the very thin type I cell, the common basal lamina between the type I cell and the capillary epithelium, and the plasma membranes and cytoplasm of the endothelial cell. Thus, molecules of oxygen must diffuse through plasma membranes five times before reaching the hemoglobin in a RBC.
Type I cells
terminally differentiated and do not divide. They are replenished through division of their progenitors, the type II cells. The type I cells bear considerable oxidative stress and are replaced about every 20 days. The factors that promote type II cell division are not clear, but these cells can be grown in culture where they divide in the presence of alveolar fluid, epidermal growth factor and insulin.
Type II cells
contain granules having multilamellar contents as viewed by the EM. The granules contain surfactant, which lowers surface tension in alveoli and prevents both lung collapse and excessive drying. The surfactant coats the inner (type I) cell surfaces exposed to the air surface. The primary component of surfactant is phospholipid (about 85%), mainly satu- rated phosphatidylcholine. At least 4 surfactant-specific proteins have been cloned (SP-A to D). They have different functions-biophysical, protective and regulatory. For example, SP-A binds to phospholipids and is required for formation of the tubular myelin form of surfactant, whereas SP-D binds to bacteria and inactivates endotoxins. The secretion and removal of surfactant is regulated, with turnover estimated at 5-10 hours. Some components are recycled by type II cells. The molecular organization of surfactant is dynamic. For instance, during long periods of shallow breathing the more peripheral alveoli are not used and the surfactant rearranges leading to increased surface tension. With a few deeper breaths the surface area is expanded with concomitant surfactant rearrangement, decreasing surface tension and enabling ventilation of the previously closed alveoli. Lack of adequate surfactant is a major problem in premature births, where infants who would normally still be receiving placental oxygenation suddenly have to ventilate through the lungs.
Alveolar Defense
In addition to type I and II pneumocytes, the alveolar septa contain, within the loose connective tissue, monocytes, neutrophils and fibroblasts. Monocytes differentiate into alveolar macrophages which can enter the alveolar space. Alveolar macrophages serve as a third line of defense. They phagocytose, right within the air spaces of the alveoli, small inhaled particles and bacteria. They can enter the respiratory bronchioles where they get swept along in the mucous flow, by the millions daily. They can also pass out into lung lymphatics and enter lymph nodes where they function as antigen-presenting cells. Chronic exposure to excessive dust that is undigestable by macrophages is usually workplace-related. In black lung (coal miners), silicosis (fiberglass workers) or chronic exposure to asbestos fibers, macrophages en- gulf particles but cannot digest the material and die in the alveoli. Other macrophages ingest the dead macrophages but also die in the process. An overwhelming amount of undigestible material that cannot be cleared up the respiratory bronchioles accumulates, leading to alveolar damage and less surface area for exchange.
The elasticity of the alveolar septa
is very important to normal ventilation. Expansion through stretching enables exhalation to occur without effort. Loss of elasticity occurs in em- phasema, and is often accompanied by destruction of alveolar septa. Patients especially prone to this disease have an 〈antitrypsin defiency (an inhibitor of trypsin). They display a continued lysis of elastin in alveolar septa which is fatal in homozygotes. In addition, fibrotic dis- eases in which fibroblasts in the septa produce excessive collagen lead to impairment of expansion and gas exchange. The collagen also further separates the normally close apposition of capillary endothelial cells and type I pneumocytes, further limiting gas exchange.
Vasculature of the Lung
The lung receives blood from both systemic arteries (bronchial arteries from the aorta) and the pulmonary arteries from the right ventricle. The pulmonary system is relatively low pressure (about 20-25 mm Hg systole). Pulmonary arteries course along the respective bronchi and terminate in the extensive interalveolar network of capillaries. They do not supply oxygen to the conduction system, but pick up oxygen in alveoli. Oxygenated blood returns to the heart via the pulmonary veins, which sweep up toward the hilus and bring oxygenated blood from the capillaries surrounding the alveoli via the visceral pleura and intersegmental connective tissue back to left atrium of the heart. The bronchial arteries also follow the branches of the bronchi and supply oxygen only to the conduction system. Most of the blood of this system mixes with the pulmonary supply through anastamoses with small pulmonary arterioles and pulmonary capillaries. Bronchial veins drain only the connective tissue of the hilar region of the lungs to the azygous vein.
Respiratory muscles
Inspiration is an active process, which is carried out by the contraction of the inspiratory muscles. It expands the thoracic cavity by moving the diaphragm and the ribs. The most important inspiratory muscle is the diaphragm, which is innervated solely from the phrenic nerves. It contracts during inspiration and as a result the domes of the diaphragm descend and the lower ribs elevate and rotate. When the diaphragm contracts alone, the upper ribs are drawn inwards. During normal breathing the excursion of the domes of the diaphragm is 1.5 cm, increasing to 6-7 cm during deep breathing. Other muscles active during inspiration are the external intercostals, which function by pulling the ribs forward and outward. The sternomastoids and scalenes are generally silent during normal breathing and they are thus considered accessory inspiratory muscles. They become relevant when ventilation or the respiratory load is increased, as during exercise. Their function is to elevate the rib cage.
Active vs. passive respiration
During normal breathing, expiration is passive, as no muscle movement is necessary for it to occur. Active expiration may become necessary at minute volumes higher than 40 lt./min, or in the face of significant expiratory resistance. The most important expiratory muscles are those of the abdominal wall. Their use in breathing is complicated by their role in the maintenance of posture. So, the abdominal muscles are normally active in the upright position, but silent during quiet breathing in the supine position. During active expiration, they act by pushing the diaphragm upwards. The internal intercostals may also assist by pulling the ribs inward and downward and decreasing the thoracic volume.
Diaphragm’s role in disease
The status of the main respiratory muscles, specifically the diaphragm, can contribute directly to problems in breathing during disease. Consider that, in general, the force generated by muscle is a function of its length. The relationship for the diaphragm is shown in. Note that maximal tension (maximal force) for the diaphragm is achieved at 130% of its resting length, and decreases quite steeply for reductions in length. For chronic obstructive diseases such as asthma, chronic bronchitis, and emphysema, there is a tendency to breath at higher-than- normal lung volumes (you’ll hear why later), which is a condition in which the diaphragm is more contracted and reduced in length. Thus, the diaphragm in these patients operates at a mechanical disadvantage. An additional mechanical disadvantage arises out of the fact that the diaphragm at high lung volumes operates at a greater radius of curvature (this reduces the pressure generated by the muscle).
