Reaping the benefits of renal protective lipid autacoids

The Journal of Immunology

2009

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102

Exacerbated inflammation plays an important role in the pathogenesis of ischemic renal injury (IRI), which is the major cause of intrinsic acute renal failure. Clinical studies suggest that long-term treatment with ω-3 polyunsaturated fatty acids (PUFA) improves renal function and lowers the risk of death or end-stage renal disease. Docosahexaenoic acid, a principle ω-3 PUFA of fish oils, is of particular interest as it is found in most human tissues and is converted to protectin D1 (PD1), which exhibits antiinflammatory and proresolving bioactions. We set out to investigate the impact of acute dietary modulation of ω-3 or ω-6 PUFA on IRI and renal lipid autacoid circuits, using an established mouse model and liquid chromatography-mass spectroscopy/mass spectroscopy-based lipidomics. Thirty minutes of renal ischemia significantly elevated serum creatinine in the ω-6 diet group while renal function remained normal in the matched ω-3 diet group. Notably, extending ischemia to 45 min caused 100% mortality in the ω-6 group, in sharp contrast to 0% mortality in the ω-3 group. Protection against IRI in the ω-3 group correlated with decreased polymorphonuclear leukocyte recruitment, chemokine and cytokine levels, abrogated formation of lipoxygenase- and cyclooxygenase-derived eicosanoids, and increased renal levels of PD1. Systemic treatment with PD1 reduced kidney polymorphonuclear leukocyte influx and, more importantly, amplified renoprotective heme-oxygenase-1 protein and mRNA expression in injured and uninjured kidneys. These findings suggest therapeutic or dietary amplification of PD1 circuits restrains acute renal injury and that short-term changes in dietary ω-3 and ω-6 PUFA dramatically impacts renal lipid autacoid formation and outcome of IRI.

Section: Discussionmentioning

confidence: 99%

Acute Changes in Dietary ω-3 and ω-6 Polyunsaturated Fatty Acids Have a Pronounced Impact on Survival following Ischemic Renal Injury and Formation of Renoprotective Docosahexaenoic Acid-Derived Protectin D1

Hassan

The Journal of Immunology

2009

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102

“…The anti-inflammatory, cardioprotective and immunosuppressive actions of dietary ω-3 PUFA are well established based on long standing research efforts; but the molecular mechanism for this striking actions was only recently uncovered (Bazan, 2006; Gronert & Hassan, 2007; Gronert, 2008; Serhan et al , 2008a; Serhan et al , 2008b). Specifically, EPA and DHA are transformed in a fashion analogous to eicosanoid biosynthesis to novel classes of ω-3 PUFA-derived mediators.…”

Section: Pathways For Inflammatory Resolution In the Eyementioning

confidence: 99%

“…These mediators have been named resolvins and protectins as they are formed during the resolution phase of inflammation and exhibit potent anti-inflammatory, pro-resolving and neuroprotective properties. Reports from several laboratories provide compelling evidence that these protective ω-3 PUFA-derived mediators provide the elusive molecular mechanism for the remarkable beneficial and essential effects of dietary ω-3 PUFA(Lukiw et al , 2005; Gonzalez-Periz et al , 2006; Connor et al , 2007; Gronert & Hassan, 2007; Levy et al , 2007; Schwab et al , 2007; Serhan et al , 2008a; Bazan, 2009; Gonzalez-Periz et al , 2009; Hassan & Gronert, 2009; Kenchgowda & Bazan, 2009). …”

