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Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Am+J+Physiol+Lung+Cell+Mol+Physiol 2015 ; 308 (12): L1212-23 Nephropedia Template TP
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The relative balance of GM-CSF and TGF-?1 regulates lung epithelial barrier function #MMPMID25888574
Overgaard CE; Schlingmann B; Dorsainvil White S; Ward C; Fan X; Swarnakar S; Brown LAS; Guidot DM; Koval M
Am J Physiol Lung Cell Mol Physiol 2015[Jun]; 308 (12): L1212-23 PMID25888574show ga
Lung barrier dysfunction is a cardinal feature of the acute respiratory distress syndrome (ARDS). Alcohol abuse, which increases the risk of ARDS two- to fourfold, induces transforming growth factor (TGF)-?1, which increases epithelial permeability and impairs granulocyte/macrophage colony-stimulating factor (GM-CSF)-dependent barrier integrity in experimental models. We hypothesized that the relative balance of GM-CSF and TGF-?1 signaling regulates lung epithelial barrier function. GM-CSF and TGF-?1 were tested separately and simultaneously for their effects on lung epithelial cell barrier function in vitro. TGF-?1 alone caused an ?25% decrease in transepithelial resistance (TER), increased paracellular flux, and was associated with projections perpendicular to tight junctions (?spikes?) containing claudin-18 that colocalized with F-actin. In contrast, GM-CSF treatment induced an ?20% increase in TER, decreased paracellular flux, and showed decreased colocalization of spike-associated claudin-18 with F-actin. When simultaneously administered to lung epithelial cells, GM-CSF antagonized the effects of TGF-?1 on epithelial barrier function in cultured cells. Given this, GM-CSF and TGF-?1 levels were measured in bronchoalveolar lavage (BAL) fluid from patients with ventilator-associated pneumonia and correlated with markers for pulmonary edema and patient outcome. In patient BAL fluid, protein markers of lung barrier dysfunction, serum ?2-macroglobulin, and IgM levels were increased at lower ratios of GM-CSF/TGF-?1. Critically, patients who survived had significantly higher GM-CSF/TGF-?1 ratios than nonsurviving patients. This study provides experimental and clinical evidence that the relative balance between GM-CSF and TGF-?1 signaling is a key regulator of lung epithelial barrier function. The GM-CSF/TGF-?1 ratio in BAL fluid may provide a concentration-independent biomarker that can predict patient outcomes in ARDS.