Unresolved inflammation underlies the development of fibrosis and organ failure. Here, we investigate the potential of the proresolving eicosanoid lipoxinA₄ (LXA₄) and its synthetic analog benzo-LXA₄ to prophylactically modulate fibrotic and inflammatory responses in a model of early renal fibrosis, unilateral ureteric obstruction (UUO). Male Wistar rats (Animalia, Chordata, Rattus norvegicus) were injected intravenously with vehicle (0.1% ethanol), LXA₄ (45 μg/250-g rat), or benzo-LXA₄ (15 μg/250-g rat) 15 min prior to surgery and sacrificed 3 d postligation. Renal gene and protein expression, collagen deposition, macrophage infiltration, and apoptosis were analyzed using manipulated kidneys from sham operations as control. Lipoxins (LXs) attenuated collagen deposition and renal apoptosis (P<0.05) and shifted the inflammatory milieu toward resolution, inhibiting TNF-α and IFN-γ expression, while stimulating proresolving IL-10. LXs attenuated UUO-induced activation of MAP kinases, Akt, and Smads (P<0.05) in injured kidneys. We explored whether the underlying mechanism reflected LX-induced modulation of fibroblast activation. Using cultured rat renal NRK-49F fibroblasts, we report that LXA₄ (1 nM) inhibits TGF-β1 (10 ng/ml)-induced activation of Smad2 and MAP-kinases (P<0.05), and furthermore, LXA₄ reduced TGF-β1-stimulated PAI-1 luciferase activation (P<0.05) relative to vehicle-stimulated cells. We propose that LXs may represent a potentially useful and novel therapeutic strategy for consideration in the context of renal fibrosis.

Telephone 353-1-716-6731 AbstractPersistent inflammation underlies many of the most prevalent diseases in the developed world including atherosclerosis and diabetes. There is a growing appreciation that inflammation and its active resolution may be modulated by endogenously produced lipids [1]. Preeminent amongst these mediators are the lipoxins [LX]. The acronym lipoxins describes the provenance of these mediators: lipoxygenase interacting products . The LX are eicosanoids and display both anti-inflammatory and pro-resolving bioactions [2]. More recently other pro-resolving lipid mediators have been described including the resolvins and neuroprotectins [3]. In effective host defence LX biosynthesis is characterised by a switch from pro-inflammatory prostaglandin and leukotriene (LT) generation from arachidonic acid (AA) to LX production coincident with a return to tissue homeostasis. Here we will provide an overview of LX pharmacokinetics, bioactions and summarise the evidence to date that indicates that LX are potential therapeutic agents for disorders involving cardiovascular and renal inflammation, leading to tissue damage and organ fibrosis. LX: synthesis, metabolism and cellular targets LX are typically formed by transcellular metabolism of arachidonate involving sequential lipoxygenase [LO] activity within an inflammatory milieu. Epithelial-monocyte 15 LO activity produces 15(S)hydroperoxyeicosatetraneoic acid from AA which can then be converted by neutrophil 5-LO to generate LXA 4 [5S,6R,15S-trihydroxyl-7,9,13-trans-11-ciseicosatetraenoic acid] [2]. Production of LXA4 by this pathway diverts metabolism of AA from biosynthesis of proinflammatory leukotrienes . LXA4 can also be generated by the actions of platelet 12-LO to convert the 5-LO epoxide product LTA4 to LXA4 and its positional isoimer LXB4 [2]. Aspirin acetylation of COX-2 in endothelial and epithelial cells inhibits the formation of prostaglandins and thromboxanes whilst shifting its enzymatic activity towards the generation of 15R-HETE which is converted by leukocyte 5LO to generate 15-epi-LX , designated aspirintriggered LX i.e. ATL (See figure 1) [2]. Other potential sources of LX synthesis are linked to storage of precursors in membranes of inflammatory cells that may be released at the site of injury [4]. LXA4 binds with high affinity to at least one G-protein coupled receptor (GPCR) that has been cloned, characterised and designated ALX/FPR2 receptor [5]. This receptor is part of the formyl peptide receptor superfamily. A specific LX recognition site was initially established in human polymorphonuclear neutrophils (PMN), however further experiments have demonstrated that this receptor is expressed in cells of diverse lineages including myeloid, epithelial and mesenchymal cells [6]. In addition to binding LXA4 with high affinity [subnanomolar Kd] the ALX /FPR2 binds several other agonists including lipids and peptides with different affinities resulting in activation of distinct signalling pathways that depend on the cell type and system....

Since the early observation that similarities between thyroiditis and insulitis existed, the important role played by inflammation in the development of diabetes has been appreciated. More recently, experiments have shown that inflammation also plays a prominent role in the development of target organ damage arising as complications, with both elements of the innate and the adaptive immune system being involved, and that cytokines contributing to local tissue damage may arise from both infiltrating and resident cells. This review will discuss the experimental evidence that shows that inflammatory cellmediated apoptosis contributes to target organ damage, from beta cell destruction to both micro-and macro-vascular disease complications, and also how alterations in leukocyte turnover affects immune function.

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Portopulmonary hypertension (PoPH) is a poorly understood complication of liver disease which affects about 10% of patients with pulmonary hypertension. This case report outlines the difficulties in diagnosing and managing a patient with advanced disease, and the impact of these delays on the patient.PoPH has a significant risk of mortality with a 2-year survival rate of 67%. There are also few treatment options available and those which do exist are associated with multiple contraindications and risks. Patients with PoPH commonly present with dyspnoea, pulmonary hypertension and portal hypertension. The presence of coexisting chronic liver disease is also sometimes present. Traditional management for heart failure can temporarily alleviate symptoms but there is no proven long-term benefit. As a result, an understanding of the pathophysiology, diagnostics and management is crucial to ensure the best possible patient outcomes.