Resolvin and lipoxin metabolism network regulated by Hyssopus Cuspidatus Boriss extract in asthmatic mice.

Resolvin (Rv) and lipoxin (Lx) play important regulative roles in the development of several inflammation-related diseases. The dysregulation of their metabolic network is believed to be closely related to the occurrence and development of asthma. The Hyssopus Cuspidatus Boriss extract (SXCF) has long been used as a treatment for asthma, while the mechanism of anti-inflammatory and anti-asthma action targeting Rv and Lx has not been thoroughly investigated. In this study, we aimed to investigate the effects of SXCF on Rv, Lx in ovalbumin (OVA)-sensitized asthmatic mice. The changes of Rv, Lx before and after drug administration were analyzed based on high sensitivity chromatography-multiple response monitoring (UHPLC-MRM) analysis and multivariate statistics. The pathology exploration included behavioral changes of mice, IgE in serum, cytokines in BALF, and lung tissue sections stained with H&E. It was found that SXCF significantly modulated the metabolic disturbance of Rv, Lx due to asthma. Its modulation effect was significantly better than that of dexamethasone and rosmarinic acid which is the first-line clinical medicine and the main component of Hyssopus Cuspidatus Boriss, respectively. SXCF is demonstrated to be a potential anti-asthmatic drug with significant disease-modifying effects on OVA-induced asthma. The modulation of Rv and Lx is a possible underlying mechanism of the SXCF effects.

Resolution-Based Therapies: The Potential of Lipoxins to Treat Human Diseases.

Inflammation is an a physiological response instead an essential response of the organism to injury and its adequate resolution is essential to restore homeostasis. However, defective resolution can be the precursor of severe forms of chronic inflammation and fibrosis. Nowadays, it is known that an excessive inflammatory response underlies the most prevalent human pathologies worldwide. Therefore, great biomedical research efforts have been driven toward discovering new strategies to promote the resolution of inflammation with fewer side-effects and more specificity than the available anti-inflammatory treatments. In this line, the use of endogenous specialized pro-resolving mediators (SPMs) has gained a prominent interest. Among the different SPMs described, lipoxins stand out as one of the most studied and their deficiency has been widely associated with a wide range of pathologies. In this review, we examined the current knowledge on the therapeutic potential of lipoxins to treat diseases characterized by a severe inflammatory background affecting main physiological systems, paying special attention to the signaling pathways involved. Altogether, we provide an updated overview of the evidence suggesting that increasing endogenously generated lipoxins may emerge as a new therapeutic approach to prevent and treat many of the most prevalent diseases underpinned by an increased inflammatory response.

Role of aspirin-triggered lipoxin A4, aspirin, and salicylic acid in the modulation of the oxidative and inflammatory responses induced by plasma from women with pre-eclampsia.

PROBLEM: Oxidative stress and inflammation are key events leading to pre-eclampsia, involved in several maternal deaths. Low doses of acetylsalicylic acid (ASA) are used in the prevention and treatment of pre-eclampsia. The synthesis of aspirin-triggered lipoxin (ATL) by cyclooxygenase-2 acetylation is an alternative mechanism of ASA, which could explain the effectiveness of ASA treatments. The aim of this study was to evaluate the role of ASA, salicylates, and ATL in the modulation of the oxidative and inflammatory responses induced by plasma from women with pre-eclampsia. METHOD OF STUDY: Plasma from 14 women with pre-eclampsia and 17 normotensive pregnant women was probed for inducing oxidative and inflammatory responses on endothelial cells and U937 promonocytes. The role of ATL, ASA, and salicylic acid (SA) on these events was evaluated. RESULTS: Plasma from women with pre-eclampsia induced TBARS and nitrotyrosine production on endothelial and U937 cells. Pre-treatment with both ATL and ASA decreased the TBARS production, while ATL decreased the nitrotyrosine. Pre-eclamptic plasma augmented the translocation of NF-kB on U937 cells, which decreased by a high dose of ASA and SA. Finally, the pre-eclamptic plasma increased the adhesion of leukocytes-PMN and monocytes-to endothelium, and we were able to determine a state of resolution of inflammation, since ATL decreased the PMN adhesion, and conversely, it increased the monocytes adhesion to endothelium. CONCLUSION: Together, these results suggest that ATL could explain the beneficial actions of ASA and support further research on mechanisms, real efficacy, and rational use of ASA in pre-eclampsia.

