Liver: The formation and actions of aspirin-triggered lipoxins

doi:10.1016/j.plefa.2005.05.017

Prostaglandins, Leukotrienes and Essential Fatty Acids

Volume 73, Issues 3–4, September–October 2005, Pages 277-282

https://doi.org/10.1016/j.plefa.2005.05.017 Get rights and content

Abstract

Eicosanoids play a key role in the initiation, progression and resolution of the inflammatory response. Although most current anti-inflammatory strategies are focused on the pharmacological inhibition of pro-inflammatory eicosanoids, such as prostaglandins and leukotrienes, mounting evidence indicates the existence of potent endogenous eicosanoids able to control inflammation and orchestrate its resolution. The first eicosanoids recognized as anti-inflammatory compounds generated by our own organism were the lipoxins (LXs). More recently, a new series of carbon-15 epimers of LXs, with anti-inflammatory properties similar to those of native LXs, was identified during aspirin treatment. Since their formation is specific to this venerable non-steroidal anti-inflammatory drug, the term aspirin-triggered LXs (ATLs) was coined for these compounds. This chapter deals with the biosynthesis of LXs and ATLs in the liver, the largest solid organ/gland in the body, and discusses the most relevant actions of these lipid mediators in the context of liver inflammation and injury.

Section snippets

The hepatic sinusoid

The liver contains a complex architecture composed of several cell types. To ensure full hepatic functionality, hepatocytes, which represent about 70% of liver cell population, are arranged within the hepatic lobule in a peculiar fenestrated capillary network known as the hepatic sinusoid [1]. The morphological features of the hepatic sinusoid provide a unique environment where each single hepatocyte is in close contact with other hepatocytes as well as with sinusoidal cells. Liver sinusoidal

Biosynthesis of lipoxins and aspirin-triggered lipoxins in the hepatic sinusoid

Lipoxins (LXs) are conjugated trihydroxytetraene-containing eicosanoids generated through cell–cell interactions by a process known as transcellular biosynthesis [6]. Transcellular metabolism is a common finding in eicosanoid formation and involves the processing of a metabolic intermediate generated by one cell (donor cell) by a vicinal cell (acceptor cell) for the production of an active eicosanoid which neither cell can generate alone [7], [8]. In mammals, a major route of transcellular LX

Hepatic actions of LXs and ATL

Unlike other 5-LO products (i.e. LTs), which are pro-inflammatory and facilitate neutrophil adhesion to the vascular wall and recruitment at the site of inflammation and leukocyte respiratory burst and degranulation [27], LXs and ATL display inhibitory activities in leukocytes promoting resolution [6]. In human neutrophils, LXs and ATL and their stable analogs act as “stop-signals” for inflammation and inhibit chemotaxis, selectin- and integrin-mediated adhesion to and transmigration across

Future directions

Considering the anti-inflammatory properties of LXs and ATL and the availability of potent and stable analogs, further studies are warranted to test the therapeutic potential of these compounds in experimental models of liver disease. In addition, it is interesting to characterize the hepatic formation and actions of other recently identified endogenous anti-inflammatory systems, such as those originated from the ω-3 polyunsaturated fatty acids EPA and DHA, termed resolvins [44]. Since

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Cited by (13)

