As of 2004, >73 million people were prescribed antiinflammatory medication. Despite the extensive number of current products, many people still suffer from their diseases or the pharmacological properties (side effects) of the medications. Therefore, developing therapeutic strategies to treat inflammation remains an important endeavor. Here, we demonstrate that the soluble epoxide hydrolase (sEH) is a key pharmacologic target for treating acute systemic inflammation. Lipopolysaccharide-induced mortality, systemic hypotension, and histologically evaluated tissue injury were substantially diminished by administration of urea-based, small-molecule inhibitors of sEH to C57BL͞6 mice. Moreover, sEH inhibitors decreased plasma levels of proinflammatory cytokines and nitric oxide metabolites while promoting the formation of lipoxins, thus supporting inflammatory resolution. These data suggest that sEH inhibitors have therapeutic efficacy in the treatment and management of acute inflammatory diseases.cyclooxygenase ͉ lipoxin A4 ͉ lipoxygenase ͉ proinflammatory mediators ͉ epoxygenase T he oxidative metabolism of polyunsaturated fatty acids produces potent inflammatory mediators (1). The bulk of research has focused on the arachidonic acid derivatives processed by cyclooxygenase (COX) (prostaglandins) and lipoxygenases (LOX) (leukotrienes), as well as cytokines and oxygen͞ nitrogen radicals. To this end, many pharmaceuticals have been produced to alleviate inflammatory conditions in rheumatoid arthritis, psoriasis, osteoarthritis, and asthma. These drugs include nonsteroidal antiinflammatory drugs (acetylsalicylic acid), specific COX-2 inhibitors (Rofecoxib), and 5-LOX inhibitors (Zileuton).One critical pathway, still relatively unexplored, is mediated by cytochrome P450 enzymes, transforming arachidonic and linoleic acids to various biologically active compounds, including epoxyeicosatrienoic acids (EETs) or hydroxyeicosatrienoic acids (HETEs) (2, 3) and epoxyoctadecenoic acids (EpOMEs), respectively. EETs are endothelium-derived hyperpolarizing factor candidates that mediate vascular relaxation responses (4) and possess antiinflammatory properties (5-8). EETs and EpOMEs are further metabolized by soluble epoxide hydrolase (sEH) to their corresponding diols, dihydroxyeicosatrienoic acids (DHETs; also known as DiHETs) and dihydroxyoctadecenoic acids (DiHOMEs) (Fig. 5, which is published as supporting information on the PNAS web site) (9).Based on the antiinflammatory action of EETs, we surmised that increasing cellular EETs by inhibition of sEH would decrease the inflammatory effects of acute endotoxin [i.e., lipopolysaccharide (LPS)] exposure. Endotoxin exposure is a common model of septicemia, a disease with mortality rates of 40-70% (1). LPS is the primary Gram-negative bacteria surface antigen responsible for eliciting immunologic responses. These responses include leukocyte activation, cytokine production, enhanced proinflammatory gene expression, increased reactive oxygen͞nitrogen species production, and enhanced bi...

Combination therapies have long been used to treat inflammation while reducing side effects. The present study was designed to evaluate the therapeutic potential of combination treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) and previously undescribed soluble epoxide hydrolase inhibitors (sEHIs) in lipopolysaccharide (LPS)-challenged mice. NSAIDs inhibit cyclooxygenase (COX) enzymes and thereby decrease production of metabolites that lead to pain and inflammation. The sEHIs, such as 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE), stabilize anti-inflammatory epoxy-eicosatrienoic acids, which indirectly reduce the expression of COX-2 protein. Here we demonstrate that the combination therapy of NSAIDs and sEHIs produces significantly beneficial effects that are additive for alleviating pain and enhanced effects in reducing COX-2 protein expression and shifting oxylipin metabolomic profiles. When administered alone, AUDA-BE decreased protein expression of COX-2 to 73 ؎ 6% of control mice treated with LPS only without altering COX-1 expression and decreased PGE 2 levels to 52 ؎ 8% compared with LPS-treated mice not receiving any therapeutic intervention. When AUDA-BE was used in combination with low doses of indomethacin, celecoxib, or rofecoxib, PGE 2 concentrations dropped to 51 ؎ 7, 84 ؎ 9, and 91 ؎ 8%, respectively, versus LPS control, without disrupting prostacyclin and thromboxane levels. These data suggest that these drug combinations (NSAIDs and sEHIs) produce a valuable beneficial analgesic and anti-inflammatory effect while prospectively decreasing side effects such as cardiovascular toxicity.arachidonic acid ͉ cyclooxygenase ͉ epoxygenase ͉ pain ͉ linoleic acid

The glycocalyx of the endothelium is an intravascular compartment that creates a barrier between circulating blood and the vessel wall. The glycocalyx is suggested to play an important role in numerous physiological processes including the regulation of vascular permeability, the prevention of the margination of blood cells to the vessel wall, and the transmission of shear stress. Various theoretical models and experimental approaches provide data about changes to the structure and functions of the glycocalyx under various types of inflammatory conditions. These alterations are suggested to promote inflammatory processes in vessels and contribute to the pathogenesis of number of diseases. In this review we summarize current knowledge about the modulation of the glycocalyx under inflammatory conditions and the consequences for the course of inflammation in vessels. The structure and functions of endothelial glycocalyx are briefly discussed in the context of methodological approaches regarding the determination of endothelial glycocalyx and the uncertainty and challenges involved in glycocalyx structure determination. In addition, the modulation of glycocalyx structure under inflammatory conditions and the possible consequences for pathogenesis of selected diseases and medical conditions (in particular, diabetes, atherosclerosis, ischemia/reperfusion, and sepsis) are summarized. Finally, therapeutic strategies to ameliorate glycocalyx dysfunction suggested by various authors are discussed.