J Nippon Med Sch 1997; 64(6) (495)1 -Reviews- The endothelium of the pulmonary microvessels Oichi Kawanami Department of Molecular Pathology, Institute of Gerontology, Nippon Medical School Introduction In the normal lung, the bronchial airways are lined by a pseudostratified arrangement of several types of epithelial cells such as ciliated cells, goblet cells, basal cells, Clara cells and undifferentiated bronchiolar cuboidal cells. They are adherent to the underlying basement membrane which is com- posed of laminin, type IV collagen and other Fig. 1 Type VII collagen, which is a main constitute of epidermal anchoring fibrils, is highly reactive proteoglycans. The basement membrane in the along the basement membrane zone (white tri- airways is subjacently supported by type VII col- angle) from trachea, brounchus to respiratory lagen which is a main composition of the electron bronchiole, suggesting that airway basal cells microscopic features of anchoring fibrils. Type VII retain a common characteristics with epidermal basal cells in producing type VII collagen. The collagen seems to precipitate as a distinct arc-form microvesels (arrow heads) being located sub- structure in the upper airways', but the fibrillar jacent to type VII collagen are originated exclu- structure becomes rather vague in the distal por- sively from bronchial artery system, but not from pulmonary artery system. BL: bronchial tions of the bronchial airways despite a clear im- lumen. ABC immunoperoxidase stain for type munohistological reaction to type VII collagen6 VII collagen (x75) (Fig. 1). The microvessels located subjacent to type VII collagen are originated exclusively from the bronchial artery system, and not from the pulmo- deemed to be in continuity with the lining endoth- nary artery system. The alveolar walls, which play elial cells of vessels distributed in the lung and any the most important role in gas-exchange function, other organs. never show a positive reactivity for type VII col- However, there is increasing evidence that the lagen. The epithelial lining in the alveolar walls in endothelial cells in the aorta differ from the endoth- man is composed of only two types of epithelial elial cells of arterioles in visceral organs cells, type I and type II alveolar epithelial cells. The Furthermore microvascular endothelium, such as type I alveolar epithelial cells are exposed to air- that in the lung, apparently retains its own prop- space on one side, and the other side of the cells erties in morphology and function when compared firmly adheres to the single layer of basement with the endothelium in larger vessels in the same membrane, which in turn faces the flat cytoplasm of organ. Morphologically, capillary endothelial the endothelial cells of the alveolar capillaries. The cells are classified into two types based on the capillary endothelial cells make up 30% of the lung ultrastructural features (Fig. 2): continuous type cells'. They cover the inner surface of blood vessels, and non-continuous type". Usually, capillary en- not only capillaries, but the aorta, arteries and veins dothelial cells have flat cytoplasmic extensions with as well. They tightly attach to each other by jun- no defect (continuous type), and the cytoplasm of ctional structures which protect blood components other capillary endothelial cells contains either from leaking. Thus, any single endothelial cell is fenestrae or relatively large defects (non-continuous * Professor 2(496) ucts of which are central to endothelial repair and remodeling. Neovascularization implies that a pair of endothelial cells sprouts from parent vessels to induce new capillaries. Basic knowledge of this phenomenon has now gradually broadened in view of the complex interactions of growth factors, as well as proteoglycans and adhesion molecules". 1. Dual blood circulation in the lung The pulmonary vasculature includes dual arterial systems: to pulmonary artery and bronchial Fig. 2 Ultrastructural schema of two types of capil artery"-". They develop corresponding drainage -laries indicates. one is continuous and non- vessels for venous return to the heart. The pulmo- fenestrated type at the left and the other is discontinuous and fenestrated (diaphragm- nary artery originates from the right ventricle of forming; arrows) type at the right. The cyto the heart, and supplies venous blood to the vessels - plasms of both capillaries contain lots of which distribute along the bronchial trees. The pinocytotic vesicles. blood flow eventually reaches alveolar capillaries at areas of respiratory bronchioles. The alveolar capil- type) as in the hepatic sinusoid. The latter type of laries play an unequivocal role in the gas-exchange capillaries is localized in limited regions of some through