Phospholipid Ozonation Products Activate the 5-Lipoxygenase Pathway in Macrophages

Abstract

Ozone is a highly reactive environmental toxicant that can react with the double bonds of lipids in pulmonary surfactant. This study was undertaken to investigate the proinflammatory properties of the major lipid-ozone product in pulmonary surfactant, 1-palmitoyl-2-(9’-oxo-nonanoyl)-glycerophosphocholine (16:0/9al-PC), with respect to eicosanoid production. A dose-dependent increase in the formation of 5-lipoxygenase (5-LO) products was observed in murine resident peritoneal macrophages (RPM) and alveolar macrophages (AM) upon treatment with 16:0/9al-PC. In contrast, the production of cyclooxygenase (COX) derived eicosanoids did not change from basal levels in the presence of 16:0/9al-PC. When 16:0/9al-PC and the TLR2 ligand, zymosan, were added to RPM or AM, an enhancement of 5-LO product formation along with a concomitant decrease in COX product formation was observed. Neither intracellular calcium levels or arachidonic acid release were influenced by the addition of 16:0/9al-PC to RPM. Results from mitogen-activated protein kinase (MAPK) inhibitor studies and direct measurement of phosphorylation of MAPKs revealed that 16:0/9al-PC activates the p38 MAPK pathway in RPM, which results in activation of 5-LO. Our results indicate that 16:0/9al-PC has a profound effect on the eicosanoid pathway, which may have implications in inflammatory pulmonary disease states where eicosanoids have been shown to play a role.

Air Pollution and Angioedema

“…LOPs and ROS have been purported to increase inflammation, through the 5-lipooxygenase pathway, and cause vasodilation, through the nitric oxide (NO) pathway. 24-26 At the same time, activation of the bradykinin pathway has been shown to lead to increased levels of vascular permeability factors and activation of NO synthase. 27,28 Thus, patients with a hereditary or acquired angioedema, who already have elevated levels of these factors that increase blood circulation, may be pushed out of equilibrium and into an angioedema episode by the presence of elevated ozone levels in the atmosphere via LOPs and ROS.…”

“…Most important, ozone reacts with polyunsaturated fatty acids, which leads to the formation of lipid oxidation products (LOPs) and reactive oxygen species (ROS), such as hydrogen peroxide. LOPs and ROS have been purported to increase inflammation, through the 5‐lipooxygenase pathway, and cause vasodilation, through the nitric oxide (NO) pathway 24–26 . At the same time, activation of the bradykinin pathway has been shown to lead to increased levels of vascular permeability factors and activation of NO synthase 27 , 28 .…”

The Biological and Molecular Action of Ozone and Its Derivatives: State-of-the-Art, Enhanced Scenarios, and Quality Insights

“…In any case, extensive phenomena of uncontrolled lipid peroxidation can variously alter the control functions of cell membranes on the flow of energy, metabolites, and signals [98,99]. For instance, ozone-oxidized membrane phospholipids are powerful triggers of inflammation [100]. Interestingly, ozone can potentially oxidize circulating microvesicles, which are important vehicles of biologically active molecules (including nucleotides and nucleic acids) [101] (another potential, often neglected, target of ozone treatment).…”