Intrapleural pressure and lung expansion
The critical factor that translates the movement of the thoracic cavity into expansion of the lung is the pressure outside of the lung, called the intrapleural pressure PIP. This pressure develops in the intrapleural space, which is a thin film of fluid interposed between the lung and the chest cavity. The source of PIP is the intrinsic elastic properties of the lung and the chest wall, together with the fact that, in a healthy person, the lung and chest wall deviate significantly from their “intrinsic” equilibrium positions (i.e., what their volumes would be if the lung and chest wall were separated from each other). The lung is more inflated than its intrinsic equilibrium position, and thus there is a force that tends to make the lung deflate. The chest wall, in contrast, is more deflated than its intrinsic equilibrium position, and thus there is a force for it to expand. The two opposing forces on the intrapleural space result in a negative PIP (a vacuum). This essentially acts to “glue” the lung to the chest cavity. During inspiration, the expanding chest cavity thus pulls the lung open, resulting in a larger lung volume. If the connection is broken, as in the case of pneumothorax when air enters the pleural cavity, the chest wall springs out and the lungs collapse.
Measurement of interpleural pressure
Intrapleural pressure can be measured by placing a needle into the pleural cavity and connecting the needle to a water manometer. PIP is generally reported as a difference from atmospheric pressure (in cm H2O). At least within healthy individuals, PIP is negative throughout the breathing cycle, varying between about –5 cm H2O at the end of expiration and –30 cm H2O at the end of inspiration. The heightened (more negative) intrapleural pressure near the end of inspiration is mainly the result of the tendency of the lung to recoil towards its intrinsic equilibrium position and the resulting forces on the intrapleural space; these are their largest when the lung is maximally inflated.
Air-flow during inspiration and expiration
Whether air flows into and out of the lung depends on the gradient between the air pressure at the mouth (Pmouth) and the air pressure in the lung (PL). During inspiration, air flows into the lung because the lung pressure becomes negative with respect to Pmouth (always at atmospheric pressure), while during expiration, air flows out of the lung because the lung pressure becomes positive with respect to Pmouth.
Air flow during inspiration
At the end of both expiration (just before inspiration), there is no air-flow because the lung pressure is zero. To understand how PL becomes negative with respect to Pmouth during inspiration, we need to introduce an additional pressure term, the transpulmonary pressure PTP (sometimes called the transmural pressure), which is the difference between PL and the intrapleural pressure PIP (PTP = PL - PIP). As we will see below in the discussion of lung compliance, PTP provides the driving force for changing lung volume during breathing. Here it is relevant because if we rearrange the equation for PTP to solve for PL, the resulting expression, PL = PTP + PIP, allows us to see that PL will be a function of PTP and PIP. It turns out that during inspiration, both PTP and PIP are rapidly changing, both becoming more negative, but the increase in negativity for PIP happens more quickly than for PTP. This causes PL to transiently achieve negative values. Understanding why the change in PTP lags behind that of PIP requires a full understanding of lung compliance; it basically has to do with the time it takes for the airflow to occur that is associated with lung inflation. One needs to remember mainly that the cause of PL achieving negative values during inspiration is the increase in negativity in PIP that occurs as a result of the lung inflating.
Air-flow during expiration
At the end of inspiration, air-flow stops because air has already flowed into the lung, increasing its pressure back to be the same as Pmouth. During expiration, the chest wall begins to contract, which effectively “releases” the lung from its more inflated state acquired during inspiration. The inherent tendency of the lung to recoil back toward its intrinsic equilibrium position produces a transient positive pressure inside of lung, often referred to as a lung’s elastic recoil pressure. In essence, the deflating lung acts to push air out of the lung. It should be mentioned that we can also explain the generation of the transiently positive lung pressure during expiration as a function of the changing values for PTP and PIP, as we did for inspiration, but this more intuitive explanation should suffice.
Compliance
Compliance, C, provides a measure of the elastic properties of the lung. Compliance is defined as the change in volume per unit change in pressure, C = ⊗V/⊗P. For the lung, compliance can be determined by plotting the volume of air inside the lung as a function of the pressure difference between the outside and the inside of the lung, defined above already as the transpulmonary pressure PTP. The lungs have high compliance at their volume at rest, so that it is easier for them to inflate during normal breathing. At high volumes, the compliance decreases, making expansion more difficult. Compliance is inversely proportional to the elasticity of the lung. A highly compliant lung is one that has lost its elasticity, while a non-compliant lung is highly elastic. Elastance is the reciprocal of compliance. The compliance of the lung differs during inspiration and expiration, with a greater change in transpulmonary pressure being required to effect a given volume change during inspiration. This behavior, known as hysteresis, is a property of all elastic structures. Hysteresis in the lung is due to a combination of the elastic properties of pulmonary cells and surface forces.
Respiratory diseases associated on abnormal lung compliance
Numerous respiratory diseases are associated with abnormal lung compliance. One of these, fibrosis, a disease caused by the infiltration of connective tissue, is associated with low lung compliance, making inspiration difficult. In contrast, emphysema is a disease caused by the loss of elastic tissue, which results in high lung compliance. Although the high compliance makes expansion of the lungs, and therefore inspiration, easier, it creates problems for expiration. Recall from above that, at the end of inspiration, the expanded lungs utilize the stored elastic energy (elastic recoil pressure) to push the air out during expiration. A high compliance will provide less elastic recoil pressure, making it difficult to expire.
Contribution of chest wall compliance
The thoracic cage has to move during breathing, too. The elastic properties of the chest wall are therefore crucial for respiration, and abnormalities in the chest wall compliance can cause respiratory problems. Examples include abnormalities of the bony thorax and of the soft tissue (extreme obesity). Old age is characterized by a general reduction in chest wall compliance. The main impact that this has on breathing is a reduction in the change in volume that the lung undergoes during normal breathing (the tidal volume). Reduced tidal volume ultimately results in reduced air-flow in the lung.
FEV1/FVC
the ratio of the volume of air exhaled in the 1st second of a forceful exhalation to the functional vital capacity. A normal FEV1/FVC ratio is 80%. In obstructive lung diseases, the FEV1/FVC ratio is typically less than 80%. In restrictive lung disease, the FEV1/FVC ratio is greater than 80%.
The A-a (alveolar-arterial) gradient
the difference between the partial pressure of oxygen in the alveoli (PAO2) and the arterial (PaO2) circulation. A normal A-a gradient is generally 5-15 mm Hg, and can be estimated by age using the formula (Age/4) + 4. In order to calculate the A-a gradient, a few other variables need to be figured out.
