Murine lung injury caused by Leptospira interrogans glycolipoprotein, a specific Na/K-ATPase inhibitor
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-...
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| Veröffentlicht in: | Respiratory research 2014-08, Vol.15 (1), p.93-93, Article 93 |
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| creator | Gonçalves-de-Albuquerque, Cassiano Felippe Burth, Patrícia Silva, Adriana Ribeiro de Moraes, Isabel Matos Medeiros Oliveira, Flora Magno de Jesus Santelli, Ricardo Erthal Freire, Aline Soares de Lima, Gerson Silva da Silva, Emilson Domingos da Silva, Camila Ignácio Morandi, Verônica Bozza, Patrícia Torres Younes-Ibrahim, Mauricio de Castro Faria Neto, Hugo Caire de Castro Faria, Mauro Velho |
| description | 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.
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.
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.
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. |
| doi_str_mv | 10.1186/s12931-014-0093-2 |
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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.
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.
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.</description><identifier>ISSN: 1465-993X</identifier><identifier>ISSN: 1465-9921</identifier><identifier>EISSN: 1465-993X</identifier><identifier>EISSN: 1465-9921</identifier><identifier>DOI: 10.1186/s12931-014-0093-2</identifier><identifier>PMID: 25265888</identifier><language>eng</language><publisher>England: BioMed Central Ltd</publisher><subject>Animals ; Cell adhesion & migration ; Cell Line, Tumor ; Comparative analysis ; Edema ; Enzyme Inhibitors - toxicity ; Experiments ; Fatty acids ; Human Umbilical Vein Endothelial Cells - drug effects ; Human Umbilical Vein Endothelial Cells - enzymology ; Humans ; Infections ; Kinases ; Leptospira interrogans ; Leptospirosis ; Lipids ; Lipopolysaccharides - toxicity ; Lipoproteins - toxicity ; Lung Injury - chemically induced ; Lung Injury - enzymology ; Lung Injury - pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mitogens ; Mortality ; Physiological aspects ; Potassium ; Protein kinases ; Proteins ; Respiratory distress syndrome ; Respiratory function ; Rodents ; Rubidium ; Sodium-Potassium-Exchanging ATPase - antagonists & inhibitors ; Sodium-Potassium-Exchanging ATPase - metabolism</subject><ispartof>Respiratory research, 2014-08, Vol.15 (1), p.93-93, Article 93</ispartof><rights>COPYRIGHT 2014 BioMed Central Ltd.</rights><rights>2014 Gonçalves-de-Albuquerque et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.</rights><rights>Gonçalves-de-Albuquerque et al.; licensee BioMed Central Ltd. 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c593t-2bbb03aeb38cb689d97fc24f6ca9ba6b647c6e4ddeb5578361e685f8bae9a64a3</citedby><cites>FETCH-LOGICAL-c593t-2bbb03aeb38cb689d97fc24f6ca9ba6b647c6e4ddeb5578361e685f8bae9a64a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151191/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151191/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25265888$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gonçalves-de-Albuquerque, Cassiano Felippe</creatorcontrib><creatorcontrib>Burth, Patrícia</creatorcontrib><creatorcontrib>Silva, Adriana Ribeiro</creatorcontrib><creatorcontrib>de Moraes, Isabel Matos Medeiros</creatorcontrib><creatorcontrib>Oliveira, Flora Magno de Jesus</creatorcontrib><creatorcontrib>Santelli, Ricardo Erthal</creatorcontrib><creatorcontrib>Freire, Aline Soares</creatorcontrib><creatorcontrib>de Lima, Gerson Silva</creatorcontrib><creatorcontrib>da Silva, Emilson Domingos</creatorcontrib><creatorcontrib>da Silva, Camila Ignácio</creatorcontrib><creatorcontrib>Morandi, Verônica</creatorcontrib><creatorcontrib>Bozza, Patrícia Torres</creatorcontrib><creatorcontrib>Younes-Ibrahim, Mauricio</creatorcontrib><creatorcontrib>de Castro Faria Neto, Hugo Caire</creatorcontrib><creatorcontrib>de Castro Faria, Mauro Velho</creatorcontrib><title>Murine lung injury caused by Leptospira interrogans glycolipoprotein, a specific Na/K-ATPase inhibitor</title><title>Respiratory research</title><addtitle>Respir Res</addtitle><description>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.
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.
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.
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.</description><subject>Animals</subject><subject>Cell adhesion & migration</subject><subject>Cell Line, Tumor</subject><subject>Comparative analysis</subject><subject>Edema</subject><subject>Enzyme Inhibitors - toxicity</subject><subject>Experiments</subject><subject>Fatty acids</subject><subject>Human Umbilical Vein Endothelial Cells - drug effects</subject><subject>Human Umbilical Vein Endothelial Cells - enzymology</subject><subject>Humans</subject><subject>Infections</subject><subject>Kinases</subject><subject>Leptospira interrogans</subject><subject>Leptospirosis</subject><subject>Lipids</subject><subject>Lipopolysaccharides - toxicity</subject><subject>Lipoproteins - toxicity</subject><subject>Lung Injury - chemically induced</subject><subject>Lung Injury - enzymology</subject><subject>Lung Injury - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mitogens</subject><subject>Mortality</subject><subject>Physiological aspects</subject><subject>Potassium</subject><subject>Protein kinases</subject><subject>Proteins</subject><subject>Respiratory distress syndrome</subject><subject>Respiratory function</subject><subject>Rodents</subject><subject>Rubidium</subject><subject>Sodium-Potassium-Exchanging ATPase - 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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.
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.
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.
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.</abstract><cop>England</cop><pub>BioMed Central Ltd</pub><pmid>25265888</pmid><doi>10.1186/s12931-014-0093-2</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4151191 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; SpringerLink Journals - AutoHoldings; PubMed Central Open Access; Springer Nature OA Free Journals |
| subjects | Animals Cell adhesion & migration Cell Line, Tumor Comparative analysis Edema Enzyme Inhibitors - toxicity Experiments Fatty acids Human Umbilical Vein Endothelial Cells - drug effects Human Umbilical Vein Endothelial Cells - enzymology Humans Infections Kinases Leptospira interrogans Leptospirosis Lipids Lipopolysaccharides - toxicity Lipoproteins - toxicity Lung Injury - chemically induced Lung Injury - enzymology Lung Injury - pathology Male Mice Mice, Inbred C57BL Mitogens Mortality Physiological aspects Potassium Protein kinases Proteins Respiratory distress syndrome Respiratory function Rodents Rubidium Sodium-Potassium-Exchanging ATPase - antagonists & inhibitors Sodium-Potassium-Exchanging ATPase - metabolism |
| title | Murine lung injury caused by Leptospira interrogans glycolipoprotein, a specific Na/K-ATPase inhibitor |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-06T23%3A37%3A35IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Murine%20lung%20injury%20caused%20by%20Leptospira%20interrogans%20glycolipoprotein,%20a%20specific%20Na/K-ATPase%20inhibitor&rft.jtitle=Respiratory%20research&rft.au=Gon%C3%A7alves-de-Albuquerque,%20Cassiano%20Felippe&rft.date=2014-08-14&rft.volume=15&rft.issue=1&rft.spage=93&rft.epage=93&rft.pages=93-93&rft.artnum=93&rft.issn=1465-993X&rft.eissn=1465-993X&rft_id=info:doi/10.1186/s12931-014-0093-2&rft_dat=%3Cgale_pubme%3EA539619063%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1554376523&rft_id=info:pmid/25265888&rft_galeid=A539619063&rfr_iscdi=true |