Normal Lung VIII

The proportion of the alveolar septum of the human lung that is interstitium is substantially greater than in many other species, as shown in Fig. 14. The alveolar interstitium increases as a function of age in both rodents and humans. The high amount of interstitium in the human lung likely reflects the substantially longer life span of the human and exposure to environmental air pollutants. The lungs of children have substantially less interstitial connective tissue and interstitial matrix elements than do adult human lungs (Fig. 14.) The alveolar macrophages on the alveolar surfaces in a normal nonsmoking human make up only about 3% of total alveolar cells. The number of alveolar macrophages is substantially elevated in smokers and can be 10% of the alveolar septal cells. The normal human alveolus has a diameter of about 225 µm and a surface area of 120,000 µm2; it is made up of 148 endothelial cells, 106 interstitial cells, and 107 epithelial cells (types I and II) and contains 12 alveolar macrophages. The comparative cellular anatomy of an average alveolus from the mouse to the human is shown in Fig. 15. The relative cell composition of the alveolar septa is similar across species. The larger alveoli of larger species are generally contain more cells of the same average size rather than larger cells. The differences in cellular size and shape between cells of different function are dramatic, as shown in Table 2, with the alveolar type I epithelial cell being four times larger than a capillary endothelial cell and having a sixfold greater surface area. Thus, cellular function, not species or organ size, determines characteristics of each class of cell.

FIG. 14. Composition of the tissues of the alveolar region in mammalian lungs. The ratios of endothelium, interstitium, epithelium, and alveolar macrophages are shown. Note that the human lung has proportionally more interstitium than do the other species illustrated. This is likely related to the extensive environmental pollutants to which human lungs are exposed, leading to microscopic fibrotic interstitial reactions.

FIG. 15. The cellular makeup of alveoli in mouse, rat, rabbit, and human. Numbers along the right vertical axis correspond to the data for human lungs. The typical human alveolus is made up of almost 400 cells.

Pulmonary Circulation

The main pulmonary artery and the next several generations of pulmonary arteries with diameters greater than 0.5 cm are called elastic arteries. The walls of these vessels contain multiple concentric elastic lamina as well as smooth muscle and collagen layers. These vessels enter the lung at the hilum and lie adjacent to and branch with each of the bronchi. Arteries with diameters ranging from 0.1 to 0.5 cm are termed muscular pulmonary arteries. These vessels contain circular smooth muscle located between an internal and external elastic lamina. Muscular pulmonary arteries begin at the level of smaller bronchi, have the same approximate diameter as the bronchi, and travel and branch with the bronchi. These arteries continue to follow bronchioles and respiratory bronchioles and enter into the center of the acinus, branching with alveolar ducts. Their size decreases as they move peripherally, and by the time they reach the acinus they are substantially smaller than the alveolar ducts.

Pulmonary veins travel in the peripheral walls of acini and along the connective tissue planes of sublobular and lobular septa. Thus, blood enters the acinus alongside the airways and then moves outward across the acinus to the periphery, where pulmonary veins collect blood from multiple adjacent acini. Each vein drains a much larger zone than is supplied by a single small muscular pulmonary artery.

A separate circulation and nutrient supply to the bronchi and the walls of their adjacent pulmonary arteries arises from the systemic circulation via bronchial arteries. These arteries come directly from the aorta or from the internal mammary, subclavian, or intercostal arteries. This systemic arterial supply to the bronchi travels as small vessels in the walls of the bronchi and extends to the level of the bronchioles. Bronchial veins exist only in the most central bronchi and empty into the azygos and hemiazygos veins. The remainder of the bronchial arterial circulation drains into pulmonary veins and moves by that circuit to the left atrium.

The relative surface areas and volumes of different components of the pulmonary vascular bed are given in Table 3. The volume of blood in the lung is normally approximately equally distributed between the arterial system, capillary network, and venous system. Ninety-six percent of the pulmonary vascular surface area is in the capillary bed. The capillary network has the capacity for substantial expansion if all capillary beds are recruited and functional, as under conditions of exercise. When the capillary network is fully recruited, the proportion of the pulmonary blood volume in the capillary bed can increase from 30% to 50%–60%.

TABLE 3. Human pulmonary vascular system

The pulmonary vascular system is a low-pressure circulation, and the pulmonary arteries are substantially more distensible than are systemic arteries. Pulmonary veins are also highly distensible at relatively low transmural pressures. Distensibility of the pulmonary vascular bed makes it possible for the blood volume to change readily in response to vasomotor stimuli or hydrostatic/orthostatic conditions. The pulmonary vascular bed acts as a capacitance reservoir for the left side of the heart. Sufficient blood is contained in the elastic reservoir to support two to three heartbeats. Pulmonary blood volume can increase 30% during a change of position from standing to lying. Up to half of the pulmonary blood volume can be forced out of the lungs by Valsalva's maneuver (increasing intrathoracic pressure against a closed glottis).

The vertical height of a normal human lung is about 25 cm, with the hilum situated about one-third the distance from the top of the lungs (Fig. 2). Pulmonary capillary pressure varies from the top to the bottom of the lung. With an average pulmonary arterial pressure of 20 cm H2O, the pulmonary arterial pressure from the top to the bottom of the lung varies from 12 cm H2O to 36 cm H2O. Pulmonary venous pressure varies from approximately 0 at the top of the lung to 24 cm H2O at the bottom, with a mean pressure of 6 to 8 cm H2O at the hilum. Thus, with a highly distensible pulmonary vascular bed, pulmonary blood volume is preferentially distributed toward the dependent portions of the lung. The effects of gravity and distensibility are balanced by vasomotor tone regulating blood flow across the pulmonary vascular bed. Because muscular arteries extend into the acinus, local vasomotor control can influence distribution of blood flow to each lung unit and thereby determine the ventilation-perfusion ratio of each of these units.

