Mapping the metabolomic and lipidomic changes in the Bleomycin model of pulmonary fibrosis in young and aged mice

Alterations in metabolic pathways were recently recognized as potential underlying drivers of idiopathic pulmonary fibrosis (IPF), translating into novel therapeutic targets. However, knowledge of metabolic and lipid regulation in fibrotic lungs is limited. To comprehensively characterize metabolic perturbations in the Bleomycin mouse model of IPF we analyzed the metabolome and lipidome by mass spectrometry. We identified increased tissue turnover and repair, evident by enhanced breakdown of proteins, nucleic acids, lipids and ECM turnover. Energy production was upregulated, including glycolysis, tricarboxylic acid (TCA) cycle, glutaminolysis, lactate production and increased fatty acid oxidation. Higher eicosanoid synthesis indicated inflammatory processes. Since the risk of IPF increases with age, we investigated how age influences metabolomic and lipidomic changes in the Bleomycin-induced pulmonary fibrosis model. Surprisingly, except cytidine, we did not detect any significantly differential metabolites or lipids between old and young Bleomycin-treated lungs. Together, we identified metabolomic and lipidomic changes in fibrosis that reflect higher energy demand, proliferation, tissue remodeling, collagen deposition and inflammation that might serve for improving diagnostic and therapeutic options for fibrotic lung diseases in the future.

Eicosanoids

This article describes the pathways of eicosanoid synthesis, eicosanoid receptors, the action of eicosanoids in different physiological systems, the roles of eicosanoids in selected diseases, and the major inhibitors of eicosanoid synthesis and action. Eicosanoids are oxidised derivatives of 20-carbon polyunsaturated fatty acids (PUFAs) formed by the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (cytP450) pathways. Arachidonic acid (ARA) is the usual substrate for eicosanoid synthesis. The COX pathways form prostaglandins (PGs) and thromboxanes (TXs), the LOX pathways form leukotrienes (LTs) and lipoxins (LXs), and the cytP450 pathways form various epoxy, hydroxy and dihydroxy derivatives. Eicosanoids are highly bioactive acting on many cell types through cell membrane G-protein coupled receptors, although some eicosanoids are also ligands for nuclear receptors. Because they are rapidly catabolised, eicosanoids mainly act locally to the site of their production. Many eicosanoids have multiple, sometimes pleiotropic, effects on inflammation and immunity. The most widely studied is PGE2. Many eicosanoids have roles in the regulation of the vascular, renal, gastrointestinal and female reproductive systems. Despite their vital role in physiology, eicosanoids are often associated with disease, including inflammatory disease and cancer. Inhibitors have been developed that interfere with the synthesis or action of various eicosanoids and some of these are used in disease treatment, especially for inflammation.

Modern prospects for using polyene unsaturated fatty acids in obstetrics and gynecology

Unsaturated fatty acids is the key block of cellular membranes, they determine the specificity of high-differentiated cells and are the precursors of eicosanoid synthesis (prostaglandins, thromboxanes, leukotrienes). A marked antiinflammatory, antisclerotic, antiarrhythmic, anticoagulant, neuroprotective and other effects of omega-3 polyunsaturated fatty acids, established in biochemical and experimental studies, stimulated implementation of a large number of epidemiological and clinical investigations. Successful application of polyunsaturated fatty acids in cardiology, neurology and other fields of therapy focuses on such spheres as obstetrics and gynecology.

Sickle Cell Inflammatory Environment Is Associated with Products of the Eicosanoid Synthesis Pathways

Background: Sickle cell disease (SCD) is a group of inherited anemia characterized by heterogeneous clinical outcome, including hemolysis, chronic inflammation, and vaso-occlusive/painful crisis. Aims: We evaluated inflammatory and anti-inflammatory mediators, such as TNFα, IL-10, IL-12, IL-1β, IL-6, and IL-8, TGF-beta, tissue inhibitor of metalloproteinase (TIMP1), matrix metalloproteinase 9 (MMP9), heme, and leukotriene B4 (LTB4), and prostaglandin E2 (PGE2), the last two are products of the eicosanoid synthesis pathways, in SCD patients (in steady-state and in crisis-state) and healthy controls. For the same groups, in order to establish biomarkers of crisis and steady-state, we also investigated association among inflammatory/anti-inflammatory mediators and markers of hemolysis, inflammation, hepatic dysfunction, renal and lipid metabolism. Methods. We assessed 129 SCD steady-state patients (SP), 23 SCD in crisis patients (CP), and 67 healthy individuals (HC) age- and sex-matched with patients groups. Hematological analyzes were performed by automatic cell counter and hemoglobin profile by HPLC. Biochemistry analyses of inflammation and infection markers, as well as lipid, hepatic, and kidney metabolism markers were investigated by immunochemistry assays. Plasma levels of TNFα, IL-10, IL-12, IL-1β, IL-6 and IL-8 were measured using Cytometric Bead Array (CBA) according to the manufacturer's protocol. Plasma concentration of total heme was measured by QuantiChrom Heme Assay Kit. PGE2, LTB4, TGF-beta, TIMP1 and MMP9 levels were estimated in plasma samples and supernatants by ELISA, according to the manufacturer's instructions. Results . Steady-state SCD patients had the highest values of LTB4, PGE2, TIMP1, MMP9, IL-8, and IL-12 concentration compared with CP and HC groups (p < 0.0001). However, crisis-state SCD patients had the highest values of IL-1β, IL-6, IL-10, TNFα compared to HC and SP groups, and had a the lowest levels of LTB4, PGE2,TGF-β, MMP9, IL-8 and IL-12 levels (p < 0.0001 for both analysis). Significant difference of heme levels was not finding among the three groups. The ROC curve showed that LTB4, PGE2 and TGF- β are important markers related to steady state and IL-1β, IL-6, and TNFα are markers of crisis in SCD. Conclusions: The finding of difference in inflammatory markers level in steady state and crisis SCD patients suggest that these markers can be used to monitoring patients and to predict crisis events. The finding of similar heme concentration between steady-state and crisis-state SCD patients may be explained by the hyperhemolysis phenomenon, showing that even in steady-state, these patients continuous to have hemolysis and, consequently, continuous to generate heme and reactive oxygen species. Disclosures No relevant conflicts of interest to declare.