The alveolar gas equation
PAO2 = PiO2 – (PaCO2/R). PAO2=alveolar PO2in mmHg. PiO2= pressure of inspired oxygen in mmHg (can sometimes be approximated to 150). PaCO2=arterial PCO2in mmHg. R = respiratory quotient, which= (CO2eliminated)/(O2consumed). The alveolar gas equation allows us to calculate thePAO2from an arterial blood gas sample, whichcan beused to ultimatelyestimate the A-a gradient. When breathing environmental air at sea level, the PiO2can be approximated to ~150 (shown below as an example). However, if there is a known altitude change, to calculate the altitude adjusted PiO2:Take the atmospheric pressure (ex: 760 if at sea level) and subtractthe H2O vapor pressure (normally ~ 47) which is the moistureadded to inspired air as it is humidified by the respiratory mucosa. For example, at sea level this would be:(760–47) = 713. Then multiplythe result by the FiO2, which is thepercentage of O2in the air (normally 21%). So continuing with the example at sea level, (713) x(.21) = 149.73. Therefore, theFiO2of room air is 0.21 and thePiO2of room air is 150 mmHg. The A-a gradientis a value that reflects theintegrity of oxygen diffusionacross the alveolar and pulmonary arterial membranes. The A-a gradient can be calculated by subtracting that arterial oxygen concentration and subtracting that from the alveolar oxygen concentration(PAO2 – PaO2)
PAO2= alveolar oxygen pressure PaO2= arterial oxygen pressure
A normal resting A-a gradient in healthy middle aged adults~5-10 mmHg. A-a gradient is normal during conditions of hypoxia caused by: Hypoventilation, Decreased FiO2(experimentally, or at high altitudedue to decreased PiO2). Increased A-a gradient may occur in: Shunting, V/Q mismatch, Aging, Diffusion impairments(ex:interstitial fibrosis or pulmonary edema)
Ventilation
depends on both airway resistance and compliance. In general, ventilation is the amount of air-flow in the lungs. Pulmonary physiologists usually refer to two specific types of ventilation: minute ventilation, which is the volume of air that flows into or out of the lung in one minute, and alveolar ventilation, which is the volume of air that flows into or out of the alveolar space in one minute. Because minute ventilation includes air flowing in the conducting paths, as well as alveoli, it will always be larger than alveolar ventilation. Typical values for minute and alveolar ventilation under resting conditions, respectively, are 6 L and 4.2 L. Alveolar ventilation is usually designated V ̇A .
Factors that influence alveolar ventilation
bronchodilators and constrictors, exercise, altitude, obstructive disease and restrictive diseases, and gravity
Bronchodilators and constrictors affect of alveolar ventilation
Recall from above the list of chemical factors that can influence airway resistance. The same factors that influence airway resistance also alter ventilation. Bronchodilators increase alveolar ventilation, whereas bronchoconstrictors reduce ventilation.
Exercise affect of alveolar ventilation
During moderate exercise, ventilation can increase ~10-fold in order to meet the demands of increased CO2 production.
Altitude affect of alveolar ventilation
Ventilation increases to meet the increased demands of O2. Obstructive diseases and restrictive diseases. These can reduce ventilation by increasing airway resistance or altering lung compliance. A good example is emphysema, which reduces ventilation by increasing airway resistance (owing to dynamic airway collapse) and increasing lung compliance (which makes it more difficult to expire). For many obstructive diseases, especially for mild-to-moderate forms, overall ventilation does not go down, but there are reductions in ventilation regionally that are balanced by increases elsewhere. This condition can be just as bad for exchange of oxygen.
Gravity affect of alveolar ventilation
This factor is also an important contributor to regional differences in ventilation. To understand the role of gravity in ventilation, recall again the concept of intrapleural pressure (PIP), the pressure outside of the lung. Previously, we considered PIP as if it were uniformly distributed. But, PIP is not uniform; it is smaller at the base than the apex of the lung. A cause for this difference is the weight of the lung, which would result in a stronger pull from the chest wall at the apex. Because the intrapleural pressure is larger (more negative) at the apex, the bronchioles and alveoli there will have larger volumes (the vacuum in the intrapleural space essentially pulls them open). Somewhat counter-intuitively, the larger volume means that they will be less well ventilated. The reason for this can be understood by considering again the pressure-volume curve for the lung, here altered to consider the volume of individual alveoli. As for the entire lung, the curve for alveoli is steep at low volumes, but becomes considerably less so at high volumes, meaning that they are less compliant at high volumes. The smaller compliance of alveoli at the top of the lung means that they will undergo a smaller change of volume with each breath, thus ventilating much less. The bottom of the lung, on average, ventilates ~2.5 times more than the top.
Work of breathing
The combined impacts of lung compliance and airway resistance not only affect the magnitude of air flow in the lung (ventilation), but they also impact how we breath. By this, we mean the frequency of breathing and the volume of air in each breath (called the tidal volume, for quiet breathing). Do we breath at high frequencies with low tidal volumes or at low frequencies and large tidal volumes? The answer can be obtained by considering that breathing involves a certain amount of “work” that is done by the respiratory muscles on the lungs. The work done in moving the lungs has two major components: (a) work done against the elastic recoil of the lungs and (b) work done against airway resistance. An increase in the work of breathing can occur because of an increase in elastic recoil (decreased compliance) of the respiratory system, because of an increase in airway resistance, or a combination of the two. The different components of work terms vary under normal conditions for different types of respiration, as defined by frequency and tidal volume (VT). For small tidal volumes (the right side of the x-axis) the work required to overcome elastic recoil is small, but the work required to overcome airway resistance is large. The larger work combating airway resistance results from the fact that when you breath at high frequencies, you will not inflate your lung to large lung volumes during inspiration, a condition which, as discussed above, opens up the airways. For large tidal volumes, the reverse is true. The work to overcome elastic recoil increases, while the work required to overcome airway resistance drops for much of the breathing cycle. Somewhere in the middle (the low point on the “Total Work” curve) is the point of least amount of work, which is where a person typically breathes. Irregularities in the compliance and resistance during disease produce deviations in the plot. Someone who has a decrease in respiratory compliance (e.g., with pulmonary fibrosis) would breath at a smaller tidal volume with an increase in respiratory rate, in order to reduce the elastic work. In contrast, someone whose primary problem is an increase in airway resistance would want to breath with larger tidal volumes in order to reduce the resistance work.
Dead-Space
A last remaining issue related to airflow in the airways is the concept of dead-space. As discussed above, not all of the air that is taken in with each breath actually reaches the alveoli, the sites of gas exchange. Of the 500 ml of air in each breath (the average tidal volume), about 150 ml (or 30%) remains in the conducting path. This air is termed anatomic dead-space. In some sense, this airflow is wasted, insofar as it does not engage in gas exchange. Thus, an increase in the relative proportion of the anatomic dead-space can profoundly impact the efficiency of breathing. Such increases can happen under conditions in which we breath rapidly and at small tidal volumes (when much of the tidal volume fails to reach alveoli) or during snorkeling (which increases the total conducting path for air).
alveolar dead space
Apart from anatomic dead space, there is also alveolar dead space. These are alveoli that are well-ventilated but nevertheless do not participate in gas exchange. Such alveoli do not eliminate CO2, just like the conducting airways. Such alveoli would be those that are in unperfused regions of the lung, i.e., regions that lack blood flow (we will come back to the issue of lung perfusion in a later lecture). As with anatomical dead-space, increases in alveolar dead- space leads to wasted ventilation and decreases in the efficiency of breathing. The sum of the anatomic dead-space and the alveolar dead-space is called the physiologic dead-space. Physiologic dead space is, in general larger, than anatomic dead space, though for healthy individuals the difference between the two volumes is too small to be measured. Significant differences between anatomic and physiologic dead space are an indication of disease. Both anatomic and physiologic dead-space can be measured with relatively straightforward pulmonary function tests.
