Back to Search
Start Over
Murine lung injury caused by Leptospira interrogans glycolipoprotein, a specific Na/K-ATPase inhibitor.
- Source :
-
Respiratory research [Respir Res] 2014 Aug 14; Vol. 15, pp. 93. Date of Electronic Publication: 2014 Aug 14. - Publication Year :
- 2014
-
Abstract
- Background: Leptospiral glycolipoprotein (GLP) is a potent and specific Na/K-ATPase inhibitor. Severe pulmonary form of leptospirosis is characterized by edema, inflammation and intra-alveolar hemorrhage having a dismal prognosis. Resolution of edema and inflammation determines the outcome of lung injury. Na/K-ATPase activity is responsible for edema clearance. This enzyme works as a cell receptor that triggers activation of mitogen-activated protein kinase (MAPK) intracellular signaling pathway. Therefore, injection of GLP into lungs induces injury by triggering inflammation.<br />Methods: We injected GLP and ouabain, into mice lungs and compared their effects. Bronchoalveolar lavage fluid (BALF) was collected for cell and lipid body counting and measurement of protein and lipid mediators (PGE2 and LTB4). The levels of the IL-6, TNFα, IL-1B and MIP-1α were also quantified. Lung images illustrate the injury and whole-body plethysmography was performed to assay lung function. We used Toll-like receptor 4 (TLR4) knockout mice to evaluate leptospiral GLP-induced lung injury. Na/K-ATPase activity was determined in lung cells by nonradioactive rubidium incorporation. We analyzed MAPK p38 activation in lung and in epithelial and endothelial cells.<br />Results: Leptospiral GLP and ouabain induced lung edema, cell migration and activation, production of lipid mediators and cytokines and hemorrhage. They induced lung function alterations and inhibited rubidium incorporation. Using TLR4 knockout mice, we showed that the GLP action was not dependent on TLR4 activation. GLP activated of p38 and enhanced cytokine production in cell cultures which was reversed by a selective p38 inhibitor.<br />Conclusions: GLP and ouabain induced lung injury, as evidenced by increased lung inflammation and hemorrhage. To our knowledge, this is the first report showing GLP induces lung injury. GLP and ouabain are Na/K-ATPase targets, triggering intracellular signaling pathways. We showed p38 activation by GLP-induced lung injury, which was may be linked to Na/K-ATPase inhibition. Lung inflammation induced by GLP was not dependent on TLR4 activation.
- Subjects :
- Animals
Cell Line, Tumor
Enzyme Inhibitors toxicity
Human Umbilical Vein Endothelial Cells drug effects
Human Umbilical Vein Endothelial Cells enzymology
Humans
Lung Injury pathology
Male
Mice
Mice, Inbred C57BL
Sodium-Potassium-Exchanging ATPase metabolism
Leptospira interrogans
Lipopolysaccharides toxicity
Lipoproteins toxicity
Lung Injury chemically induced
Lung Injury enzymology
Sodium-Potassium-Exchanging ATPase antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1465-993X
- Volume :
- 15
- Database :
- MEDLINE
- Journal :
- Respiratory research
- Publication Type :
- Academic Journal
- Accession number :
- 25265888
- Full Text :
- https://doi.org/10.1186/s12931-014-0093-2