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Respiratory Research
Published in: Respiratory Research 1/2014

Open Access 01-12-2014 | Research

Murine lung injury caused by Leptospira interrogans glycolipoprotein, a specific Na/K-ATPase inhibitor

Authors: Cassiano Felippe Gonçalves-de-Albuquerque, Patrícia Burth, Adriana Ribeiro Silva, Isabel Matos Medeiros de Moraes, Flora Magno de Jesus Oliveira, Ricardo Erthal Santelli, Aline Soares Freire, Gerson Silva de Lima, Emilson Domingos da Silva, Camila Ignácio da Silva, Verônica Morandi, Patrícia Torres Bozza, Mauricio Younes-Ibrahim, Hugo Caire de Castro Faria Neto, Mauro Velho de Castro Faria

Published in: Respiratory Research | Issue 1/2014

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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.

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.

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.

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.
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Metadata
Title
Murine lung injury caused by Leptospira interrogans glycolipoprotein, a specific Na/K-ATPase inhibitor
Authors
Cassiano Felippe Gonçalves-de-Albuquerque
Patrícia Burth
Adriana Ribeiro Silva
Isabel Matos Medeiros de Moraes
Flora Magno de Jesus Oliveira
Ricardo Erthal Santelli
Aline Soares Freire
Gerson Silva de Lima
Emilson Domingos da Silva
Camila Ignácio da Silva
Verônica Morandi
Patrícia Torres Bozza
Mauricio Younes-Ibrahim
Hugo Caire de Castro Faria Neto
Mauro Velho de Castro Faria
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2014
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-014-0093-2

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