PATHOPHYSIOLOGY OF PULMONARY SYSTEM
Breathing through the lungs has two functions: firstly, to supply O2 to the blood and, secondly, to regulate the acid–base balance via the CO2 concentration in the blood. The mechanics of breathing serve to ventilate the alveoli, through whose walls O2 can diffuse into the blood and CO2 can diffuse out. Respiratory gases in the blood are largely transported in bound form. The amount transported depends, among other factors, on the concentration in blood and on pulmonary blood flow (perfusion). It is the task of respiratory regulation to adapt ventilation to the specific requirements.
A number of disorders can affect breathing in such a manner that ultimately sufficient O2 uptake and CO2 release cao longer be guaranteed.
In obstructive lung disease flow resistance in the respiratory tract is raised and ventilation of the alveoli is thus impaired. The primary consequence is hypoventilation in some alveoli (abnormal distribution) or of all alveoli (global hypoventilation). If alveolar ventilation ceases completely, a functional arteriovenous shunt occurs. However, hypoxia leads to constriction of the supplying vessels, thus diminishing blood flow to the under ventilated alveoli.
In restrictive lung disease the loss of functioning lung tissue reduces the area of diffusion and in this way impairs gaseous exchange. There is also a reduced area of diffusion in emphysema, a condition characterized by alveoli that have a large lumen but are also diminished iumber. Disorders of diffusion canal so be caused by an increased distance between alveoli and blood capillaries. If alveoli and capillaries are completely separated from one another, this results in both a functional dead space (nonperfused alveoli) and an arteriovenous shunt.
Restrictive and obstructive lung disease as well as cardiovascular disease may affect lung perfusion. Decreased perfusion results in a reduced amount of gases being transported in blood, despite adequate O2 saturation and CO2 removal in the alveoli. If flow resistance is increased, severe consequences for the circulation are possible, because the entire cardiac output (CO) must pass through the lungs. Breathing is also impaired in dysfunction of the respiratory neurons as well as of the motoneurons, nerves, and muscles that are controlled by them. The changes in breathing movement that occur when the breathing regulation is abnormal do not, however, necessarily lead to corresponding changes of alveolar ventilation.
Consequences of inadequate breathing can be hypoxemia, hypercapnia or hypocapnia (increased or decreased CO2 content, respectively) in arterialized blood. The supply of O2 to the cells as well as the removal of CO2 from the periphery do not only depend on adequate respiration but also on unimpaired oxygen transport in the blood and on intact circulation.
Pathophysiology of Respiration
Ventilation, Perfusion Abnormalities
To reach the alveoli, inspired air must pass through those respiratory pathways in which no gaseous exchange takes place (dead space), i.e., normally the mouth, pharynx and larynx, trachea, bronchi and bronchioles. On its way the air will be warmed, saturated with water vapor, and cleansed.
The tidal volume (VT) contains, in addition to the volume of air that reaches the alveoli (VA), the volume of air that remains in the dead space (VD). If tidal volume is less than VD (normally ca. 150 ml), the alveoli are not ventilated with fresh air. When tidal volume is greater than VD, the proportion of alveolar ventilation rises with increasing VT. Alveolar ventilation may even be reduced during hyperpnea, if the depth of each breath, i.e., VT, is low and mainly fills the dead space.
Increased ventilation can occur as a result of either physiologically (e.g., during work) or pathophysiologically (e.g., in metabolic acidosis) increased demand, or due to an inappropriate hyperactivity of the respiratory neurons.
Decreased ventilation can occur not only when the demand is reduced, but also when the respiratory cells are damaged, or wheeural or neuromuscular transmission is abnormal. Further causes include diseases of the respiratory muscles, decreased thoracic mobility (e.g., deformity, inflammation of the joints), enlargement of the pleural space by pleural effusion or pneumothorax as well as restrictive or obstructive lung disease.