residual volume RV
The smallest lung volume of interest is the residual volume RV, which is the volume of air remaining in the lungs after a maximal expiration. This is on the order of 1.5 liters.
functional residual capacity, FRC
The volume of gas present in the lung and upper airways at the end of a normal expiration is called functional residual capacity, FRC, and is ~ 2.5 liters.
total lung capacity, TLC
The volume of air inside the lungs at the end of a maximal inspiration is the total lung capacity, TLC. This is the maximal volume that can be obtained by the lung and is ~7.5 liters.
tidal volume, VT
There are also important volumes that reflect differences in lung states. For example, tidal volume, VT, is the difference in lung volume between a normal inspiration and normal expiration. Tidal volume is, thus, also the volume of air that enters and exits the lungs in one normal breathing cycle. A typical value for VT is 500 ml.
vital capacity, VC
The volume of air exhaled after a maximal inspiration followed by a maximal expiration is called vital capacity, VC. VC = TLC - RV.
minute ventilation or minute volume (ml/min)
The tidal volume (ml)∗frequency of breathing (breaths/min) product is called minute ventilation or minute volume (ml/min).
Measurements of lung volumes
Changes in the lung volume (VT and VC) can be measured with a spirometer. This test is simple and widely used. In order to measure the other volumes, such as the functional residual capacity FRC, different approaches have to be employed.
body plethysmograph method
In one method, the body plethysmograph method, the subject sits in an airtight chamber, breathing through a mouthpiece. FRC is estimated essentially from the change in pressure that occurs when the lung expands.
forced expirogram
There are also dynamic measurements of lung volume. The most common of these is called the forced expirogram, which is particularly effective in separating normal from obstructive and restrictive anomalies. the volumes measured by a spirometer when a subject inspires maximally and then exhales as hard and as completely as possible. The volume exhaled in the first second is called the forced expiratory volume, FEV1.0. The total volume exhaled is the forced vital capacity, FVC (or just vital capacity VC). For normal subjects, the ratio FEV1.0/FVC is about 80%. This test is particularly effective in diagnosing diseases that impact airway resistance and some diseases that increase compliance.
a restrictive disease and pulmonary function tests
such as pulmonary fibrosis. Recall from a previous lecture that this is a disease caused by the infiltration of connective tissue, which decreases lung compliance, making inspiration difficult. With this disease, we predict that there will be a change in the vital capacity, VC, since the difficulty in expanding the lung will prevent the patient from inflating his lung maximally upon a forced inspiration. A restrictive disease however may not show up as a significant reduction in the rate of air-flow during dynamic measurements of expiration (the ratio between FEV1.0/FVC). That’s because restrictive diseases do not impact airway resistance; also, the decrease in lung compliance can actually cause small increases in the FEV1.0/FVC ratio.
Obstructive diseases and pulmonary function tests
such as chronic bronchitis and asthma are associated with increases in airway resistance. Thus, there are pronounced effects on dynamic measurements of expiration; the FEV1.0/FVC ratio decreases significantly. In terms of static lung volumes, obstructive diseases are typically associated with increases in the functional residual capacity FRC and residual volume RV. One reason is air- trapping. Because of the limitation of airflow during expiration, there may be extra air trapped inside the lungs at the end of expiration. Also, patients tend to breath at higher lung volumes, both so that they can lower airway resistance and, also, so that they can increase the elastic recoil pressure. In measurements of changes in lung volume, such as vital capacity VC, these obstructive diseases cause decreases. That’s related to the increase in airway resistance and the air-trapping phenomenon, which increase RV.
Emphysema and pulmonary function tests
is also an example of an obstructive disease since it increases airway resistance, through dynamic airway collapse. Patients tend to inspire quickly and expire slowly through pursed lips. Emphysema shows up during pulmonary function tests as a reduced rate of expiration (a reduced FEV1.0/FVC ratio) and an increase in the functional residual capacity FRC, like other obstructive diseases. Unlike the other obstructive diseases, emphysema can be associated with unchanged or small increases (not decreases) in vital capacity. That’s because the increase in lung compliance allows emphysema patients to achieve higher maximal lung volumes (total lung capacity) upon forced inspiration.
Oxygen transport in the airways
O2 transport in the airways can be separated into two steps: (1) transport of O2 from the outside air into the airways; and (2) transport of O2 through the airways into alveoli. The latter depends on ventilation, or, more formally, alveolar ventilation, which was discussed in an earlier lecture. These two steps yield specific quantities of O2: PIO2, which is the partial pressure of O2 in inspired air at the point at which it has just entered the airways, and PAO2, the partial pressure of O2 in alveoli. These numbers, PIO2 and PAO2, are of obvious interest because they place upper limits on the amount of O2 that can ultimately enter blood.
barometric pressure (PB) of air
the sum of the partial pressures of the gas mixture in air: PB = PIN2 + PIO2 + PICO2 + etc.
Dalton’s Law for inspired air
For estimating PIO2 for inspired air, one cannot however simply multiply these fractions times the barometric pressure PB. These fractions were for dry air. One has to take into account the fact that when atmospheric air enters the airways, it becomes saturated with water vapor at 37 0C. At this temperature, the partial pressure of water vapor is 47 Torr. Estimating PIO2 using the fractional values of O2 for dry air thus requires that we first subtract off the water vapor pressure from the barometric pressure: PIO2 = (PB – 47 Torr) ⋅ 0.21. At sea-level, the barometric pressure is 760 Torr, which substituting into the equation, gives a value of PIO2 = 150 Torr. With increases in altitude, it is important to point out that the water vapor pressure stays constant (47 Torr). Thus, in Denver, where PB is typically 620 Torr, PIO2 is estimated to be 120 Torr.
Alveolar oxygen (PAO2)
The partial pressure of oxygen in inspired air PIO2 sets the upper limit for the partial O2 pressure in alveoli, PAO2. For understanding the degree of decrement in oxygen between inspired air and alveolar air, consider a bolus of air that is moving from the airways into an alveolus. Notice that, whereas inspired air has only two main components, oxygen and nitrogen, alveolar air also has a third component CO2, which is expelled from the blood. This presents a bit of a problem for this system, which must maintain near-constant total barometric air pressure PB throughout the airway (of course, there may be some small pressure gradients to account for air movement). In order to accommodate the extra CO2 component in alveolar air while maintaining near-constant barometric pressures, some of the oxygen and/or nitrogen in alveolar air must be replaced by CO2.
How much of the alveolar oxygen and nitrogen is replaced by CO2?
