Elastin Peptides as a Potential Disease Vector in the Pathogenesis of Pulmonary Emphysema: An Investigation of This Hypothesis

Abstract

The degradation of elastic fibers is a fundamental characteristic of pulmonary emphysema, resulting in the release of proinflammatory elastin peptides. The findings discussed in this paper support the hypothesis that these peptides act as carriers of disease, interacting with elastin receptor complexes that promote inflammation, elastic fiber damage, and airspace enlargement. Studies from our laboratory show that the breakdown of these fibers is significantly enhanced by intratracheal instillation of elastin peptides in a lipopolysaccharide-induced model of acute lung injury. This result is consistent with a mechanism of elastic fiber injury in which an expanding pool of elastin peptides generates further elastolysis. The accelerating release of the peptides results in a self-perpetuating disease process with the features of an epidemic, where self-replicating agents spread disease. As in the case of an epidemic, elastin peptides resemble disease vectors that transmit alveolar wall injury throughout the lung. This concept may provide a framework for developing novel therapeutic approaches specifically designed to protect elastic fibers from various enzymatic and oxidative insults, thereby slowing the progression of a disease with no robust treatment options.

Keywords: desmosine; disease vector; elastic fibers; elastin peptides; pulmonary emphysema.

Figure 1

(Left) Photomicrograph of elastic fibers from a postmortem human emphysematous lung showing their unraveling (arrowhead) and fragmentation (arrows). Reprinted with permission [10]. (Right) Diagram of lung elastic fiber network showing intact (solid lines) and fragmented (dotted lines) fibers. Foci of alveolar wall distention and rupture (arrows) associated with the loss of intact fibers gradually undergo expansion and become confluent. Elastin peptides (individual dots) bind to elastin receptor complexes in the extracellular matrix and act as a vector in propagating emphysematous changes.

Figure 2

Concurrent intratracheal instillation of LPS and elastin peptides resulted in a significant increase in elastolysis as measured by BALF levels of free desmosine. The proinflammatory effect of the peptides is consistent with their role as a vector in the spread of airspace enlargement through the lungs. Reprinted with permission [10]. T-bars indicate the standard error of the mean (SEM). The numbers above bars denote N.

Figure 3

The combination of elastin peptides and LPS significantly increased the chemotactic activity of alveolar macrophages compared to either agent alone. Reprinted with permission [10]. T-bars indicate SEM. The numbers above bars denote N.

Figure 4

The repair of elastic fibers results in an exponential increase in desmosine crosslink density when the alveolar diameter exceeds 300 µm and levels off at 400 µm. Reprinted with permission [42].

Figure 5

(Upper) Immunofluorescent staining for elastin shows increased deposition of this component in postmortem lungs with moderate pulmonary emphysema (right) compared to one with no disease (left). Reprinted with permission [42]. (Lower) Diagram modeling this process as a transition from an orderly network of elastin peptides (lines) and crosslinks (intersection points) to an irregular meshwork that produces uneven transmission of mechanical forces.

Figure 6

The curve of a communicable disease is similar to that associated with the increase in desmosine crosslink density (Figure 4). The dashed line indicates the upper limit of cases.

Figure 7

Aerosolized HA binds to elastic fibers, protecting them from injury and reducing the interaction of elastin peptides with inflammatory cells. Reprinted with permission from Elsevier.