1. Physiologic Control Anatomy and Physiology of the Airway Circulation1,2 JOHN WIDDICOMBE
Structure of Vasculature The conventional view of the structure of the vasculature of the tracheobronchial tree is that it consists of two networks, mucosal and peribronchial, joined by connecting vessels passing through and past smooth muscle and cartilage (l). Strictly speaking, this description is undeniable since vascular beds exist in both the submucosa and the peribronchial tissues. (The only tissue that seems to have a sparse vasculature bed is the smooth muscle, and of course the cartilage has none.) However, no functional importance for the arrangement has been described. More recent studies have tended to havea physiologicslant; they emphasize the copious subepithelial network of capillaries, present in all species, that connects to a system of capacitance vessels deeper in the mucosa (2-4). The latter are sometimes called sinusoids or sinuses, and they are not always easy to distinguish from venules. The main function of the subepithelial capillary network presumably is to provide nutrients to the epithelium. The latter has one of the highest metabolic rates per unit cellular weight in the body, presumably because of the energy required for ciliary beating and active transport mechanisms across the epithelium (5). However, the capillary network may have subsidiary functions, especially in pathologic conditions. It will constitute a barrier for mediators and drugs passing from the airway lumen to target tissues such as smooth muscle. It will be the source of plasma-borne nutrients, mediators, and cells that pass into the submucosa in physiologic and pathologic conditions. And it will be the source of water and plasma transudation in conditions where there is mucosal edema and luminal exudate, such as in asthma. In this last respect the presence or absence of fenestrations between capillary endothelial walls could be important. For the nose the capillaries are fenestrated, but for the tracheobronchial tree there are species differences (6). For all species studied, the capillaries in glands and under neuroepithelial bodies seemto be fenestrated, but those under other areas of epithelium often have a continuous epithelium, at least in dogs, sheep (2, 3), and healthy humans. Rats and guinea pigs have fenestrations. The presence of fenestrated epithelium may be related more to water transport than to protein transudation. The function of the deeper capacitance system of vessels is harder to visualize, at least for the tracheobronchial tree. For the nose, where the system is especially well developed and the capacitance vessels have much smooth
SUMMARY Both for the nose and the lower airways there is an extensive subepithelial capillary network. That for the nose is fenestrated, and this is true forthe tracheobronchial tree of rats, guinea pigs, and hamsters, and for that of human asthmatics. However, healthy humans, dogs, and sheep have capillaries without fenestrations except for those close to neuroepithelial bodies and submucosal glands. Deeper in the mucosa there Is a capacitance system of vessels, conspicuous In the nose but present also in the lower airways of rabbits and sheep and, to a lesser extent, in those of dogs and humans. Both for the nose and the lower airways, parasympathetic nerves are vasodilator, sympathetic nerves are vasoconstrictor, and sensory nerves are able to release dilator neuropeptides. Most inflammatory and immunologic mediators are vasodilator. A conspicuous difference between the nasal and lower airway vasculatures Is the presence of arteriovenous anastomoses only In the former. Countercurren! mechanisms also exist in the nose to increase its efficiency in air conditioning, but they have not been established for the trachea. The pulmonary vasculature could be part of such a system for the bronchI. Distension of the airway vaseutature thickens the mucosa, probably both by vascular distension and by edema formation. The latter can lead to exudation Into the airway lumen. These processes have not been well quantitated, and the balance sheet of capillary and capacitance vessel volumes, Interstitial liquid volume, and exudate volume needs to be worked out in physiologic and pathologic conditions. AM REV RESPIR DIS 1992; 146:S3-S7