the air-blood barrier of alveolar walls. It is organs. well understood that the alveolar blood flow returns A large number of studies describing the results to pulmonary veins through the drainage system of obtained from experiments on endothelial cells in the interlobular blood vessels which parallel fine vitro have accumulated In these studies, networks of lymph vessels". The microvessels of endothelial cells were collected in relatively simple both pulmonary veins and bronchial veins are procedures" from vessels such as the human umbili- devoid of valves. In addition, extrapulmonary bron- cal cord vein", saphenous vein" and pulmonary chial veins infrequently possess valves near the lung vessels". Since the natural characteristics of en- hilus26,29. And the pulmonary veins in rats have dothelial cell biology are rapidly modified in the regular thin bands of sphincters that cause pulmo- artificial environments of a culture dish20, and of nary edema by a physical stimulus to the brain". chicken chorioallantoic membranes21, it is not easy Using resin casting of the vasculature, Peao et all' to make any immediate inference as to in vivo also found vascular sphincters at the junction reactions from results based upon in vitro, experi- between alveolar capillaries and pulmonary venules ments. Thus, it is indispensable to categorize the in the mouse lung. They offer a structural setting vascular endothelial cells of the lung tissue accord- for the existence of postcapillary control of blood ing to their in vivo, as against in vitro, biological flow in the pulmonary circulation. characteristics. Studies on the bronchial circulation system have Among all the organs of the body, the respiratory not been sufficiently carried out for a long period of microvessels seems to carry special properties in time although Leonard da Vinci in the 15th cen- terms of their dynamic dual blood circulations, and tury"," had depicted the bronchial arteries originat- their specific functions. The ultrastructual pheno- ing from the aorta. Cudkowicz and his group" have types of their endothelial cells are of interest as they made a great contribution by revealing the detailed may alter indifferent lung environments 14. distribution of the bronchial artery system using Particular interest exists in the repair processes arteriography. They showed histological changes in of endothelial cells following damage to thems22. In relation to various lung lesions. this condition, vascular endothelial cells, under (1) . Anatomy of the normal bronchial arteries profound influence of cytokine regulation", immedi- The origin of the bronchial arteries was shown to ately respond by expressing various genes" , prod- be located between the upper border of the fourth ( .197 ) 3 thoracic vertebra (T 4) and the lower border of T 6 in 90% of 40 fresh adult cadavers. The right bronchial arteries arise from the right intercostal bronchial artery trunk that originated from the thoracic aorta. And the one or two left bronchial arteries are directly connected to the thoracic aorta. Nagaishi et applied angiogram and resin casting techniques to examine the bronchial artery system. According to their results, the bronchial artery ultimately distributes in the mucosa of the bronchial wall, muscle and surrounding connective tissue layers, perichondrium, and large vessels. Extrapul- monary bronchial arteries supply their branches to Fig. 3 The pulmonary artery (PA) is visible situated par- alled to a bronchial airway which is branching at lymph nodes, and pleural and interlobular connec- the right lower corner (BR). Bronchial arteries are tive tissues. not obvious, but their microvessels (arrows) are distributed along the connective tissue sheaths of Intrapulmonary bronchial arteries are located the airways and large vessels. Those vessels are in a together with pulmonary arteries and lymph vessels close apposition to alveolar capillaries. Respiratory along the bronchial airways" (Fig. 3,4). Bronchial bronchiol (RB) and alveolar ducts (AD) are clearly seen in the middle of this picture. Scanning electron arteries appear much smaller in size when compar- micrograph of terminal bronchiole. ( x 1000 original) ed with associating pulmonary arteries in bron- chovascular connective tissue bands. It is almost impossible to differentiate the bronchial arteries The larger bronchi have a double venous net- from the pulmonary arteries at the periphery of work, one is located in the mucos a and the other in airways. The arterioles of bronchial circulation the connective tissue located external to the bron- have widely concentric muscle bundles bordered by chial cartilage. They are closely connected with internal elastic lamina. The vessels often appear each other. Approximately one-third