ABSTRACT
Platelet-activating factor (PAF) is a potent inflammatory agonist. In Swiss albino mice, intraperitoneal injection of PAF causes sudden death with oxidative stress and disseminated intravascular coagulation (DIC), characterized by prolonged prothrombin time, thrombocytopenia, reduced fibrinogen content, and increased levels of fibrinogen degradation products. However, the underlying mechanism(s) is unknown. The PAF-R antagonist WEB-2086 protected mice against PAF-induced death by reducing DIC and oxidative stress. Accordingly, general antioxidants such as ascorbic acid, α-tocopherol, gallic acid, and N-acetylcysteine partially protected mice from PAF-induced death. N-acetylcysteine, a clinically used antioxidant, prevented death in 67% of mice, ameliorated DIC characteristics and histological alterations in the liver, and reduced oxidative stress. WEB-2086 suppressed H2O2-mediated oxidative stress in isolated mouse peritoneal macrophages, suggesting that PAF signaling may be a downstream effector of reactive oxygen species generation. PAF stimulated all three (ERK, JNK, and p38) of the MAP-kinases, which were also inhibited by N-acetylcysteine. Furthermore, a JNK inhibitor (SP600125) and ERK inhibitor (SCH772984) partially protected mice against PAF-induced death, whereas a p38 MAP-kinase inhibitor (SB203580) provided complete protection against DIC and death. In human platelets, which have the canonical PAF-R and functional MAP-kinases, JNK and p38 inhibitors abolished PAF-induced platelet aggregation, but the ERK inhibitor was ineffective. Our studies identify p38 MAP-kinase as a critical, but unrecognized component in PAF-induced mortality in mice. These findings suggest an alternative therapeutic strategy to address PAF-mediated pathogenicity, which plays a role in a broad range of inflammatory diseases.
Subject(s)
Death, Sudden/prevention & control , Enzyme Inhibitors/pharmacology , Oxidative Stress , Platelet Activating Factor/toxicity , Protective Agents/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Acetylcysteine/pharmacology , Animals , Death, Sudden/etiology , Death, Sudden/pathology , Female , Free Radical Scavengers/pharmacology , Male , Mice , Mice, Inbred C57BL , Reactive Oxygen Species/metabolismABSTRACT
Prevalence of obesity among infants and children below 5 years of age is rising dramatically, and early childhood obesity is a forerunner of obesity and obesity-associated diseases in adulthood. Childhood obesity is hence one of the most serious public health challenges today. Here, we have identified a mother-to-child lipid signaling that protects from obesity. We have found that breast milk-specific lipid species, so-called alkylglycerol-type (AKG-type) ether lipids, which are absent from infant formula and adult-type diets, maintain beige adipose tissue (BeAT) in the infant and impede the transformation of BeAT into lipid-storing white adipose tissue (WAT). Breast milk AKGs are metabolized by adipose tissue macrophages (ATMs) to platelet-activating factor (PAF), which ultimately activates IL-6/STAT3 signaling in adipocytes and triggers BeAT development in the infant. Accordingly, lack of AKG intake in infancy leads to a premature loss of BeAT and increases fat accumulation. AKG signaling is specific for infants and is inactivated in adulthood. However, in obese adipose tissue, ATMs regain their ability to metabolize AKGs, which reduces obesity. In summary, AKGs are specific lipid signals of breast milk that are essential for healthy adipose tissue development.
