Participation of NADPH Oxidase-Related Reactive Oxygen Species in Leptin-Promoted Pulmonary Inflammation: Regulation of cPLA2α and COX-2 Expression

Abstract

Obesity is a worldwide epidemic problem and correlates to varieties of acute or chronic lung diseases such as acute respiratory distress syndrome, chronic obstructive pulmonary disease, and pulmonary fibrosis. An increase of leptin, a kind of adipokine, in lean mice plasma has been found to impair immune responses and facilitate the infection of Klebsiella pneumoniae, resulting in increased pneumonia severity. Also, a higher leptin level is found in exhaled breath condensates of obese or asthmatic subjects, compared to healthy ones, suggesting that leptin is involved in the occurrence or exacerbation of lung injury. In previous studies, we showed that leptin stimulated cytosolic phospholipase A2-α (cPLA2α) gene expression in lung alveolar type II cells via mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB)-activated coactivator p300. Herein, we show that the in vivo application of leptin in the respiratory system upregulated the expression of inflammatory proteins cPLA2α and cyclooxygenase-2 (COX-2) together with leukocyte infiltration. Treatment with an ROS scavenger (N-acetylcysteine, NAC), an NADPH oxidase inhibitor (apocynin), or an activating protein (AP)-1 inhibitor (tanshinone IIA) attenuated leptin-mediated cPLA2α/COX-2 expression and leukocyte recruitment in the lung. Leptin increased intracellular oxidative stress in a leptin receptor (OB-R) and NADPH oxidase-dependent manner, leading to the phosphorylation of the AP-1 subunit c-Jun. In summation, leptin increased lung cPLA2α/COX-2 expression and leukocyte recruitment via the NADPH oxidase/ROS/AP-1 pathway. Understanding the inflammatory effects of leptin on the pulmonary system provides opportunities to develop strategies against lung injury related to metabolic syndrome or obesity.

A Positive Feed Forward Loop between Wnt/β-Catenin and NOX4 Promotes Silicon Dioxide-Induced Epithelial-Mesenchymal Transition of Lung Epithelial Cells

“…ROS are also required for the maintenance and differentiation of primary lung fibroblasts for lung tissue homeostasis [ 19 ]. However, a continuously excessive production of ROS (oxidative stress) in the lung by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) may result in tissue injury and dysregulated injury/repair and ultimately lead to chronic pulmonary diseases, such as pulmonary fibrosis [ 19 , 20 ]. In addition, exposure to silica dust was demonstrated to induce ROS production and lung injury in animal models [ 17 , 21 ], suggesting a pathogenetic role of ROS in the development of silicosis.…”

Targeting ROS and cPLA2/COX2 Expressions Ameliorated Renal Damage in Obese Mice with Endotoxemia

“…Similarly, the nephrotoxic agent, aristolochic acid I, increases protein abundance of the NADPH oxidase subunits NOX4, p47 phox , p22 phox and 3-nitrotyrosine in rats within 8 to 24 weeks [17]. Moreover, upregulation of intracellular ROS promotes the expression of inflammatory genes, including cPLA2 and COX-2 [18,19]. In fact, ameliorating oxidative stress via modulating forkhead box class O1 (FOXO1) expression attenuated high glucose-induced renal proximal tubular cell injury [20].…”

Study on Anti-Inflammatory Activity of Niloticin by Targeting MD-2 Based on Computer-Aided Drug Design and Biolayer Interferometry

“…In the present study, the release of NO and the expression of iNOS could be suppressed by niloticin. In addition, niloticin could also downregulate the expression of COX-2, which is related to the severity of inflammation [34]. A previous study showed that COX-2-deficient rats could delay the infiltration of leukocytes into important organs and resist infection mediated by LPS [35].…”