Alveolar fluid transport: a changing paradigm

Abstract

UNLIKE OTHER EPITHELIAL TISSUES that transport large amounts of solutes and water, the alveolar epithelium is faced with a unique physiological challenge. To facilitate optimal gas exchange and to trap airborne particulate matter, it must maintain a thin layer of fluid on the luminal surface of its extensive alveolar network. However, the thickness of the fluid layer must be tightly regulated, since even slight increases in the fluid depth could adversely affect gas exchange, whereas dehydration of the surface would impair ciliary clearance. The alveolar flooding associated with acute respiratory distress syndrome or the airway dehydration in cystic fibrosis represents two pathological extremes of a failure to maintain proper airway fluid balance. Both of these conditions account for a significant burden of morbidity and mortality worldwide (16, 20). Extensive research done in the last two decades has shown that precise regulation of alveolar surface fluid layer is achieved through vectorial transport of solutes between the alveolar surface and interstitial spaces with active Na transport across the alveolar epithelium generating the osmotic force for movement of water (12, 17). The broadly accepted paradigm for Na transport in the alveoli involves a two-step process: movement of Na through cation channels in the apical cell membrane constitutes the first step, and extrusion of the excess Na thus acquired via basolateral Na-K-ATPase is the second step (19). However, despite extensive research using many different approaches that support this paradigm, gaps still exist in our understanding of how this fine balance is achieved in vivo (19). In particular, there are several unresolved questions that, when resolved, could significantly affect our view of alveolar fluid clearance. First, type 1 cells constitute 95% of the alveolar surface area, but their role in ion transport is not completely clear. If there are significant differences between the transport characteristics of type I and type II cells, the current paradigm describing alveolar fluid clearance would need to be modified. Second, although cation permeability pathways have been described fairly well, the precise pathways for movement of anions are unclear. The character of these channels is important since anion channels could form either co-ion pathways for the concomitant movement of Na and Cl or a secretory pathway to increase alveolar fluid. Finally, alveolar fluid clearance appears to consist of a basal and stimulated component of reabsorption. The relative contribution of different ion channels and different cell types to these two components of clearance is far from clear. These questions are all underscored by the differences between the robust increases in transport that can be produced by several different treatments in vitro and the often weak clearance response of the in vivo lung epithelium to the same treatments