An important clue is provided by recalling that CO2 is a metabolic product of the same biochemical reactions in tissues that utilize oxygen. In fact, when those metabolic reactions produce the exact same quantity of CO2 as oxygen consumed, oxygen in the alveolus is exchanged for CO2 in a one-to- one fashion. In this situation, the additional CO2 in the alveolus is entirely accounted for by a reduction in oxygen. These considerations lead naturally to the first equation that describes the decrement in alveolar oxygen PAO2 with respect to PIO2: PAO2 = PIO2 - PACO2 (equation for R=1). Here PAO2 will simply reflect oxygen in inspired air minus the carbon dioxide. This equation is the simplest form of the alveolar gas equation. For a typical PIO2 at sea level = 150 Torr and a typical PACO2 = 40 Torr, the equation gives PAO2 = 110 Torr.
respiratory exchange ratio (R)
for many important metabolic reactions such as oxidative phosphorylation, there is less carbon dioxide produced as compared to oxygen consumed. The exact relationship between O2 consumed and CO2 produced is given by the respiratory exchange ratio (R), which is the ratio of the amount of CO2 generated ( V ̇CO 2) per amount of O2 consumed ( V ̇O 2 ): R= V ̇CO2/ V ̇ O 2. R varies for different metabolites. It is near one for carbohydrates but drops to 0.7 for fats (meaning that for every 10 molecules of O consumed, only 7 molecules of CO are produced). For a typical diet, R is about 0.8
CO2 transport in the airways
CO2 is of course transported in a direction opposite from O2: from our blood, through airways, and out into the outside air. We begin the discussion of CO2 transport in airways by also discussing the transport step that just precedes it: diffusion of CO2 from pulmonary capillaries into alveoli. The step of CO2 transport from alveoli to outside air will depend on alveolar ventilation V ̇A . There are 2 main principles that form the basis for understanding much of CO2 transport. The first is that the diffusion-step is extremely fast, meaning that, for all practical purposes, CO2 in alveoli and in pulmonary capillaries equilibrates near-perfectly. This is true even under quite severe disease conditions. A result of this near-perfect equilibration is that the partial pressures of CO2 in alveoli (PACO2) and that ultimately seen in arterial blood (PaCO2) will be very nearly equivalent: PACO2 = PaCO2. The second main principle is a corollary to the first: how efficiently the body transports CO2 out of the body is much more dependent on the step of CO2 transport between alveoli and the outside air. Accordingly, many more things can go wrong with CO2 transport due to problems with this step. Consider for example what would happen if alveolar ventilation V ̇A goes down. First, PACO2 will increase, as a result of the fact that the rate of removal of CO2 from alveoli will decrease, leading to CO2 accumulation. Then, because blood CO2 equilibrates near perfectly with alveolar CO2, PaCO2 will increase by a near-equivalent amount. This is bad, because PaCO2 is ultimately what we care about. If VA goes up, PACO2 and PaCO2 will decrease by near-equivalent amounts.
How does one relate PACO2 to alveolar ventilation V ̇A in a quantitative way?
For setting up this equation, imagine a body that is constantly producing CO2 and also getting rid of it through the ventilation process. At equilibrium, the rate of CO2 production must be matched by the rate of removal of CO2 from alveoli (or else our blood would have ever-increasing concentrations of CO2!). If we express the CO2 quantity being ventilated in terms of volumes and CO2 concentrations CACO2, this equilibrium situation can be expressed as: V ̇CO2 =V ̇A xCACO2. where V ̇CO 2 is the quantity of CO2 produced in one minute. Rearranging, we have CACO2= V ̇CO2/ V ̇A.
alveolar ventilation equation
PACO2= V ̇CO2/ ̇VA * K. where k is a constant the value of which is given according to the units and the conditions. Because PACO2 is essentially equivalent to
PaCO2
one can also substitute PaCO2 for PACO2 in the equation. This expression is useful for determining exactly what effect different ventilation rates will have on arterial PaCO2.The very tight relation between alveolar ventilation and PACO2/PaCO2, as expressed in the alveolar ventilation equation, is of crucial importance. For example, the equation shows that if the alveolar ventilation rate is doubled (and CO2 production remains unchanged), PACO2 and PaCO2 will be exactly halved.
Measurement of alveolar ventilation
Rearranging the ventilation V ̇A and PACO2 terms in the above equation yields the modified expression: VA=VCO2/PACO2*K. This equation shows how alveolar ventilation V ̇A can be estimated under practical conditions. V ̇ (CO production in one minute) can be measured by catching the air expired by a subject, and measuring the volume of expired air and concentration of CO2 (done with a CO2 analyzer). PACO2 can be estimated from arterial PCO2 (since, again, alveolar and arterial PCO2 are nearly equivalent), and k can be looked up in a book
Hypoventilation and hyperventilation
The discussion of the relationship between alveolar ventilation and PACO2 /PaCO2 brings us to some important definitions for words that you will hear repeatedly. The terms “hypoventilation” and “hyperventilation” are used to indicate that alveolar ventilation is abnormally low or abnormally high, in relation to CO2 production and elimination rate. In a subject breathing atmospheric air, a decrease in PaCO2 (and an associated increase in V ̇A ) means
hyperventilation
while an increase in PaCO2 (a decrease in V ̇A ) means hypoventilation. At sea level, a “normal” PaCO2 ranges between 35-45 Torr; if a patient deviates from this range, he is said to be hyper- or hypoventilating. In Denver, the normal PaCO2 range is 30-40 Torr (lower because of chronic hypoxia, which increases ventilation). Common causes of hyperventilation include acute hypoxemia (low arterial oxygen), metabolic acidosis, or CNS stimulation. Hypoventilation can be caused by obstructive/restrictive disease, metabolic alkalosis, or CNS depression. It is important to remember that hyperventilation and hypoventilation refer to ventilation and not frequency of breathing! A higher than normal frequency of breathing is referred to as tachypnea (Greek for fast-breathing). Also, an increase in ventilation that is not accompanied by a reduction in PaCO2 will not be called hyperventilation either. For example, during moderate exercise, the increase in V ̇A matches the increase in CO2 production V ̇CO 2 , resulting in a PaCO2 that is the same as at rest. The increase in ventilation during moderate exercise is called hyperpnea (Greek for lots-a-breathing).
Basic properties of oxygen in blood
Oxygen in blood is carried in two basic forms, reflected in the equation: CaO2 = hemoglobin-bound O2 concentration + freely-dissolved O2 concentration. CaO2 is the arterial oxygen content, which is the total concentration of O2 in blood. For a healthy person CaO2 is about 9.1 mM (expressed in millimoles) or 20.7 ml O2/100 ml blood (a more common way of expressing it in a clinical setting). Of the total arterial oxygen content, the vast majority of it (>98%) is bound to hemoglobin (called oxy-hemoglobin). The freely-dissolved concentration is much smaller, but it is the component that is reflected in partial pressure values (PO2) typically provided for arterial blood (called PaO2). In the next two subsections, we consider (1) the reasons why so little O2 is freely-dissolved, and (2) the basic properties of O2 binding to hemoglobin as reflected in the oxy-hemoglobin dissociation curve.