muscle in their walls (7), the effect of vascular distension is to increase the thickness of the mucosa and to block the nose. This may be beneficial in terms of nasal filtration of pollutants, and it could influence the airconditioning role of the nose (8). However, in humans nasal blockage caused by congestion leads to breathing through the mouth, so in terms of protection of the lower airways and lungs the primary response in the nose may be harmful. In the lower airways there are striking species differences both in the extent and the structure of the capacitance systems of vessels. They are especially welldeveloped in the rabbit and sheep (2, 9), but in the former species the walls of the sinuses contain much smooth muscle, which is virtually absent (apart from a fewpericytes)in the sheep. Some species, for example the cat and the guinea pig, have a poorly developed capacitance system in the lower airways. Humans are probably intermediate, with clear capacitance vesselsthat contain smooth muscle in their walls. The junctions between the endothelial cells of the sinuses are "tight," long, and convoluted (2), suggesting that passage of liquid and solutes through the intercellular gaps is restricted. In view of the large diameter of the sinuses (as much as 0.5 mm in sheep), Laplace's law implies a high mural tension for any given sinus blood pressure, and the intercellular junctions would have to resist this tension. "Vasodilation," presumably with congestion of the capacitance system, can almost
double tracheal mucosal thickness in the sheep (10)(figure 1), with smaller effects in the dog where the capacitance system is less well developed (11). Because of the large diameter of the trachea, such a change in thickness would have insignificant effects on tracheal airflow resistance (Poiseuille's law). However, if changes similar in magnitude also occur in the bronchi and smaller airways, where capacitance vessels are known to exist although fewer than for the trachea (2, 3), the changes in mucosal thickness could have a significant effect on airway obstruction. There would not only be a mechanical blockage of the airway lumen but the compliance of the airway wall might be decreased. However, measurements of vascular-induced changes in mucosal thickness have not been made for the smaller airways. Given that the tracheobronchial mucosa can thicken with vascular congestion, the pathophysiologic role for such a change seems obscure, unlike that for the nose. As with any other airway obstruction, mucosal thickening would enhance the uptake of inhaled pollutants at the more proximal sitesof the airways, and possibly the benefits from this process
1 From the Department of Physiology, St George's Hospital Medical School, London, United Kingdom. 2 Correspondence and requests for reprints should be addressed to John Widdicombe, Department of Physiology, St George's Hospital Medical School, Cranmer Terrace,London SW17ORE, UK.
53
54
JOHN WIDDICOMBE
200iA ~ 0
150
.~"8
100
"'-E
"0~:o
5
Structure of Vasculature The conventional view of the structure of the vasculature of the tracheobronchial tree is that it consists of two networks, mucosal and peribronchial, joined by connecting vessels passing through and past smooth muscle and cartilage (l). Strictly speaking, this description is undeniable since vascular beds exist in both the submucosa and the peribronchial tissues. (The only tissue that seems to have a sparse vasculature bed is the smooth muscle, and of course the cartilage has none.) However, no functional importance for the arrangement has been described. More recent studies have tended to havea physiologicslant; they emphasize the copious subepithelial network of capillaries, present in all species, that connects to a system of capacitance vessels deeper in the mucosa (2-4). The latter are sometimes called sinusoids or sinuses, and they are not always easy to distinguish from venules. The main function of the subepithelial capillary network presumably is to provide nutrients to the epithelium. The latter has one of the highest metabolic rates per unit cellular weight in the body, presumably because of the energy required for ciliary beating and active transport mechanisms across the epithelium (5). However, the capillary network may have subsidiary functions, especially in pathologic conditions. It will constitute a barrier for mediators and drugs passing from the airway lumen to target tissues such as smooth muscle. It will be the source of plasma-borne nutrients, mediators, and cells that pass into the submucosa in physiologic and pathologic conditions. And it will be the source of water and plasma transudation in conditions where there is mucosal edema and luminal exudate, such as in asthma. In this last respect the presence or absence of fenestrations between capillary endothelial walls could be important. For the nose the capillaries are fenestrated, but for the tracheobronchial tree there are species differences (6). For all species studied, the capillaries in glands and under neuroepithelial bodies seemto be fenestrated, but those under other areas of epithelium often have a continuous epithelium, at least in dogs, sheep (2, 3), and healthy humans. Rats and guinea pigs have fenestrations. The presence of fenestrated epithelium may be related more to water transport than to protein transudation. The function of the deeper capacitance system of vessels is harder to visualize, at least for the tracheobronchial tree. For the nose, where the system is especially well developed and the capacitance vessels have much smooth
