150 Chapter 12 Tropoelastin is the soluble monomer precursor of elastin, and is secreted as a 60-kDa mature protein produced, through variable splicing, by diverse elastogenic cell types in the lung, including chondroblasts, myofibroblasts, mesothelial cells, and smooth muscle cells5. Tropoelastin self-aggregates on the cell surface before being deposited onto fibrillar microfibrils and crosslinked to form elastic fibers, in a complex multistep process collectively referred to as elastogenesis255 257 258 259. Tropoelastin has a unique structure, possessing a mosaic of domains in various states of order. The free energy landscape of tropoelastin encompasses multiple energy minima with no sizeable barriers between them257 260. The molecule transitions easily between these low energy minima, giving rise to a conformational ensemble that comprises a wide array of structurally related but dissimilar states. This allows flexibility at a molecular level, providing, at the end of elastogenesis, the functional elasticity required in lung parenchyma for breathing, i.e., maintaining the patency of alveoli, small airways, and adjacent lymph vessels. Elastin expression occurs over a narrow window of development, beginning in midgestation and continuing at high levels throughout the postnatal period261. The mature elastic fiber is an insoluble and stable protein with a very long lifespan of ⁓ 80 years262 263, consistent with the lack of tropoelastin expression in adults (animal model261). Furthermore, elastin is extensively distributed in most human lung compartments, including the pleura, alveolar septa, large vessels, and cartilage261. The crude connective tissue dry weight concentrations of elastin are 20–30% in the respiratory parenchyma, 7–16% in the pulmonary blood vessels, and 3–5% in the airways. The elastic fiber scaffold is known to be an important supportive structure of the normal alveoli9. Alveolar size increases with age254. The delicate three-dimensional network forms a looping system encircling the alveoli and alveolar duct, and ensures that applied forces will be transmitted equally to all parts of the lung261. In functional terms, during exhalation the elastic fibers recoil and maintain a regular, spaced alveolar structure and the diameter of the small airways. A histochemical elastic fiber stain may be useful for recognition of the underlying pulmonary architecture. Two forms of elastic fiber have been described in ultrastructural and threedimensional image studies: thick and thin elastic fibers. The main framework of the alveoli is constructed of thick elastic fibers, forming the alveolar orifice and also the sides of the polygonal alveoli where three neighboring alveoli join. Thin elastic fibers branch from the thick elastic fibers intercrossed in the alveolar wall, and support the alveolar wall264 265 265. Type II pneumocytes are located along thick elastic fibers265.
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