Role of Nicotinamide Adenine Dinucleotide Phosphate–Reduced Oxidase Proteins in Pseudomonas aeruginosa–Induced Lung Inflammation and Permeability
Autor: | Ruxana T. Sadikot, Syed Mansoor, Panfeng Fu, Chinnaswamy Tiruppathi, Viswanathan Natarajan, Vijay Mohan |
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Rok vydání: | 2013 |
Předmět: |
Pulmonary and Respiratory Medicine
Clinical Biochemistry Vascular permeability Nicotinamide adenine dinucleotide Gene Expression Regulation Enzymologic Capillary Permeability Mice chemistry.chemical_compound Pneumonia Bacterial medicine Animals Humans Pseudomonas Infections Molecular Biology Cells Cultured Mice Knockout chemistry.chemical_classification Reactive oxygen species Blood-Air Barrier Membrane Glycoproteins NADPH oxidase biology urogenital system NADPH Oxidases NOX4 Blood–air barrier Articles Cell Biology respiratory system Molecular biology medicine.anatomical_structure chemistry NADPH Oxidase 4 NOX1 NADPH Oxidase 2 Pseudomonas aeruginosa cardiovascular system biology.protein Reactive Oxygen Species NADP Nicotinamide adenine dinucleotide phosphate |
Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 48:477-488 |
ISSN: | 1535-4989 1044-1549 |
Popis: | Earlier studies indicated a role for reactive oxygen species (ROS) in host defense against Pseudomonas aeruginosa infection. However, the role of nicotinamide adenine dinucleotide phosphate–reduced (NADPH) oxidase (NOX) proteins and the mechanism of activation for NADPH oxidase in P. aeruginosa infection are not well-defined. Here, we investigated the role of NOX2 and NOX4 proteins in P. aeruginosa infection, ROS generation, and endothelial barrier function in murine lungs and in human lung microvascular endothelial cells (HLMVECs). Airway instillation of P. aeruginosa strain 103 (PA103) significantly increased ROS concentrations in bronchial alveolar lavage (BAL) fluid, along with the expression of NOX2 and NOX4, but not NOX1 and NOX3, in lung tissue. In addition, PA103-infected HLMVECs revealed elevated concentrations of ROS, NOX2, and NOX4. In murine lungs and HLMVECs, PA103 induced the NF-κB pathway, and its inhibition blocked PA103-dependent NOX2 and NOX4 expression. Barrier function analysis showed that heat-killed PA103 induced endothelial permeability in a dose-dependent manner, which was attenuated by treatment with small interfering (si)RNA specific for NOX4, but not NOX2. Furthermore, the knockdown of NOX4, but not NOX2, with siRNA reduced PA103-mediated apoptosis in HLMVECs. In vivo, the down-regulation of NOX4 with NOX4 siRNA attenuated PA103-induced lung vascular permeability. The deletion of NOX2 in mice exerted no effect on permeability, but offered significant resistance to P. aeruginosa–induced lung inflammation. These data show that P. aeruginosa lung infection up-regulates NOX2 and NOX4 expression and ROS generation, which play distinct roles in regulating lung inflammation, apoptosis, and permeability. |
Databáze: | OpenAIRE |
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