Coagulation-dependent mechanisms and asthma

Abstract

In several clinical disorders, there are interactions between inflammation-dependent tissue injury and thrombin formation, fibrin deposition, and impaired fibrinolysis. New evidence generated from a mouse model of allergic airway hyperreactivity suggests that disordered coagulation and fibrinolysis may contribute to the pathogenesis of asthma. The inflammatory mechanisms that lead to airway smooth muscle contraction and airway hyperresponsiveness may be associated with accumulation of extravascular fibrin, plasma exudates, and inflammatory cells that can lead to airway closure.

Figure 1

Schematic diagram of the alveoli and a terminal airway. Most of the alveolar surface is covered by thin type I epithelial cells. The type II epithelial cells secrete surfactant from lamellar bodies (LBs) into the thin layer of alveolar surface liquid lining the alveoli. The terminal airways are lined by cuboidal epithelial cells and have bands of smooth muscle cells in their walls. A thin liquid layer, the surface tension of which is decreased by the presence of surfactant, lines both alveoli and terminal airways. Because the fluid layer is continuous in the alveoli and the small airways, surfactant can move readily between them, tending to equalize surface tension. The component of pressure due to surface tension is expected to be about four times as large in alveoli as in terminal airways because the radii of curvature are smaller in the quasi-spherical alveoli compared with those in the quasi-cylindrical airways. Thus, the tendency to collapse from surface tension is greater in the alveoli than in the terminal airways. In addition, alveolar surface tension can make a strong contribution to the tethering forces that tend to expand the terminal airways. The presence of plasma from cytokine-dependent inflammation can collect in the distal airways. When inflammation associated with asthma occurs, plasma exudate, mucus, and fibrin accumulate in the airways, potentially leading to airway closure (see Figure 2). The cellular and molecular basis for airway inflammation in asthma was reviewed recently (17).

Figure 2

Schematic cross-sectional diagram of terminal airways illustrating the transition from an opened to a closed airway. Contraction of smooth muscle cells favors airway constriction coupled with variable quantities of plasma proteins in the airway wall and the airway lumen, including fibrin deposition (see Figure 1 in Wagers et al. [ref. 6]). Normally there are tethering forces that will tend to expand terminal airways, while the quantity and quality of airway liquid (and mucus) favor airway obstruction. Although surface tension in the distal airways would be expected to play a minor role in decreasing patency under these conditions, administration of exogenous surfactant might help expel occluding material by dilution, dispersion, and rapid lowering of surface tension at the surfaces of the plugs.