The alveolar barrier is formed by monolayers of alveolar epithelium (AE) and endothelium. It separates distal air spaces from blood. A thin fluid film on its surface is required for gas exchange. Any disturbance of barrier function and thickening of the fluid film impairs gas exchange and causes hypoxemia and tissue hypoxia; whereas the layer of endothelial cells is quite leaky, alveolar epithelium forms a tight monolayer which prevents permeation of plasma water into alveolar space. Another protective mechanism is alveolar reabsorption: active reabsorption of Na⁺ from the alveolar surface, which is mediated by apical epithelial Na-channels and basolateral Na/K-ATPase in alveolar epithelial cells, generates the osmotic driving force for water.

Hypoxia of the alveolar barrier occurs when fluid accumulates at its surface subsequent to increased capillary filtration pressure or upon inflammation-induced malfunction of junction proteins. It increases its permeability and also inhibits reabsorption thus impeding potentially protective mechanisms. Although pathogens can also directly affect alveolar epithelial cells to modify their function, most negative effects are mediated or enhanced by signaling molecules released from alveolar macrophages. Amongst those are TNF-alpha, TGF-beta, interleukins, and NO. The mechanisms involved in the impairment of barrier function are only poorly understood. They appear to involve enzyme-mediated processes such as ERK1/2, MAP kinases, but also direct protein nitrosylation.

Reabsorption and barrier tightness can be improved by beta2-adrenergic and glucocorticoid stimulation, which affect protein compartmentalization and biosynthesis. Although hypoxia and inflammation seem to impair signaling as well, stimulation still occurs and can restore normal barrier function.