Abstract
Critically ill patients with respiratory failure from acute respiratory distress syndrome (ARDS) have reduced ability to clear alveolar edema fluid. This reduction in alveolar fluid clearance (AFC) contributes to the morbidity and mortality in ARDS. Thus, it is important to understand why AFC is reduced in ARDS in order to design targeted therapies. In this review, we highlight experiments that have advanced our understanding of ARDS pathogenesis, with particular reference to the alveolar epithelium. First, we review how vectorial ion transport drives the clearance of alveolar edema fluid in the uninjured lung. Next, we describe how alveolar edema fluid is less effectively cleared in lungs affected by ARDS and describe selected in vitro and in vivo experiments that have elucidated some of the molecular mechanisms responsible for the reduced AFC. Finally, we describe one potential therapy that targets this pathway: bone marrow-derived mesenchymal stem (stromal) cells (MSCs). Based on preclinical studies, MSCs enhance AFC and promote the resolution of pulmonary edema and thus may offer a promising cell-based therapy for ARDS.
Highlights
Pulmonary edema is the abnormal accumulation of fluid in the interstitium and air spaces of the lungs, which leads to impaired gas exchange and respiratory failure
We have discussed how vectorial ion channels in alveolar epithelium generate an osmotic gradient that drives alveolar fluid clearance (AFC) in both physiologic and pathologic conditions. Both AFC and paracellular permeability can be measured using in vitro and in vivo models of ARDS, and these studies indicate that vectorial ion transport is less effective in injured lungs than in uninjured lungs
Recent studies suggest that MSCs interact with alveolar epithelium and ion channels to increase AFC and may serve as a promising treatment for ARDS
Summary
Pulmonary edema is the abnormal accumulation of fluid in the interstitium and air spaces of the lungs, which leads to impaired gas exchange and respiratory failure. In 2006, Fang et al developed a model of a polarized human alveolar type II cell that facilitated in vitro studies of AFC (32) (Figure 2) Using this model, Lee et al found that transepithelial fluid transport is less effective in the presence of ARDS edema fluid and found that there are increased levels of cytokines and decreased levels of ion transport proteins in the presence of ARDS edema fluid compared to a plasma control (33). MSCs enhance bacterial clearance and improve survival in mouse and rat models of sepsis (41, 51), and they have beneficial effects in ventilator-induced acute lung injury (52) Based on this preclinical data, phase 1 and 2 clinical trials are currently testing MSCs as a therapy for ARDS (53). Several mechanisms may explain MSC-mediated resolution of lung injury, and further studies are needed to fully characterize this process
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