Pro-resolving mediators promote resolution in a human skin model of UV-killed Escherichia coli-driven acute inflammation.

While the treatment of inflammatory disorders is generally based on inhibiting factors that drive onset of inflammation, these therapies can compromise healing (NSAIDs) or dampen immunity against infections (biologics). In search of new antiinflammatories, efforts have focused on harnessing endogenous pathways that drive resolution of inflammation for therapeutic gain. Identification of specialized pro-resolving mediators (SPMs) (lipoxins, resolvins, protectins, maresins) as effector molecules of resolution has shown promise in this regard. However, their action on inflammatory resolution in humans is unknown. Here, we demonstrate using a model of UV-killed Escherichia coli-triggered skin inflammation that SPMs are biosynthesized at the local site at the start of resolution, coinciding with the expression of receptors that transduce their actions. These include receptors for lipoxin A4 (ALX/FPR2), resolvin E1 (ChemR23), resolvin D2 (GPR18), and resolvin D1 (GPR32) that were differentially expressed on the endothelium and infiltrating leukocytes. Administering SPMs into the inflamed site 4 hours after bacterial injection caused a reduction in PMN numbers over the ensuing 6 hours, the phase of active resolution in this model. These results indicate that in humans, the appearance of SPMs and their receptors is associated with the beginning of inflammatory resolution and that their therapeutic supplementation enhanced the resolution response.

Lipoxin A4 prevents tight junction disruption and delays the colonization of cystic fibrosis bronchial epithelial cells by Pseudomonas aeruginosa.

The specialized proresolution lipid mediator lipoxin A4 (LXA4) is abnormally produced in cystic fibrosis (CF) airways. LXA4 increases the CF airway surface liquid height and stimulates airway epithelial repair and tight junction formation. We report here a protective effect of LXA4 (1 nM) against tight junction disruption caused by Pseudomonas aeruginosa bacterial challenge together with a delaying action against bacterial invasion in CF airway epithelial cells from patients with CF and immortalized cell lines. Bacterial invasion and tight junction integrity were measured by gentamicin exclusion assays and confocal fluorescence microscopy in non-CF (NuLi-1) and CF (CuFi-1) bronchial epithelial cell lines and in primary CF cultures, grown under an air/liquid interface, exposed to either a clinical or laboratory strains of P. aeruginosa LXA4 delayed P. aeruginosa invasion and transepithelial migration in CF and normal bronchial epithelial cell cultures. These protective effects of LXA4 were inhibited by the ALX/FPR2 lipoxin receptor antagonist BOC-2. LXA4 prevented the reduction in mRNA biosynthesis and protein abundance of the tight junction protein ZO-1 and reduced tight junction disruption induced by P. aeruginsosa inoculation. In conclusion, LXA4 plays a protective role in bronchial epithelium by stimulating tight junction repair and by delaying and reducing the invasion of CF bronchial epithelial cells by P. aeruginsosa.

Does the use of specialized proresolving molecules in critical care offer a more focused approach to controlling inflammation than that of fish oils?

PURPOSE OF REVIEW: The literature regarding the use of fish oils in the critically ill to limit the inflammatory and catabolic response have been inconsistent. The objective of this manuscript is to review a newly discovered class of specialized proresolving molecules (SPMs), which could help elucidate the discrepancies reported in the critical care literature regarding the anti-inflammatory benefits of fish oil/ω-3 fatty acids. RECENT FINDINGS: Although use of fish oil has traditionally been thought to reduce or limit the inflammatory process in the critical ill, a new class of endogenously produced highly active lipid mediators derived from arachidonic acid and ω-3 fatty acids (lipoxins, resolvins, protectins, and maresins) have been shown to actively enhance resolution of inflammation. These SPMs stimulate the cardinal signs of resolution of inflammation, which include the cessation of leukocytic infiltration, a countering of the effects of proinflammatory mediators, stimulation of the uptake of apoptotic neutrophils, promotion of the clearance of necrotic cellular debris, and enhancement of the host's ability to eliminate microbial invasion. SUMMARY: By actively turning off inflammation (instead of simply attenuating its natural course), SPMs have shown more consistent effects in decreasing pain and risk of sepsis, increasing epithelialization and wound healing, promoting tissue regeneration, potentiating the effects of antibiotics, and enhancing adaptive immunity.