Resolvin D3 and aspirin-triggered resolvin D3 are potent immunoresolvents
2013, Chemistry and Biology
Citation Excerpt :
However, the anti-inflammatory actions of low-dose aspirin (75–81 mg doses) and its anti-inflammatory capacity with antineutrophil activities were not appreciated until the aspirin-triggered pathways for novel anti-inflammatory mediators were uncovered (Chiang and Serhan, 2004; Morris et al., 2009). It is now apparent from evidence obtained by many investigators (for example, Clària and Planagumà, 2005 and references within Maderna and Godson, 2005 and Wu et al., 2012) that aspirin can jump-start resolution by not only blocking thromboxane and certain prostaglandins, but also by triggering aspirin-triggered lipid mediators, such as the aspirin-triggered lipoxins and the aspirin-triggered resolvins (Serhan et al., 2002). Along these lines, aspirin-triggered lipoxin A4 (LXA4) is produced on dermal challenge (Morris et al., 2009), and a stable aspirin-triggered LXA4 analog 15R/S-methyl-LXA4 was found effective in treating infantile eczema in a double-blind two-center clinical trial (Wu et al., 2012).
Resolvins are a family of n-3 lipid mediators initially identified in resolving inflammatory exudates that temper inflammatory responses to promote catabasis. Here, temporal metabololipidomics with self-limited resolving exudates revealed that resolvin (Rv) D3 has a distinct time frame from other lipid mediators, appearing late in the resolution phase. Using synthetic materials prepared by stereocontrolled total organic synthesis and metabololipidomics, we established complete stereochemistry of RvD3 and its aspirin-triggered 17R-epimer (AT-RvD3). Both synthetic resolvins potently regulated neutrophils and mediators, reducing murine peritonitis and dermal inflammation. RvD3 and AT-RvD3 displayed leukocyte-directed actions, e.g., blocking human neutrophil transmigration and enhancing macrophage phagocytosis and efferocytosis. These results position RvD3 uniquely within the inflammation-resolution time frame to vantage and contribute to the beneficial actions of aspirin and essential n-3 fatty acids.
Study on alanine aminotransferase kinetics by microchip electrophoresis
2012, Analytical Biochemistry
Alanine aminotransferase (ALT), which catalyzes the reversible conversion between l-glutamic acid (l-Glu) and l-alanine (l-Ala), is one of the most active aminotransferases in the clinical diagnosis of liver diseases. This work displays a microanalytical method for evaluating ALT enzyme kinetics using a microchip electrophoresis laser-induced fluorescence system. Four groups of amino acid (AA) mixtures, including the substrates of ALT (l-Glu and l-Ala), were effectively separated. Under the optimized conditions, the quantitative analysis of l-Glu and l-Ala was conducted and limits of detection (signal/noise = 3) for l-Glu and l-Ala were 4.0 × 10⁻⁷ and 2.0 × 10⁻⁷ M, respectively. In the reaction catalyzed by ALT, enzyme kinetic constants were determined for both the forward and reverse reactions by monitoring the concentration decrease of substrate AAs (l-Ala and l-Glu), and the K_m and V_max values were 10.12 mM and 0.48 mM/min for forward reaction and 3.22 mM and 0.22 mM/min for reverse reaction, respectively. Furthermore, the applicability of this assay was assessed by analysis of real serum samples. The results demonstrated that the proposed method could be used for kinetic study of ALT and shows great potential in the real application.
Aspirin augments 15-epi-lipoxin A<inf>4</inf> production by lipopolysaccharide, but blocks the pioglitazone and atorvastatin induction of 15-epi-lipoxin A<inf>4</inf> in the rat heart
2007, Prostaglandins and Other Lipid Mediators
Aspirin (ASA) inhibits cycloxygenase-1 and modifies cycloxygenase-2 (COX2) by acetylation at Ser⁵³⁰, leading to a shift from production of PGH₂, the precursor of prostaglandin, to 15-R-HETE which is converted by 5-lipoxygenase to 15-epi-lipoxin A₄ (15-epi-LXA4), a potent anti-inflammatory mediator. Both atorvastatin (ATV) and pioglitazone (PIO) increase COX2 expression. ATV activates COX2 by S-nitrosylation at Cys⁵²⁶ to produce 15-epi-LXA4 and 6-keto-PGF_1α (the stable metabolite of PGI₂). We assessed the effect of ASA on the myocardial production of 15-epi-LXA4 and PGI₂ after induction by lipopolysaccharide (LPS) or PIO + ATV. Sprague–Dawley rats were pretreated with: control; ASA 10 mg/kg; ASA 50 mg/kg; LPS alone; LPS + ASA 10 mg/kg; LPS + ASA 50 mg/kg; LPS + ASA 200 mg/kg; PIO (10 mg/kg/d) + ATV (10 mg/kg/d); PIO + ATV + ASA 10 mg/kg; PIO + ATV + ASA 50 mg/kg; PIO + ATV + ASA 50 mg/kg + 1400 W, a specific iNOS inhibitor; or PIO + ATV + 1400 W. ASA alone had no effect on myocardial 15-epi-LXA4. LPS increased 15-epi-LXA4 and 6-keto-PGF_1α levels. ASA (50 mg/kg and 200 mg/kg, but not 10 mg/kg) augmented the LPS effect on 15-epi-LXA4 but attenuated the effect on 6-keto-PGF_1α. PIO + ATV increased 15-epi-LXA4 and 6-keto-PGF_1α levels. ASA and 1400 W attenuated the effects of PIO + ATV on 15-epi-LXA4 and 6-keto-PGF_1α. However, when both ASA and 1400 W were administered with PIO + ATV, there was a marked increase in 15-epi-LXA4, whereas the production of 6-keto-PGF_1α was attenuated. In conclusion, COX2 acetylation by ASA shifts enzyme from producing 6-keto-PGF_1α to 15-epi-LXA4. In contrast, S-nitrosylation by PIO + ASA augments the production of both 15-epi-LXA4 and 6-keto-PGF_1α. However, when COX2 is both acetylated and S-nitrosylated, it is inactivated. We suggest potential adverse interactions among statins, thiazolidinediones, and high-dose ASA.
Resolving inflammation in heart failure: Novel protective lipid mediators
2016, Current Drug Targets
The neuroimmune guidance cue netrin-1 controls resolution programs and promotes liver regeneration
2016, Hepatology
Association between aspirin use and the prevalence of nonalcoholic fatty liver disease: A cross-sectional study from the Third National Health and Nutrition Examination Survey
2014, Alimentary Pharmacology and Therapeutics

