Blockade of equilibrative nucleoside transporter 1/2 protects against Pseudomonas aeruginosa-induced acute lung injury and NLRP3 inflammasome activation
Autor: | Alexander Vang, Michael R. Blackburn, Qing Lu, Gaurav Choudhary, Eboni Chambers, Alfred Ayala, Tingting Weng, Alexis White, Zhengke Wang, Sharon Rounds |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Male ARDS Inflammasomes Acute Lung Injury Pharmacology Lung injury Equilibrative nucleoside transporter 1 Biochemistry Article Equilibrative Nucleoside Transporter 1 03 medical and health sciences Mice 0302 clinical medicine Thioinosine NLR Family Pyrin Domain-Containing 3 Protein Genetics medicine Animals Lung volumes Pseudomonas Infections Equilibrative-Nucleoside Transporter 2 Molecular Biology biology business.industry Equilibrative nucleoside transporter Inflammasome respiratory system medicine.disease Adenosine Adenosine receptor respiratory tract diseases 030104 developmental biology Pseudomonas aeruginosa biology.protein business 030217 neurology & neurosurgery Biotechnology medicine.drug |
Zdroj: | FASEB J |
ISSN: | 1530-6860 |
Popis: | Pseudomonas aeruginosa (P. aeruginosa) infections are increasingly multidrug resistant and cause healthcare associated pneumonia, a major risk factor for acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS). Adenosine is a signaling nucleoside with potential opposing effects; adenosine can either protect against acute lung injury via adenosine receptors or cause lung injury via adenosine receptors or equilibrative nucleoside transporter (ENT)-dependent intracellular adenosine uptake. We hypothesized that blockade of intracellular adenosine uptake by inhibition of ENT1/2 would increase adenosine receptor signaling and protect against P. aeruginosa-induced acute lung injury. We observed that P. aeruginosa (strain: PA103) infection induced acute lung injury in C57BL/6 mice in a dose- and time-dependent manner. Using ENT1/2 pharmacological inhibitor, nitrobenzylthioinosine (NBTI), and ENT1-null mice, we demonstrated that ENT blockade elevated lung adenosine levels and significantly attenuated P. aeruginosa-induced acute lung injury, as assessed by lung wet-to-dry weight ratio, BAL protein levels, BAL inflammatory cell counts, pro-inflammatory cytokines, and pulmonary function (total lung volume, static lung compliance, tissue damping, and tissue elastance). Using both agonists and antagonists directed against adenosine receptors A(2A)R and A(2B)R, we further demonstrated that ENT1/2 blockade protected against P. aeruginosa-induced acute lung injury via activation of A(2A)R and A(2B)R. Additionally, ENT1/2 chemical inhibition and ENT1 knockout prevented P. aeruginosa-induced lung NLRP3 inflammasome activation. Finally, inhibition of inflammasome prevented P. aeruginosa-induced acute lung injury. Our results suggest that targeting ENT1/2 and NLRP3 inflammasome may be novel strategies for prevention and treatment of P. aeruginosa-induced pneumonia and subsequent ARDS. |
Databáze: | OpenAIRE |
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