Changes in alveolar ventilation do not have the same effect on O2 uptake into the blood and CO2 release into the alveoli. Because of the sigmoid shape of the O2 dissociation curve, O2 uptake in the lungs is largely independent of alveolar partial pressure (PAO2). If there is only minor hypoventilation, the partial pressure of O2 in the alveoli and thus in blood is reduced, but the O2 dissociation is at the flat part of the curve, so that the degree of hemoglobin saturation and thus O2 uptake in blood is practically unchanged. On the other hand, the simultaneous increase in CO2 partial pressure in the alveoli and blood leads to a noticeable impairment of CO2 release.
Massive hypoventilation lowers the O2 partial pressure in the alveoli and blood, so that oxygen is at the steep part of the O2 binding curve of hemoglobin and O2 uptake is therefore impaired much more than CO2 release is. Hyperventilation increases the O2 partial pressure in the alveoli and blood, but cannot significantly raise the level of O2 uptake into the blood because the hemoglobin is already saturated. However, hyperventilation boosts CO2 release.
Lung perfusion is increased, for example, during physical work. It can be reduced by heart or circulatory failure, or by constriction or occlusion of pulmonary vessels.
A moderate increase in lung perfusion while ventilation remains unchanged increases O2 uptake virtually in proportion to the amount of blood flow. Even though the alveolar O2 partial pressure falls slightly because of the increased O2 uptake from the alveoli into the blood, this has little influence on O2 saturation in the blood. It is only when the alveolar partial pressure of O2 falls into the steep part of the O2 dissociation curve that a decrease of alveolar O2 partial pressure significantly affects O2 uptake into blood. At those O2 partial pressures a further increase in lung perfusion only slightly increases O2 uptake. Furthermore, at very high lung perfusion flow, the contact time in the alveoli is not sufficient to guarantee that partial O2 pressure in blood approaches that in the alveoli. If lung perfusion is reduced, O2 uptake is proportionally decreased.
CO2 removal from blood is dependent on lung perfusion to a lesser extent than O2 uptake. In case of reduced lung perfusion (but constant ventilation and venous CO2 concentration) the CO2 partial pressure in the alveoli falls and thus favors the removal of CO2 from the blood. This, in turn, attenuates the effect of the reduction in perfusion. At raised lung perfusion an increase of alveolar CO2 concentration prevents a proportional rise in CO2 release.
Ventilation, Perfusion of the lungs
Diffusion Abnormalities
O2 has to diffuse from the alveoli to hemoglobin in the erythrocytes, and CO2 from the erythrocytes into the alveoli. The amount of gas (M) that diffuses across the diffusion barrier between alveoli and blood per unit time is proportional to the diffusion area (F) and the difference in partial pressure between alveolar gas (PA) and blood (Pblood), and inversely proportional to the length of the diffusion pathway (d): M = K х F (PA – Pblood)/d
Krogh’s diffusion coefficient K is about 20 times greater for CO2 than for O2. The diffusion capacity D (= K х F/d) is about 230 mL х min–1 х kPa–1 (1.75 L х min–1 х mmHg–1) in a healthy person.
A diffusion abnormality exists when the ratio of diffusion capacity to lung perfusion (or cardiac output) is reduced.
The diffusion capacity may be reduced by increased distance. When a pulmonary edema occurs, raised intravascular pressure means plasma water is exuded into the interstitial pulmonary tissue or into the alveoli, and thus increases the diffusion distance. Inflammation causes a widening of the space between alveoli and blood capillaries as a result of еdema and the formation of connective tissue. In interstitial lung fibrosis, the connective tissue forces alveoli and blood capillaries apart. It is the distance between hemoglobin and alveolar gas which matters. Thus, the distance can also be slightly increased by vessel dilation (inflammation) or anemia.
A diminished diffusion capacity may also be caused by a reduction of the diffusion area, as after unilateral lung resection, loss of alveolar septa (pulmonary emphysema), or in loss of alveoli in pneumonia, pulmonary tuberculosis, or pulmonary fibrosis. The diffusion area can also be reduced by alveolar collapse (atelectasis), pulmonary edema, or pulmonary infarction.