Role of lipoxins, resolvins, and other bioactive lipids in colon and pancreatic cancer.

Unresolved inflammation, due to insufficient production of proresolving anti-inflammatory lipid mediators, can lead to an increased risk of tumorigenesis and tumor cell invasiveness. Various bioactive lipids, particularly those formed by cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, have been well established as therapeutic targets for many epithelial cancers. Emerging studies suggest that there is a role for anti-inflammatory bioactive lipids and their mediators during the resolution phase of inflammation. These proresolving bioactive lipids, including lipoxins (LXs) and resolvins (RVs), have potent anti-inflammatory and anti-carcinogenic properties. The molecular signaling pathways controlling generation and degradation of the proresolving mediators LXs and RVs are now being elucidated, and the component molecules may serve as new targets for regulation of inflammation and inflammation-associated cancers like colon and pancreatic cancers. This review will highlight the recent advances in our understanding of how these bioactive lipids and proresolving mediators may function with various immune cells and cytokines in inhibiting tumor cell proliferation and progression and invasiveness of colon and pancreatic cancers.

Anti-inflammatory and pro-resolving properties of benzo-lipoxin A(4) analogs.

Lipoxins (LXs) are potent endogenous counter-regulatory lipid mediators that dampen acute inflammation and promote its resolution. Here, we present our investigation of a new class of thermally and metabolically stable benzo-LXA(4) analogs that are potently anti-inflammatory and easier to synthesize. Replacement of the tetraene unit of native LXA(4) with a benzo-fused ring system not only increases the thermal stability but also enables highly convergent and efficient syntheses of these analogs. In addition, they resist rapid catalysis and inactivation by eicosanoid oxidoreductase. Like native LXs, o-[9, 12]-benzo-omega6-epi-LXA(4), o-[9, 12]-benzo-deoxy-LXA(4), m-[9, 12]-benzo-omega6-epi-LXA(4) and [9, 14]-benzo-omega6-(R/S)-LXA(4) demonstrated potent time-dependent reduction, at nanogram dosages, of PMN infiltration and pro-inflammatory cytokine generation in vivo in murine peritonitis and were organ protective in hind limb ischemia-reperfusion injury of the lung. The o-[9, 12]-benzo-omega6-epi-LXA(4) and m-[9, 12]-benzo-omega6-epi-LXA(4) were most potent in nanogram doses; both decreased PMN infiltration by approximately 32%, while o-[9, 12]-benzo-deoxy-LXA(4) and [9, 15]-omega6-(R/S)-LXA(4) were less potent. The [9,12]-benzo-omega6-epi-LXA(4) also activated a lipoxin A(4) GPCR and increased macrophage phagocytic activity. Taken together, these findings demonstrate a new generation of LXA(4) stable analogs that are easy to synthesize and anti-inflammatory. These benzo-LXA(4) analogs are promising tools for new therapeutic approaches as well as assessing endogenous mechanisms in anti-inflammation and resolution.

Resolvins: Current understanding and future potential in the control of inflammation.

Research on the formation of novel enzymatic oxygenation products derived from the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has revealed the endogenous formation of several novel autacoids that have been termed resolvins and protectins. The elucidation of the chemical structures of resolvins and protectins, and the assessment of their endogenous functions, are providing a new understanding of the role of endogenous omega-3 fatty acid-derived lipid mediators in tissue protection, counteraction of inflammation and the activation of inflammation resolution. This review emphasizes the structural aspects of resolvin biosynthesis and metabolic inactivation, which are of central importance for understanding the current and future development of therapeutically relevant, stable analogs that may activate inflammation resolution.

