The relative balance of GM-CSF and TGF-β1 regulates lung epithelial barrier function

American Journal of Physiology - Lung Cellular and Molecular Physiology - Tập 308 Số 12 - Trang L1212-L1223 - 2015
Christian E. Overgaard1,2, Barbara Schlingmann1, StevenClaude Dorsainvil White1, Chris Ward1,2, Xian Fan3,1, Snehasikta Swarnakar4, Lou Ann S. Brown5,2, David M. Guidot3,1,2, Michael Koval6,1,2
1Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, Georgia
2Emory Alcohol and Lung Biology Center, Emory University, Atlanta, Georgia;
3Atlanta Veterans Affairs Medical Center, Decatur, Georgia
4Drug Development Diagnostics and Biotechnology, CSIR-Indian Institute of Chemical Biology, Kolkata, India;
5Division of Neonatology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
6Department of Cell Biology, Emory University, Atlanta, Georgia

Tóm tắt

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)-β1, 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-β1 signaling regulates lung epithelial barrier function. GM-CSF and TGF-β1 were tested separately and simultaneously for their effects on lung epithelial cell barrier function in vitro. TGF-β1 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-β1 on epithelial barrier function in cultured cells. Given this, GM-CSF and TGF-β1 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 α2-macroglobulin, and IgM levels were increased at lower ratios of GM-CSF/TGF-β1. Critically, patients who survived had significantly higher GM-CSF/TGF-β1 ratios than nonsurviving patients. This study provides experimental and clinical evidence that the relative balance between GM-CSF and TGF-β1 signaling is a key regulator of lung epithelial barrier function. The GM-CSF/TGF-β1 ratio in BAL fluid may provide a concentration-independent biomarker that can predict patient outcomes in ARDS.

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American Journal of Physiology - Lung Cellular and Molecular Physiology

Tập 308 Số 12

L1212-L1223

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