SUMMARY Both for the nose and the lower airways there is an extensive subepithelial capillary network. That for the nose is fenestrated, and this is true forthe tracheobronchial tree of rats, guinea pigs, and hamsters, and for that of human asthmatics. However, healthy humans, dogs, and sheep have capillaries without fenestrations except for those close to neuroepithelial bodies and submucosal glands. Deeper in the mucosa there Is a capacitance system of vessels, conspicuous In the nose but present also in the lower airways of rabbits and sheep and, to a lesser extent, in those of dogs and humans. Both for the nose and the lower airways, parasympathetic nerves are vasodilator, sympathetic nerves are vasoconstrictor, and sensory nerves are able to release dilator neuropeptides. Most inflammatory and immunologic mediators are vasodilator. A conspicuous difference between the nasal and lower airway vasculatures Is the presence of arteriovenous anastomoses only In the former. Countercurren! mechanisms also exist in the nose to increase its efficiency in air conditioning, but they have not been established for the trachea. The pulmonary vasculature could be part of such a system for the bronchI. Distension of the airway vaseutature thickens the mucosa, probably both by vascular distension and by edema formation. The latter can lead to exudation Into the airway lumen. These processes have not been well quantitated, and the balance sheet of capillary and capacitance vessel volumes, Interstitial liquid volume, and exudate volume needs to be worked out in physiologic and pathologic conditions. AM REV RESPIR DIS 1992; 146:S3-S7
muscle in their walls (7), the effect of vascular distension is to increase the thickness of the mucosa and to block the nose. This may be beneficial in terms of nasal filtration of pollutants, and it could influence the airconditioning role of the nose (8). However, in humans nasal blockage caused by congestion leads to breathing through the mouth, so in terms of protection of the lower airways and lungs the primary response in the nose may be harmful. In the lower airways there are striking species differences both in the extent and the structure of the capacitance systems of vessels. They are especially welldeveloped in the rabbit and sheep (2, 9), but in the former species the walls of the sinuses contain much smooth muscle, which is virtually absent (apart from a fewpericytes)in the sheep. Some species, for example the cat and the guinea pig, have a poorly developed capacitance system in the lower airways. Humans are probably intermediate, with clear capacitance vesselsthat contain smooth muscle in their walls. The junctions between the endothelial cells of the sinuses are "tight," long, and convoluted (2), suggesting that passage of liquid and solutes through the intercellular gaps is restricted. In view of the large diameter of the sinuses (as much as 0.5 mm in sheep), Laplace's law implies a high mural tension for any given sinus blood pressure, and the intercellular junctions would have to resist this tension. "Vasodilation," presumably with congestion of the capacitance system, can almost
double tracheal mucosal thickness in the sheep (10)(figure 1), with smaller effects in the dog where the capacitance system is less well developed (11). Because of the large diameter of the trachea, such a change in thickness would have insignificant effects on tracheal airflow resistance (Poiseuille's law). However, if changes similar in magnitude also occur in the bronchi and smaller airways, where capacitance vessels are known to exist although fewer than for the trachea (2, 3), the changes in mucosal thickness could have a significant effect on airway obstruction. There would not only be a mechanical blockage of the airway lumen but the compliance of the airway wall might be decreased. However, measurements of vascular-induced changes in mucosal thickness have not been made for the smaller airways. Given that the tracheobronchial mucosa can thicken with vascular congestion, the pathophysiologic role for such a change seems obscure, unlike that for the nose. As with any other airway obstruction, mucosal thickening would enhance the uptake of inhaled pollutants at the more proximal sitesof the airways, and possibly the benefits from this process
1 From the Department of Physiology, St George's Hospital Medical School, London, United Kingdom. 2 Correspondence and requests for reprints should be addressed to John Widdicombe, Department of Physiology, St George's Hospital Medical School, Cranmer Terrace,London SW17ORE, UK.
53
54
JOHN WIDDICOMBE
200iA ~ 0
150
.~"8
100
"'-E
"0~:o
5