High dose of lipoxin A4 induces apoptosis in rat renal interstitial fibroblasts.

Studies have implicated that lipoxinA4 (LXA4) inhibited nuclear factor-kappaB (NF-kappaB), Akt/PKB and PI 3-kinase activity and proliferation of glomerular mesangial cells. It is speculated that LXA4 might serve as pro-apoptotic factor. Rat renal interstitial fibroblasts (NRK-49F cells) were exposed to LXA4 in 5% FCS for 24 h. LXA4 at 0.1 and 1 microM induced 9.83% and 33.82% apoptosis of the cells, respectively, upregulated the expression of calpain 10 and Smac, the levels of [Ca2+]i and activity of caspase-3, and downregulated the activity of STAT3 and threonine phosphorylated Akt1. Transfection of calpain 10 or Smac antisense oligodeoxynucleotide into the cells inhibited the LXA4-induced apoptosis, activity of caspase-3. Pretreatment of the cells with calcium inhibitor SK&F96365 inhibited the LXA4-induced apoptosis, levels of [Ca2+]i, expression of calpain 10 and Smac. In conclusion, LXA4 at high concentrations induced apoptosis of renal interstitial fibroblasts via [Ca2+]i-dependent upregulation of calpain 10 and Smac expression.

Modification of the transcriptomic response to renal ischemia/reperfusion injury by lipoxin analog.

BACKGROUND: Lipoxins are lipoxygenase-derived eicosanoids with anti-inflammatory and proresolution bioactivities in vitro and in vivo. We have previously demonstrated that the stable synthetic LXA4 analog 15-epi-16-(FPhO)-LXA4-Me is renoprotective in murine renal ischemia/reperfusion injury, as gauged by lower serum creatinine, attenuated leukocyte infiltration, and reduced morphologic tubule injury. METHODS: We employed complementary oligonucleotide microarray and bioinformatic analyses to probe the transcriptomic events that underpin lipoxin renoprotection in this setting. RESULTS: Microarray-based analysis identified three broad categories of genes whose mRNA levels are altered in response to ischemia/reperfusion injury, including known genes previously implicated in the pathogenesis of ischemia/reperfusion injury [e.g., intercellular adhesion molecule-1 (ICAM-1), p21, KIM-1], known genes not previously associated with ischemia/reperfusion injury, and cDNAs representing yet uncharacterized genes. Characterization of expressed sequence tags (ESTs) displayed on microarrays represents a major challenge in studies of global gene expression. A bioinformatic annotation pipeline successfully annotated a large proportion of ESTs modulated during ischemia/reperfusion injury. The differential expression of a representative group of these ischemia/reperfusion injury-modulated genes was confirmed by real-time polymerase chain reaction. Prominent among the up-regulated genes were claudin-1, -3, and -7, and ADAM8. Interestingly, the former response was claudin-specific and was not observed with other claudins expressed by the kidney (e.g., claudin-8 and -6) or indeed with other components of the renal tight junctions (e.g., occludin and junctional adhesion molecule). Noteworthy among the down-regulated genes was a cluster of transport proteins (e.g., aquaporin-1) and the zinc metalloendopeptidase meprin-1 beta implicated in renal remodeling. CONCLUSION: Treatment with the lipoxin analog 15-epi-16-(FPhO)-LXA4-Me prior to injury modified the expression of many differentially expressed pathogenic mediators, including cytokines, growth factors, adhesion molecules, and proteases, suggesting a renoprotective action at the core of the pathophysiology of acute renal failure (ARF). Importantly, this lipoxin-modulated transcriptomic response included many genes expressed by renal parenchymal cells and was not merely a reflection of a reduced renal mRNA load resulting from attenuated leukocyte recruitment. The data presented herein suggest a framework for understanding drivers of kidney injury in ischemia/reperfusion and the molecular basis for renoprotection by lipoxins in this setting.