Oxygen solubility
One of the fundamental reasons for why so little O2 is carried in blood in freely-dissolved form is that O2 simply does not dissolve very well in blood (the other reason is that O2 binds quickly to hemoglobin). The tendency of any molecule to dissolve in a liquid is given by its solubility coefficient, which for O2 is expressed as aO2. At 37 0C, in isotonic NaCl solution (close enough to blood), the solubility coefficient for O2 is aO2 = 0.0013 mM/Torr. This value for aO2 is a small number. If one uses the expression [O2] = aO2 x PO2 to find the dissolved O2 concentration in blood ([O2]), one gets a value of only 0.13 mM (expressed in millimoles) at a typical arterial PO2 of 100 Torr. If one expresses dissolved concentrations in ml O2/100 ml blood, the solubility coefficient is aO2 = 0.003 ml O2/100 ml blood/Torr and the oxygen concentration (for PO2 = 100 Torr) is 0.3 ml O2/100 ml of blood. The small solubility coefficient for O2 compares with a moderate coefficient for CO2: aCO2 = 0.03 mM/Torr. Note that CO2 is about 20 times more soluble in blood than O2. As will be seen below, the differences in solubility between O2 and CO2 has implications for understanding how diffusion of these two molecules between alveoli and pulmonary capillaries is impacted by disease.
Oxy-hemoglobin dissociation curves
Since only about 0.13 mM of the oxygen in arterial blood is freely dissolved, this means that, of the 9.1 mM of arterial oxygen content, about 9 mM is oxy-hemoglobin. Here we consider some basic aspects of O2 binding to hemoglobin, as expressed in the oxy-hemoglobin dissociation curve. This curve relates oxygen saturation of hemoglobin, SO2, at equilibrium, to the PO2 in the blood. For PO2 = 100 Torr, which is normal arterial oxygen, SO2 = 97.5%. This means that in arterial blood, hemoglobin is very close to full saturation: a further increase in PO2 would not substantially increase the amount of O2 carried by hemoglobin. The high degree of hemoglobin saturation at arterial PO2 has important implications for understanding perfusion-effects on arterial oxygenation (see below). For PO2 = 40 Torr (mixed venous blood), SO2 = 75%, while half- saturation, SO2 = 50%, occurs for PO2 = 26 Torr. Importantly, the curve is steep at moderate PO2 between 20 to 60 Torr (recall that the steepness comes from the fact that O2 binding to hemoglobin is a “cooperative” process). The steep drop in SO2 with decreasing PO2 allows peripheral tissues that see relatively unsaturated hemoglobin to withdraw larger amounts of O2 for only small drops in capillary PO2. The standard ODC applies exactly only under the following conditions: pH = 7.40; PCO2 = 40 Torr; temperature = 370C; and [2,3-DPG] = 15 μmoles/gr Hb.
Diffusion
The rate of gas transfer across an arbitrary tissue plane is a function of the (1) the difference in partial pressure of the gas on the two sides of the membrane, (2) the tissue plane area (A), (3) the tissue thickness (d), and (4) a constant k reflecting the tissue solubility and molecular weight of the gas. If the gas transfer rate is defined as VG, then we have: VG = (P1-P2) x A/d x k (Fick’s Law) where P1 and P2 are the partial pressures of the gas on one or the other side of the membrane. This equation is commonly known as Fick’s Law for diffusion. In this equation, the terms A, d, and k are often grouped into a single constant called the diffusing capacity Dm: D m = A/dx k. Dm is thus a function of the physical properties of the tissue plane (A and d), as well as of the gas in question (reflected in the constant k). The most common way of determining diffusing capacity is the CO single breath method.
Factors that maximize O2 flux
If one considers oxygen diffusion across the alveolar membrane, it turns out that, under normal conditions, several factors conspire to maximize O2 flux. The first is the large surface area A of the alveolar membrane. One adult human lung has about 300 million alveoli, providing a surface area of 50-100 m2 (about half the size of a tennis court!). By contrast, a single sphere with a volume of 4 liters would have an area of only 1/100 m2. This difference illustrates how the lung morphology is well-adapted for diffusion. Equally important is the thin membrane width d, only about 0.3 μm. Since d is in the denominator of Fick’s Law, the thin membrane maximizes diffusion. A last factor that promotes oxygen diffusion is a mechanism that helps maintain a large oxygen pressure gradient between alveoli and capillaries (PAO2- PcapO2). Specifically, the low solubility of O2 in blood, together with the tendency for O2 to bind quickly to hemoglobin, ensures that PcapO2 remains low and the gradient (PAO2- PcapO2) large. The question is how quickly the capillary PO2 reaches the alveolar PAO2 = 100 Torr, which is the maximal value that PO2 can be in the blood. Under normal conditions, one can see that PO2 reaches 100 Torr very fast, in about 1/3 of the time it takes for blood to pass through the capillary bed. If PO2 reaches alveolar values in 1/3 of the time it spends in the pulmonary circulation, why, then, have all of that extra time for diffusion to occur? The extra time is essentially a safety net, to account for situations such as exercise, when the faster blood flow reduces the time that diffusion can occur. The extra time also accounts for pathologic conditions in which O2 and CO2 transfer slows.
Disease and oxygen diffusion
During interstitial disease, when there is thickening of the alveolar walls (increased d), the rate of diffusion is slowed, sometimes to the point where arterial oxygen levels do not reach alveolar levels. Diffusion can also go down during emphysema, when breakdown in lung tissue decreases the surface area for diffusion (decreased A). One last condition that can alter diffusion somewhat is abnormalities in the hemoglobin concentration, in situations of polycythemia (when diffusion increases) or anemia (when perfusion decreases). This can impact the pressure gradient for oxygen diffusion by altering free oxygen levels in blood. It should be pointed out, however, that changes in hemoglobin concentration generally exert much larger effects on tissue oxygenation by altering oxygen delivery to tissues (see next lecture) rather than through changes in oxygen diffusion.
Comparison of CO2 and O2 diffusion
In the case of CO2, PCO2 must go from a value of 45 Torr (the value in mixed venous blood coming via the pulmonary artery) to an alveolar PACO2 = 40 Torr. CO2, like O2, reaches the alveolar value in only about 1/3 of the time it takes for blood to pass through the capillary bed. An important difference between O2 and CO2 is that O2 diffusion is much more affected by disease. Recall from above that O2 is 20 times less soluble in blood than CO2. It turns out that this consideration impacts the diffusion process, since O2 diffusion between alveoli and blood requires that it be dissolved (since only dissolved O2 can cross the alveolar membrane and enter blood). Thus, while O2 diffusion is generally quite efficient for all of the reasons cited above (small d, large A, large pressure gradient), it is somewhat slowed by its poor solubility even under normal conditions, and, so, is susceptible to disease. In contrast, the ease at which CO2 dissolves means that CO2 diffusion is much less affected by disease. With extremely large reductions in diffusing capacities (by >75%), CO2 levels can fail to reach alveolar values by the time blood passes through the capillary bed, but this is extremely unusual.