Section: Pathways For Inflammatory Resolution In the Eyementioning

confidence: 99%

“…Significant endogenous formation of these protective DHA-derived mediators (NPD1, RvD1, 17-HDHA) has been reported by several laboratories, including our group, in both human and mouse tissues (Lukiw et al , 2005; Gonzalez-Periz et al , 2006; Levy et al , 2007; Serhan et al , 2008b; Gonzalez-Periz et al , 2009; Hassan & Gronert, 2009), which includes reports in the retina and cornea (Gronert et al , 2005; Bazan, 2006; Connor et al , 2007; Qin et al , 2008). The protective DHA-derived signals have distinct but overlapping bioactions and both in vitro and in vivo experiments have demonstrated that similar to LXA 4 , resolvins and protectins reduce leukocyte infiltration, regulate cytokines/chemokines and reactive oxygen species, and more importantly increase macrophage phagocytosis of apoptotic PMN (Bazan, 2006; Gronert & Hassan, 2007; Schwab et al , 2007; Gronert, 2008; Zhang & Bazan, 2010). Hence, 15-LOX sets in place a resident lipid circuit that counter-regulates inflammatory circuits, contributes to the anti-inflammatory tone of the tissue and during inflammation is amplified by recruited effector cells to promote resolution of PMN.…”

Section: Pathways For Inflammatory Resolution In the Eyementioning

confidence: 99%

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Resolution, the grail for healthy ocular inflammation

Experimental Eye Research

2010

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Acute inflammation is a frequent, essential and beneficial response to maintain normal tissue function. PMN are the primary effector cells of acute inflammatory responses and their timely resolution by macrophages from an injured, stressed or infected tissues are required for the successful execution of this routine tissue response. Dysregulation of this fundamental program is a major factor in the global disease burden and contributes to many ocular diseases. Counter-regulatory signals are critical to the controlled activation of innate and adaptive immune responses in the eye and recent studies have identified two circuits in the cornea, uvea and/or retina, namely 15-lipoxygenase and heme-oxygenase, which control inflammation, promote resolution of PMN and afford neuroprotection. The role of these counter-regulator and pro-resolution circuits may provide insight into ocular inflammatory diseases and opportunities to restore stressed ocular tissue to a preinflammatory state, namely homeostasis, rather than limiting therapeutic options to palliative inhibition of pro-inflammatory circuits.

“…The importance of essential PUFAs is underscored by the well-established roles of ω-3 PUFAs in normal growth and development, and maintaining human health [137,138,139,140,141,142,143,144]. Moreover, epidemiological studies and clinical trials have demonstrated that consumption of fish oils, which are enriched in EPA and DHA, is cardio-and renoprotective, and lowers the incidence of inflammatory and autoimmune diseases [137,138,142,145,146,147,148,149,150,151,152]. In particular, DHA has been shown to exert anti-inflammatory and immunosuppressive effects [150,153].…”

Section: ω-3 Pufa-derived Circuitsmentioning

confidence: 99%

Molecular Circuits of Resolution in the Eye

Liclican

The Scientific World JOURNAL

2010

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Lipid autacoids have well-established key roles in physiology and pathophysiology. Eicosanoids derived from ω-6 arachidonic acid (AA) have long been recognized for their roles in cardiovascular and renal functions, and vascular tone, as well as regulating inflammatory and immune functions. It is now appreciated that AA is a substrate for generating lipid mediators with anti-inflammatory and proresolving properties, namely lipoxins (i.e., LXA4), which are an integral component for the successful execution of beneficial and essential acute inflammatory responses. In addition to AA, the ω-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also serve as substrates to generate potent and protective autacoids, such as resolvins and neuroprotectin (i.e., NPD1), respectively. These ω-3–derived signals may mediate the remarkable protective action of essential dietary ω-3 PUFAs. Formation and bioactivity of lipid mediators in the eye are relatively unexplored and of considerable interest, as the eye contains highly specialized tissues, including the transparent avascular and immune-privileged cornea, and the neuro-retina. A rapidly emerging field has identified key biosynthetic enzymes, receptors, and temporally defined endogenous formation of ω-3– and ω-6–derived protective lipid circuits in the eye. Protective endogenous roles of LXA4 and NPD1 have been established utilizing lipidomic analysis, knockout mice, and pharmacological, genetic, and dietary manipulation, providing compelling evidence that these intrinsic lipid autacoid circuits play essential roles in restraining inflammation, promoting wound healing, inhibiting pathological angiogenesis, and providing neuroprotection in the delicate visual axis.