Elastin in lung development and disease pathogenesis

Abstract

Elastin is expressed in most tissues that require elastic recoil. The protein first appeared coincident with the closed circulatory system, and was critical for the evolutionary success of the vertebrate lineage. Elastin is expressed by multiple cell types in the lung, including mesothelial cells in the pleura, smooth muscle cells in airways and blood vessels, endothelial cells, and interstitial fibroblasts. This highly crosslinked protein associates with fibrillin-containing microfibrils to form the elastic fiber, which is the physiological structure that functions in the extracellular matrix. Elastic fibers can be woven into many different shapes depending on the mechanical needs of the tissue. In large pulmonary vessels, for example, elastin forms continuous sheets, or lamellae, that separate smooth muscle layers. Outside of the vasculature, elastic fibers form an extensive fiber network that originates in the central bronchi and inserts into the distal airspaces and visceral pleura. The fibrous cables form a looping system that encircle the alveolar ducts and terminal air spaces and ensures that applied force is transmitted equally to all parts of the lung. Normal lung function depends on proper secretion and assembly of elastin, and either inhibition of elastin fiber assembly or degradation of existing elastin results in lung dysfunction and disease.

Keywords: Elastic fiber; Elastin; Emphysema; Fibrillin; Lung development; Microfibril.

Figure 1

Elastin protein has a repeating domain structure consisting of lysine-containing sequences that populate crosslinking sites and hydrophobic sequences that contribute to elastic recoil (top). The ε-amino group of lysine residues in alanine-rich (KA) or proline-rich (KP) sequences are oxidized by the enzyme lysyl oxidase resulting in bifunctional and tetrafunctional crosslinks (see text). The electron micrograph of an elastic fiber shows crosslinked elastin (dark amorphous material) associated with a bed of microfibrils. In addition to facilitating elastin assembly, microfibrils have numerous signaling and mechanical roles indicated by the red arrows. Elastin also provides information to cells when fragments interact with signaling receptors on cells (green arrow).

Figure 2

In situ hybridization showing elastin gene expression in a ~7-week bovine embryonic lung. Tissue sections were hybridized with a ³⁵S-labeled riboprobe specific for elastin mRNA and exposed to photographic emulsion. Developed slides were counterstained with hematoxylin-eosin, and white silver grains over areas of hybridization were visualized with dark-field microscopy. At this stage in development, tropoelastin showed highest expression in the visceral pleura (arrowhead) with detectable expression in vessels associated with large branching airways in the parenchyma. The image on the right is a reversal of dark-field only, where the hybridization signal shows up black.

Figure 3

In situ hybridization of ~10-week bovine embryonic lung with RNA probes for elastin (A), fibrillin-1(B), and fibrillin-2 (C). Panel 3D is a composite of gene expression in the pulmonary artery indicated by the arrowhead in panels A–C. Samples were prepared as described in Figure 2. See text for interpretation and details.

Figure 4

Histological sections of lungs from adult wild-type (Eln^+/+) and elastin haploinsufficient (Eln^+/−) mice. Eln^+/− animals exhibit normal alveolar structure (top panels) but develop worse emphysema than normal mice following cigarette smoke exposure (bottom panels).