Diffusion abnormalities become obvious when cardiac output is large, blood flows rapidly through the lungs, and the contact time of blood in the alveoli is thus quite brief. In effect, diminution of the diffusion area (e.g., after unilateral lung resection) also means a shorter contact time in the remaining lung tissue, because the same amount of blood will now pass through a reduced amount of lung tissue per unit of time. An increased O2 demand during physical exercise forces an increase in cardiac output and can thus reveal a diffusion abnormality.
Abnormal diffusion primarily affects O2 transport. In order for the same amount of gas to diffuse per time, the O2 gradient must be twenty times greater than the CO2 gradient. Should the diffusion capacity in an alveolus be diminished while ventilation remains constant, O2 partial pressure will fall in the blood leaving the alveolus. If all alveoli are similarly affected, O2 partial pressure will fall in the pulmonary venous (and thus systemic arterial) blood. If O2 consumption remains constant, O2 partial pressure will necessarily be lower also in deoxygenated (systemic venous) blood. For this reason patients with a diffusion abnormality get blue lips on physical exertion (central cyanosis). The primary effects of abnormal diffusion on CO2 transport and acid–base metabolism are much less marked. Hypoxia stimulates the respiratory neurons, and the resulting increase in ventilation can produce hypocapnia. However, the hypoxemia due to abnormal diffusion can only be slightly improved by hyperventilation. In the example given, doubling of the alveolar ventilation at unchanged O2 consumption increases alveolar O2 partial pressure by only 4 kPa to 17 kPa (30 mmHg to 129 mmHg), but the increased O2 gradient does not normalize the O2 saturation of the blood. At the same time, respiratory alkalosis develops, despite the abnormal diffusion, because of the increased CO2 removal. Hypoxemia due to abnormal diffusion can be neutralized with O2 -enriched inspiratory air. The degree of hypoxemia can be lessened by decreasing O2 consumption.
Diffusion Abnormalities
Restrictive Lung Disease
Restrictive lung disease is a term given to an anatomical or functional loss of gaseous exchange area.
An anatomical loss occurs after removal (resection) or displacement (e.g., by a tumor) of lung tissue. Atelectasis may also lead to a decrease in diffusion area.
A functional decrease in exchange area occurs is if plasma water is exuded into alveoli, for example, in pulmonary edema or in inflammation (increased vascular permeability, e.g., in pneumonia). In pulmonary fibrosis proliferating connective tissue displaces intact pulmonary parenchyma (decrease in diffusion area), infiltrates between capillaries and alveoli (increase in distance), and prevents the normal expansion of the lung (impairment of alveolar air exchange). Pulmonary fibrosis can be caused by inflammatory reaction against connective tissue (so-called collagen disease) or by inhalation of dust which contains silicate or asbestos. Sometimes no cause is found (idiopathic pulmonary fibrosis [Hamman–Rich syndrome]). Local or generalized impairment of lung expansion can also occur in thoracic deformities, diaphragmatic paralysis, or adhesion of both pleural layers (as a result of inflammation [pleural fibrosis]).
Pneumothorax is also a restrictive lung disease. If there is an open connection between the pleural space and outside air (thoracic injury) or the alveoli (torn alveolar wall due to over distension), air enters and the ipsilateral lung collapses. Breathing is also impaired in the other lung, because the pleural pressure on the healthy side falls on inspiration and as a result the mediastinum is displaced to the healthy side. On expiration the pressure rises and the mediastinum moves toward the collapsed side. This mediastinal flutter reduces the breathing excursion (VT) of the healthy lung. If a valve-like mechanism develops on the injured side, allowing air into the pleural space but not out of it, tension pneumothorax develops. It is especially the burst alveoli that often act like valves: the collapsed lung expands on inspiration, allowing air to enter the pleural space through the damaged alveolus, but when lung and alveolus collapse during expiration the escape of air is prevented. The mediastinum is massively displaced by the increasing pressure toward the healthy side and breathing correspondingly impaired. The increase in intrathoracic pressure also reduces the venous return and thus right ventricular filling, as a consequence of which cardiac output falls.
