Lung hypoperfusion stimulates liquid absorption in alveoli

Tissue hypoperfusion is common in clinical settings, but how tissues respond to hypoperfusion on a microphysiological scale is not clear. We used real-time confocal microscopy of live, perfused lungs to gain insights into the effects of hypoperfusion on the microcirculation and microphysiology of lung alveoli, where gas exchange occurs. We focused on effects of hypoperfusion on alveolar liquid secretion, since alveolar liquid secretion is important for alveolar homeostatic functions. Our findings show lung hypoperfusion stimulated a reversal of alveolar liquid transport, from homeostatic liquid secretion to absorption. Specifically, lung perfusion at or near physiological perfusion pressure led to alveolar liquid secretion that depended on the alveolar epithelial cystic fibrosis transmembrane conductance regulator (CFTR), Na+-K+-Cl- cotransporters, and the Na+/K+-ATPase. Within minutes of halting lung perfusion or majorly reducing it, alveoli stopped secreting liquid and instead absorbed it via the epithelial Na+ channel, CFTR, and K+-Cl- cotransporters. We provide evidence that hypoperfusion caused alveolar microvessel lumens to shrink and airspaces to expand, leading to epithelial stretch that stimulated liquid absorption. These findings show lung hypoperfusion initiates mechanical signals that stimulate the alveolar epithelium to absorb liquid, and they may inform the pathogenesis of lung diseases characterized by acute microvascular hypoperfusion.