View all citing articles on Scopus

^☆: The authors’ laboratory is supported by grants from the Ministerio de Ciencia y Tecnología (SAF 03/0586) and Instituto de Salud Carlos III (C03/02).

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Liver: The formation and actions of aspirin-triggered lipoxins☆

Abstract

Section snippets

The hepatic sinusoid

Biosynthesis of lipoxins and aspirin-triggered lipoxins in the hepatic sinusoid

Hepatic actions of LXs and ATL

Future directions

Prostaglandins Other Lipid Mediat.

Biochem. Pharmacol.

Gastroenterology

Arch. Biochem. Biophys.

Toxicology

Biochem. Biophys. Res. Commun.

Biochim. Biophys. Acta.

Kidney Int.

Exp. Mol. Pathol.

Prostaglandins Other Lipid Mediat.

Structure and function of sinusoidal lining cells in the liver

Toxicol. Pathol.

Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review

Comp. Hepatol.

Biologically active products of stimulated liver macrophages (Kupffer cells)

Eur. J. Biochem.

Inhibition of 5-lipoxygenase induces cell growth arrest and apoptosis in rat Kupffer cells: implications for liver fibrosis

FASEB J.

Aspirin (ASA) regulates 5-lipoxygenase activity and peroxisome proliferator-activated receptor alpha-mediated CINC-1 release in rat liver cells: novel actions of lipoxin A4 (LXA4) and ASA-triggered 15-epi-LXA4

FASEB J.

Transcellular metabolism of eicosanoids

Prog. Hemost. Thromb.

Pharmacology of eicosanoids

Lipoxins: novel series of biologically active compounds formed from arachidonic acid in human leukocytes

Proc. Natl. Acad. Sci. USA

Aspirin triggers previously unrecognized bioactive eicosanoids by human endothelial cell–leukocyte interaction

Proc. Natl. Acad. Sci. USA

Aspirin-triggered lipoxins (15-epi-LX) are generated by the human lung adenocarcinoma cell line (A549)–neutrophil interactions and are potent inhibitors of cell proliferation

Mol. Med.

Aspirin: new cardiovascular uses for an old drug

Am. J. Med.

Aspirin (ASA) regulates 5-lipoxygenase activity and peroxisome proliferator-activated receptor alpha-mediated CINC-1 release in rat liver cells: novel actions of lipoxin A₄ (LXA₄) and ASA-triggered 15-epi-LXA₄