Article Update

Tuesday, April 20, 2021


The cellular composition of the alveolar capillary unit was not recognized until the era of electron microscopy. Before that time, it was thought that a single membrane separated blood and air at the level of the terminal airspace. We now know that, even at its narrowest, the boundary between blood and air is composed of at least two cell types (the type I alveolar epithelial cell and the endothelial cell) and extracellular material, namely, the surfactant lining of the alveolar surface, the basement membranes, and the so-called “endothelial fuzz.” The last is composed of mucopolysaccharides and proteoglycans (or glycocalyx) that may be involved in signal transduction, including mechanotransduction or shear stress at the endothelial surface. Plate 1-27 shows part of a terminal airspace and cross sections of surrounding capillaries. In humans, the diameter of the alveoli varies from 100 to 300 μm. The capillary segments are much smaller in diameter (10-14 μm) and may be separated from each other by even smaller distances. Each alveolus (there are 300 million alveoli in the adult human lungs) may be associated with as many as 1000 capillary segments.
The thinness of the cellular boundary between the blood and the air presents enormous surface area to air on one side and to blood on the other (  ̴70 m2 for both lungs). Given the paucity of organelles, the cells at this location likely play mainly passive roles in physiologic and metabolic events involved in the management of airborne or bloodborne substrates.
Ninety-five percent of the alveolus is lined by epithelial type I cells. The remaining cells are larger polygonal type II cells. These two cell types form a complete epithelial layer sealed by tight junctions. The cellular layer lining the alveoli is remarkably impermeable to salt-containing solutions, but little is known about specific metabolic activities of type I alveolar cells. Growing evidence suggests a more important role in the maintenance of alveolar homeostasis than previously thought, evidenced by the expression a large number of proteins such as aquaporin (AQP-5), T1α, functional ion channels, caveolins, adenosine receptors, and multidrug-resistant genes. Type II cells and endothelial cells have long been known to play active roles in the metabolic function of the lung by producing surfactant and processing circulating vasoactive substances, respectively. In addition, recent research suggests more complex roles for both of these cell types.

Alveolar Cells And Surface-Active Layer
As illustrated in Plate 1-28, in addition to being larger, the type II alveolar cell is distinguished from the type I alveolar cell by having short, blunt projections on the free alveolar surface and lamellar inclusion bodies. The intracellular origins of the lamellar bodies (LBs) and the exact mechanism for lipid transport into them are not known with certainty, although lipid translocation across the LB membrane is facilitated by the ABCA subfamily of adenosine triphosphate binding cassette transporters. The LB contains the phospholipid component of surfactant and two small hydrophobic surfactant polypeptide proteins (SP-B and SP-C) that are coreleased from the type II cell by a process similar to exocytosis. Two additional components of surfactant (large hydrophilic proteins SP-A and SP-D) are synthesized and released independent of LBs.
After release into the airspace, surfactant forms a lipid monolayer on the alveolar surface, greatly reducing surface tension. Although surfactant production, release, and recycling are critical type II cell functions, these cells are now known to have many additional functions, including repopulation of type I cells, clearance, repair, migration to areas of lung injury, and host defense (including the expression of Toll-like receptors). Type II cells also secrete and respond to an array of cytokines and chemokines and have been shown to regulate monocyte transmigration across the epithelium.
Alveolar macrophages  are migratory cells and, after fixation for microscopy, they are usually seen free in the alveolar space or closely applied to the surface of type I cells. Alveolar macrophages are characterized by irregular cytoplasmic projections and large numbers of lysosomes. Alveolar macrophages are important in the defense mechanisms of the lungs.
The cellular components of the blood-air barrier frequently consist only of the extremely flattened extensions of endothelial cells and type I alveolar cells. In other regions, the wall contains such cell types as smooth muscle cells, pericytes, fibroblasts, and occasional mononuclear cells (including plasma cells). Smooth muscle cells are found around the mouth of each alveolus in humans. Pericytes ensheathed in base- ment membrane occur around pulmonary alveolar capillaries but less frequently than on systemic capillaries. The pericytes are characterized by having finely branched cytoplasmic processes that approach the endothelial cells and a web of cytoplasmic filaments that run along the membrane close to the endothelium. Pericytes can be distinguished from fibroblasts in that the latter are free of a basement membrane sheath.

Endothelial Cell Structure
Details of the fine structure of pulmonary capillary endothelial cells are shown in Plate 1-29. The endothelium is of the continuous type (not fenestrated), and the cells are frequently linked by tight junctions. Alveolar epithelial cells and alveolar capillary endothelial cells are uniquely interactive and highly codependent during lung development. The ultrastructural features of the capillary endothelial cell are in keeping with their primary roles as fluid barriers and gas transfer facilitators. The thickest portion of the cell is in the vicinity of the nucleus, where the majority of cytoplasmic organelles, such as mitochondria, Golgi apparatus, rough endoplasmic reticulum, multivesicular bodies, microtubules, microfilaments, and Weibel-Palade bodies, reside. However, the more peripheral slender extensions of these cells are practically devoid of organelles, and may be as thin as 0.1 μm in some regions.
A growing body of evidence indicates that the endothelium plays a large number of important physiologic roles at the alveolar level, many of which appear to be mediated by the caveolae intracellulare. The caveolae are a subset of membrane (lipid) rafts, present as flask-shaped invaginations of the plasma membrane. When the pulmonary capillary endothelial cell membrane is freeze fractured, the caveolae appear as pits on the inner fracture face and as domes on the outer fracture face. Intramembranous particles, about 80 to 100 Å in diameter, are randomly scattered on both faces, except in association with caveolae, where they occur in rings or plaques. These rings correspond to the skeletal rim seen in thin sections. The intramembranous particles also occur on the curved faces of the caveola membrane.
The caveolae contain caveolin proteins, which serve as organizing centers for signal transduction. Caveolin proteins have cytoplasmic N and C termini, palmitoylation sites, and a scaffolding domain that facilitates interaction with signaling molecules. Caveolae are implicated in a wide variety of cell transport events, including transcytosis and cholesterol trafficking. Many of the caveolae intracellulares directly face the vascular lumen, but they are also found on the abluminal surface as vesicles, vastly increasing the surface of the endothelium. The luminal stoma of the caveola is spanned by a delicate diaphragm composed of a single lamella (by contrast with the unit membrane construction of the endothelial plasma membrane and caveola membrane) that helps create a specialized microenvironment within the caveola.
In addition to the caveolae, the endothelial surface has numerous fingerlike projections, which are best demonstrated in scanning electron micrographs. The size (250-350 nm in diameter; 300 to 3000 nm long) and density of the projections are such that they may prevent the formed elements of blood from approaching the endothelial surface and have the effect of directing an eddy flow of plasma along the cells. Their function is not entirely known, but they vastly increase the cell surface area for interaction with soluble elements in the blood.

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