Perfusion versus diffusion-limited transfer rates
Pulmonary physiologists use two terms to distinguish between situations in which O2 has reached its maximal value by the time it has passed through the pulmonary capillary bed and those in which it has not. If conditions do permit rapid equilibration of blood with alveolar air, and PO2 and PCO2 in blood exiting the pulmonary exchange area is similar to alveolar PO2 and PCO2, the O2 transfer rate is said to be perfusion limited. This means that for a given composition of alveolar air and of venous blood entering the lungs, the only major factor limiting the rate of oxygen uptake and CO2 excretion is pulmonary blood flow. This is the normal condition, even during moderate exercise. If these conditions do not permit the complete equilibration of alveolar air and blood, then the PO2 in the blood exiting the pulmonary exchange area will be less than alveolar PO2, and the O2 transfer rate will be diffusion limited.
Perfusion
Since blood is the carrier of O2 and CO2, the blood flow through the lung, the perfusion of the lung, is very important. Perfusion, Q ̇, is the blood flow of the pulmonary circulation available for gas exchange (in one minute). Perfusion equals the cardiac output, which for an adult at rest is Q ̇ = 5 liters/ min. At any given time, there is about 500 ml blood in the lung, comprising 40% of the lung weight. The pulmonary circulation has very low blood pressure. The reasons are the vast number of vessels and their normally dilated state. In conformity with the low pressure, the walls of the pulmonary artery and its branches are very thin and contain relatively little smooth muscle. The reason for these properties of the pulmonary vessels and circulation is related to the function of the pulmonary circulation: the lung receives all of the cardiac output and does not have to direct blood from one region to another; the low pressure keeps the work of the right heart as small as possible for efficient gas exchange.
O2 tension regulation of perfusion
The factor of overriding importance in governing minute-to-minute regulation of the pulmonary circulation is the alveolar O2 tension, PAO2. O2 diffuses through the thin alveolar walls into the smooth muscle cells of the microvessels. The response of the pulmonary vascular smooth muscle to low PO2 is opposite from that of the systemic circulation. Low alveolar PO2 constricts the nearby arterioles. This constriction, hypoxic pulmonary vasoconstriction, decreases local blood flow and shifts it to other regions of the lung.
Other chemical agents regulation of perfusion
Other agents that regulate perfusion are thromboxane and prostacyclin, two products of arachidonic acid metabolism. Thromboxane A2 is the most important vasoconstrictor, and, as with O2, its effect is mainly localized to the region of release. Prostacyclin (prostaglandin I2) is a potent vasodilator.
Capillary recruitment regulation of perfusion
In the case of moderate exercise there is passive regulation of perfusion. Cardiac output may rise 3-fold, and the increase is accommodated by the pulmonary circulation through recruitment of new capillaries and distension of previously-open microvessels. The volume of blood in the pulmonary capillaries at rest is ~75 ml. This can increase up to 200 ml through capillary recruitment.
Gravity regulation of perfusion
Because of gravity, the pulmonary blood pressure is low at the apex of the lung. At the base of the lung, the blood pressure is higher, allowing more capillaries to open and higher blood flow. Thus, perfusion increases as we go from the apex to the bottom of the lung. This change is about 6-fold. There may also be additional regional differences in perfusion due to a variety of causes, as local hypoxia, obstruction of blood vessels, etc. The significance of the variability in perfusion through the lung is related to the ratio between ventilation and perfusion (the V/Q ratio), which is a determining factor for oxygenation of blood (see below).
Perfusion problems and gas exchange
There are a number of ways in which problems in perfusion, together with ventilation, can impact gas exchange. Alveolar dead-space. Recall from a previous lecture that alveoli in unperfused regions of the lung are referred to as alveolar dead-space. Such a condition can happen if, for example, a patient has a blockage in a pulmonary capillary. These alveoli are well-ventilated, but because they do not engage in gas exchange, their ventilation is wasted.
Shunts
Alveolar dead-space corresponds to a region of the lung in which ventilation is normal but there is no perfusion. There is also shunt, which is blood perfusion where there is no ventilation. A small amount of shunt is normal because some venous blood enters the left atrium and ventricle by way of the bronchopulmonary venous anastomoses and the intracardiac Thebesian veins. This amounts to 1% to 2% of the cardiac output normally. Shunts can decrease arterial oxygenation significantly, when the well-ventilated blood mixes with the shunted blood. A shunt does not usually result in a raised arterial PCO2. The tendency for CO2 to rise is generally countered by the central chemoreceptors, which increase ventilation if PCO2 increases.
Causes of V/Q mismatch
include pulmonary disorders such as obstructive lung disease. In addition, even healthy individuals standing upright have some degree of V/Q mismatch owing to the effects of gravity. We have already discussed the decrease in ventilation and perfusion that results from gravity-effects as we go from the bottom to the apex of the lung. Because gravity has differing effects on the magnitude of ventilation and perfusion in different portions of the lung, there are resulting variations in the V/Q ratio (higher V/Q at the apex). These effects are significant enough to contribute to the 5-10 Torr difference between arterial PaO2 and alveolar PAO2 that is typically observed.
Effect of V/Q mismatch
To understand the effect of V/Q mismatch on arterial oxygenation. The key problem is that the high V/Q branch cannot add very much more oxygen as compared to the normal V/Q branch (note that the O2 content of the high V/Q branch is only slightly more than the normal branch). This is because hemoglobin is already near saturation under normal V/Q conditions. Hence, the high V/Q branch cannot make up for the deficiency in oxygenation caused by the low V/Q branch. In terms of CO2, V/Q mismatch per se generally does not reduce arterial PCO2, similar to the case of a shunt. This is because increases in PCO2 in parts of the lung with low V/Q are generally countered by increases in ventilation in other parts of the lung (these are mediated by central chemoreceptors).
Local mechanisms of V/Q mismatch regulation
There are two local mechanisms that regulate V / Q mismatch. (1) In lung areas with high V / Q ratios, the alveolar PCO2 drops, leading to an increase in local airway resistance and decreasing ventilation. Thus, V / Q tends to go down. (2) In lung areas with low V / Q ratios, the alveolar PO2 drops, leading to hypoxic vasoconstriction and decreasing local perfusion (see above). Thus, V /Q tends to go up.
Oxygen off-loading
a vast majority of O2 in arterial blood (>98%) is in a form bound to hemoglobin (called oxy-hemoglobin). This is important because it allows delivery of a significant quantity of O2 to tissues, despite the fact that O2 dissolves very poorly in blood. An equally important aspect of hemoglobin relevant to oxygen delivery is related to the dynamics of O2 unbinding from hemoglobin (called “off-loading”). The key issue here is that tissues can only use freely-dissolved oxygen, and fast unbinding makes O2 available to the tissues. Without fast unbinding, total oxygen levels might be high, but most oxygen molecules would stay bound to hemoglobin and be unavailable for use. It should be kept in mind that even though O2 unbinding rates from hemoglobin are fast, O2 binding rates are even faster, so that at any given moment in time, most O2 is bound to hemoglobin.