Blood flow in the pulmonary capillaries is pulsatile except under conditions of severe pulmonary hypertension. Blood flow in the capillary network has been estimated to have a velocity averaging about 1000 µm/sec.

The pulmonary capillary bed is made up of an extensive network of interconnected small tubules. There has been substantial debate regarding whether pulmonary capillary blood flow is best modeled as tubular flow or sheet flow. Anatomically, as illustrated in Fig. 16, the capillary bed is a combination of the two. The capillary network crosses multiple alveoli as blood flows from the central arteriole in an acinus to the venules at the acinar margins. This creates a fairly long path length over which gas exchange can occur. The average transit time of a red cell through the pulmonary capillary bed has been estimated to be 0.1 to 0.5 sec. Under normal resting conditions, red blood cells are fully saturated with oxygen during the first third of their transit through the pulmonary capillary bed. The lung has a sufficient gas exchange reserve that even heavy exercise does not produce arterial desaturation, and in fact increased blood flow throughout the entire capillary bed generally results in an increased arterial partial pressure of oxygen (PaO2) under conditions of exercise. Red cells are likely to leave the capillary bed not fully saturated with oxygen only when the inspired oxygen tension is low or when disease prevents adequate ventilation of individual gas exchange units. One of the important ventilation-perfusion regulatory pathways in the lung is hypoxic pulmonary vasoconstriction. Relative hypoxemia in small gas exchange units leads to constriction of the corresponding muscular pulmonary arteries, which maintains balanced ventilation-perfusion ratios. The pulmonary venous system also contains smooth muscle and has been shown to be equally sensitive to vasoactive mediators, thus regulating venous pooling in the lung.

FIG. 16. Schematic illustration of the pulmonary capillary bed showing the high density of short, highly interconnected capillary segments in the alveolar walls. The distribution of collagen and elastin fibers in the lung parenchyma is also shown. The drawing illustrates the high concentrations of connective tissue fibers along the alveolar duct septal edges that form the alveolar duct walls. Elastin fibers tend to be located over the major collagen bundles lining the alveolar entrance rings. Thus, the alveolar entrance rings are rich in both elastin and collagen. The alveolar walls contain thin collagen strands that interconnect adjacent alveoli by weaving between capillary segments.

The pulmonary capillary bed acts as an efficient filter of the systemic vascular system. Approximately three quarters of the blood volume of the body is contained in the systemic venous system. This blood passes through the pulmonary capillary bed on each circulation, and any microemboli forming in the systemic venous system will therefore be filtered by the lung. These microemboli produce no dysfunctional or pathologic effects in the lung and are rapidly cleared by lytic pathways or the pulmonary reticuloendothelial system. The physiologic effects of resection of one lung clearly demonstrate that up to half the pulmonary vascular system can be obstructed or removed without serious change in the hemodynamics of the remaining pulmonary vascular bed. This design of the pulmonary vascular system allows it to be an efficient filter of the body's blood supply.

Capillary endothelial cells form a continuous lining of alveolar capillaries. These cells are connected by tight junctions that, however, are more permeable to macromolecules than are the junctions between airway epithelial cells. Endothelial cell junctions contain one to three junctional strands, in which discontinuities exist. In comparison, airway epithelial cell junctions have three to five junctional strands. In addition, because alveolar type I epithelial cells are substantially larger (Table 2) and cover a much greater surface area per cell than do capillary endothelial cells, the total junctional area over which fluid and macromolecular transport can occur is substantially lower at the alveolar epithelium than it is along the pulmonary capillary endothelium. The impermeability of the alveolar epithelium to fluid and electrolyte movement explains why pulmonary vascular congestion (failure of the left side of the heart) leads to pulmonary interstitial edema substantially sooner than intra-alveolar pulmonary edema occurs.

The pulmonary capillary epithelium has a number of metabolic functions. Because it is the only capillary bed that receives the entire blood flow of the body during each circulation, the pulmonary capillary bed is in a critical position to regulate reactive bloodborne materials. Pulmonary endothelium plays a role in either activating or degrading a number of vasoactive mediators. Some substances are metabolized by enzymes on the capillary endothelial cell surface, whereas others require uptake into the endothelial cells. For example, angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II on the surface of pulmonary capillaries, producing a vasoconstrictive molecule of substantially greater physiologic potency. The same enzyme, ACE, inactivates bradykinin. Bradykinin is a highly potent, locally released vasodilator, and its inactivation in the lung prevents it from causing systemic hypotension. Other mediators, such as serotonin and norepinephrine, are metabolized by endothelial cells but require uptake into the cellular cytoplasm. Pulmonary capillary endothelium also synthesizes prostacyclin and tissue plasminogen activator. These cells are a rich source of thrombomodulin, a cell surface protein with anticoagulant properties. The endothelium secretes nitric oxide, a local vasorelaxant, and secretes endothelins, which are potent vasoconstrictor peptides. Vascular endothelium metabolizes adenonucleotides and both prostaglandins E2 and F2a. Vascular endothelium also plays a role in regulating phagocytic cell function via the expression of cell surface adhesion molecules. The adhesion molecules interact with receptors on phagocytic cells and regulate the movement of phagocytic cells through the vascular bed as well as their migration into subjacent tissues.