In whole-body plethysmography the air in the pleura is indistinguishable from that in the alveoli, because both are equally reduced on expiration. However, inspired test gas is distributed only throughout the lung. In pneumothorax, the intrathoracic volume measured by whole-body plethysmography is thus greater than the alveolar volume obtained with a test gas.
Restrictive pulmonary disease causes a fall in compliance (C), vital capacity (VC), functional residual capacity (FRC), and diffusion capacity. The latter leads to diffusion abnormality and thus to hypoxemia (SO2 = oxygen saturation of blood). Maximum breathing capacity (Vmax) and forced expiration volume in 1 second (FEV1) are usually reduced, but relative forced expiration volume (normally 80 % of VC) is generally normal. To inspire a certain volume, greater negative pressure thaormal is required in the pleural space and more energy thus has to be expended during breathing (increased work of breathing; V ˙ = ventilation flow). Reduction of the vascular bed by removing lung tissue or by compressing blood vessels increases vascular resistance. Greater pressure is required to pump the blood through the pulmonary vascular bed, pressure which must be generated by the right heart. The consequence is a raised load on the right ventricle (cor pulmonale).
Causes and Effects of Restrictive Lung Diseases
Obstructive Lung Disease
In order to reach the alveoli air must pass through the respiratory tract or airways, which present a resistance to the flow. This resistance is determined by the lumen in the tract. In particular the narrow lumen of the bronchioles can be further narrowed by mucus and the contraction of the bronchial musculature. Mucus is secreted in order to trap pathogens and dirt particles. It is transported toward the mouth by the cilia of the lining epithelium and then swallowed. As the cilia cannot propel very sticky mucus, an electrolyte solution is usually secreted that lifts the mucus from the cilia, so that mucus moves toward the mouth on a thin fluid layer. The lumen can be narrowed by the action of the bronchial muscles, which increases the likelihood of pathogens being caught in the mucus. The disadvantage, however, is that narrowing raises flow resistance. Obstructive lung diseases are characterized by an increased flow resistance.
Intrathoracic increase in resistance is usually due to a narrowing or obstruction of the bronchi, by either external compression, contraction of bronchial muscles, thickening of the lining mucus layer, or obstruction of the lumen by mucus. Most of these changes are the result of asthma or chronic bronchitis. In asthma there is an allergy to inhaled antigens (e.g., pollen). These antigens cause an inflammation of the bronchial mucosa leading to the release of histamine and leukotrienes (called slow reacting substances in anaphylaxis [SRSA]). The bronchial muscles contract and mucus secretion as well as vessel permeability (mucosal edema) are increased under the influence of these mediators. In addition to the inhaled antigens, microorganisms in the mucosa may also act as antigens (infectious–allergic asthma). Here there is no clear cut distinction between asthma and bronchitis. Obstructive lung disease can also be the result of cysticfibrosis (CF). As the result of an autosomal recessive genetic defect of the CF transmembrane regulator (CFTR) there is decreased secretion and hyperreabsorption of fluid, and mucus cao longer be cleared from the airways. The result is obstructive lung disease. The lung’s reduced ability to retract (flaccid lung) can also lead to obstructive lung disease, because reduced elastic recoil (increased compliance) of the lung requires an increase in pressure during expiration, resulting in compression of the intrathoracic air ways (see below).
Extrathoracic increase in resistance occurs, for example, in paralysis of the vocal chords, edema of the glottis, and external tracheal compression (e.g., by tumor or goitre). In tracheomalacia the tracheal wall is softened and collapses on inspiration.