Bohr effect
The rates of O2 binding/unbinding to hemoglobin are also properties that can change. This is reflected in the oxy-hemoglobin dissociation curve (ODC), introduced in the last lecture. The ODC reflects the equilibrium between O2 binding and unbinding to hemoglobin. ODCs under two conditions cause rightward shifts in the curves: decreases in pH or increases in PCO2 as compared to normal (normal pH = 7.40; normal PCO2 = 40 Torr). A rightward shift in the ODC means that O2 is binding less tightly to hemoglobin. The effect of pH on the ODC is specifically called the Bohr effect.
Rightward shift in the ODC
An ODC markedly shifted to the right of normal has the disadvantage of providing arterial blood with a low saturation, but it can also have important beneficial effects. Consider that pH decreases and PCO2 increases locally within muscles during exercise, which is when muscle cells benefit from having more available free O2. The decrease in O2 affinity to hemoglobin, corresponding to the rightward shift in the ODC, means that more O2 is available through off-loading. Notably, increases in temperature, which also happens during exercise, also cause rightward shifts in the ODC. A final factor causing a rightward shift in the ODC is an increase in [2,3-DPG], as happens during chronic hypoxia at altitude.
Leftward shift of OCD
The ODC can also shift to the left, due to decreases in [H+] (increase in pH), PCO2, temperature, or [2,3-DPG]. This has the disadvantage in that O2 binds too tightly to hemoglobin and thus there is less unloading at peripheral tissues. The normal position of the ODC can be viewed as a compromise between the ability to load and to unload O2.
Quantifying O2 delivery
Such calculations are obviously important for determining effects of diseases that impact blood oxygenation. The quantity of O2 delivery happening in one minute, D ̇O2, is equal to the cardiac output Q ̇ times the concentration of oxygen in arterial blood, CaO2: D ̇ = Q ̇ x C (in ml blood per minute) O2 aO2. CaO2 is the total concentration of oxygen, including hemoglobin-bound and freely dissolved components. These can be expressed as: CaO2 = (SaO2 ⋅ [Hb] X 1.39) + (0.003 ⋅ PaO2) (in ml O2 / 100 ml blood). hemoglobin-bound O2= SaO2 ⋅ [Hb] X 1.39. freely-dissolved O2= 0.003 ⋅ PaO2. The hemoglobin-bound term is a function of the concentration of hemoglobin [Hb] and the degree of oxygen saturation of hemoglobin SaO2. The value of 1.39 is the maximum volume of O2 (in ml) that can combine with 1 gram of hemoglobin (with units of ml/gm).
oxygen carrying capacity of hemoglobin
The term ([Hb] x 1.39) is often referred to as the oxygen carrying capacity of hemoglobin, which is the maximum amount of O2 that can be combined with hemoglobin, assuming 100% saturation (SaO2 = 1.0).
concentration of O2 carried by hemoglobin in arterial blood
For a typical saturation of 98% (SaO2 = 0.98), and a typical hemoglobin concentration [Hb] = 15 gr/100 ml, the concentration of O2 carried by hemoglobin in arterial blood is 20.4 ml O2/100 ml blood (or 9.1 mM). As you do the calculation, the units work out if you remember that the value 1.39 has a ml/gram associated with it. The concentration of freely dissolved O2 in blood is small. For a typical PaO2 = 100 Torr, this term is only 0.3 ml O2/100 ml of blood (or 0.13 mM). The total arterial oxygen content under normal conditions is the sum of the hemoglobin-bound component (20.4 ml O2/100 ml) and the freely dissolved component (0.3 ml O2/100 ml), which is 20.7 ml O2/100 ml blood. For a typical cardiac output Q ̇ = 5,000 ml/minute, the oxygen delivery will be D ̇O2 = (5,000 ml blood/min) x (20.7 ml O2/100 ml blood) = ~1,000 ml O2/min. These values are for a healthy person. It is easy to see what would happen in the case of anemia, since the hemoglobin concentration [Hb] in the equation above for C will be smaller.
Effect of hypoxemia on O2 delivery
A disease that results in reduced arterial free oxygen (hypoxemia) can decrease O2 delivery in two ways: first, by reducing the percent saturation of hemoglobin SaO2 in the hemoglobin-bound component of CaO2 (this is the main way) and, second, by reducing the free oxygen component.
Oxygen consumption
In a clinical setting, one needs to know not only the quantity of oxygen being delivered to the tissue, but also how much is being consumed. Whether a patient is receiving enough oxygen will depend on whether delivery is matching consumption. Oxygen consumption can be calculated, quite simply, from the difference between the total amount of oxygen in venous blood versus arterial blood. This makes sense since it is the capillary beds between the arterial and venous circulation where oxygen is utilized. Defining oxygen consumption as V ̇O 2 , we have: V ̇ O 2 = ( Q ̇ x C a O 2 ) – ( Q ̇ x C v O 2 ) which simplifies to: V ̇ O 2 = Q ̇ x ( C a O 2 – C v O 2 ). In this expression Q ̇ is the cardiac output and CaO2 and CvO2 are, respectively, the arterial and venous oxygen contents.
Estimating the difference in oxygen saturation of hemoglobin in arterial versus venous blood
In practice, oxygen consumption is often estimated from the difference in oxygen saturation of hemoglobin in arterial versus venous blood. Consider the expressions for arterial and venous oxygen contents: CaO2 = (SaO2 ⋅ [Hb] x 1.39) + (0.003 ⋅ PaO2). CvO2 = (SvO2 x [Hb] x 1.39) + (0.003 ⋅ PvO2). The freely-dissolved components (the second terms) are very small and essentially can be ignored. For the hemoglobin-bound components, the only factor that will vary between arterial and venous blood will be the percent saturation SaO2 and SvO2. This gives: V ̇O2 = Q ̇ x (SaO2 – SvO2) x [Hb] x 1.39 as a useful expression to estimate oxygen consumption. Hemoglobin saturation of venous blood is ~75% (SvO2 = 0.75), which is 23% less than for arterial blood (SaO2 = 0.98). Using values of [Hb] = 15 g/100 ml and Q ̇ = 5000 ml/minute, we obtain an oxygen consumption V ̇O 2 = ~240 ml O2/minute (for these calculations, again remember that the value 1.39 has a ml/gram associated with it). This value for consumption V ̇O 2 compares with an oxygen delivery of 1000 ml oxygen/minute, which indicates that in a healthy individual at rest oxygen delivery far exceeds use.
PO2 change at the level of inspired air
At the level of inspired air, PO2 depends on the barometric pressure, as well as on the fraction of oxygen present (which can be artificially increased or decreased). After oxygen is brought into the system, its partial pressure is sequentially reduced. First, the inspired oxygen is diluted by water vapor. Subsequently, oxygen in the alveoli is further diluted through gas exchange with blood and the introduction of CO2. The oxygen tension in the alveoli will depend on the alveolar ventilation, V ̇A , as well as on oxygen uptake (which is the same as oxygen consumption, V ̇O2).