The effect of obstructive lung disease is reduced ventilation. If extrathoracic obstruction occurs, it is mainly inspiration that is affected (inspiratory stridor), because during expiration the pressure rise in the prestenotic lumen widens the narrowed portion. Intrathoracic obstruction mainly impairs expiration, because the falling intrathoracic pressure during inspiration widens the airways. The ratio of the duration of expiration to that of inspiration is increased. Obstructed expiration distends the alveolar ductules (centrilobular emphysema), lung recoil decreases (compliance increases), and the midposition of breathing is shifted toward inspiration (barrel chest). This raises the functional residual capacity. Greater intrathoracic pressure is necessary for expiration because compliance and resistance are increased. This causes compression of the bronchioles so that the airway pressure increases further. While the effort required to overcome the elastic lung resistance is normal or actually decreased, the effort required to overcome the viscous lung resistance and thus the total effort of breathing is greatly increased. The obstruction reduces maximum breathing capacity (V ˙max) and FEV1, and the differing ventilation of various alveoli results in abnormal distribution. The hypoxia of under ventilated alveoli leads to vasoconstriction, increased pulmonary vascular resistance, pulmonary hypertension, and an increased right ventricular load (cor pulmonale).
Obstructive Lung Diseases
Pulmonary Emphysema
Emphysema is characterized by an increase in the volume of the airways distal to the bronchioles. Centrilobular emphysema, with predominant distension of the alveolar ducts and respiratory bronchioles, is distinguished from panlobular emphysema, in which the terminal alveoli in particular are distended. In flaccid lung there is merely a loss of elastic recoil. The disease can affect a circumscribed area (local emphysema), or the entire lung (generalized emphysema). Emphysema is one of the most frequent causes of death.
Emphysema
Centrilobular emphysema is caused mainly by obstructive lung disease: in flaccid lung there is a loss of connective tissue of unknown cause; inpanlobular emphysema there is additional loss of alveolar septa. In the elderly an increase in alveolar volume in relation to alveolar surface regularly occurs. In some patients (ca. 2 %) there is a deficiency in α1-proteinase inhibitor (α1-antitrypsin), which normally inhibits the action of proteinases (e.g., leukocyte elastase). This enzyme is produced in the liver; its mutation can affect its secretion and/or function. In either case decreased inhibition of the proteinases leads to a breakdown and thus a loss of lung tissue elasticity. If secretion is disturbed, the accumulation of the defective protein in the liver cells can additionally lead to liver damage. Finally, a lack of proteinase inhibition can also affect other tissues, for example, renal glomeruli and the pancreas may be damaged. α1-antitrypsin is oxidized and thus inhibited by smoking, which thus promotes the development of emphysema even in some one without a genetic predisposition.
In addition to a lack of inhibitors, increased elastase production may be a cause of emphysema (e.g., of a serine elastase from granulocytes, a metalloelastase from alveolar macrophages, and various proteinases from pathogens). The excess of elastases in chronic inflammatory disease leads, for example, to a breakdown of elastic fibers in the lung.
When considering the effects of pulmonary emphysema, the consequences of reduced elastic recoil are important. In the end the lung’s elastic recoil generates the positive pressure in the alveoli in comparison to ambient air necessary for normal expiration. Although positive pressure in the alveoli can also be produced by external compression, i.e., by contraction of the expiratory muscles, this will also compress the bronchioles and thus bring about a massive increase in flow resistance. Maximal expiratory flow rate (V˙max) is thus a function of the ratio between elastic recoil (K) and resistance (RL). Reduced elastic recoil can thus have the same effect as obstructive lung disease. Elastic recoil can be raised by increasing the inspiratory volume, eventually leading to a shift in the resting position toward inspiration (barrel chest). If tidal volume remains constant, both the functional residual capacity and the residual volume are increased, sometimes also the dead space. However, vital capacity is diminished because of the reduced expiratory volume. The loss of alveolar walls leads to a diminished diffusion area; the loss of pulmonary capillaries to an increase in functional dead space as well as increased pulmonary artery pressure and vascular resistance with the development of cor pulmonale. In centrilobular, but not panlobular, emphysema a distribution abnormality develops, because of differing resistances in different bronchioles. The abnormal distribution results in hypoxemia. Patients with centrilobular emphysema due to obstructive lung disease are called “blue bloaters”. In contrast, patients with panlobular emphysema at rest are called “pink puffers”, because enlargement of the functional dead space forces them to breathe more deeply. It is only when diffusion capacity is greatly reduced or oxygen consumption is increased (e.g., during physical work) that diffusion abnormality will result in hypoxemia.
Emphysema
