Lipid Mediators Are Critical in Resolving Inflammation: A Review of the Emerging Roles of Eicosanoids in Diabetes Mellitus

Tessaro, Fernando H. G.; Ayala, Thais S.; Martins, Joilson O.

doi:https://doi.org/10.1155/2015/568408

BioMed Research International

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The Role of Lipids Mediators in Inflammation and Resolution

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Volume 2015 | Article ID 568408 | https://doi.org/10.1155/2015/568408

Lipid Mediators Are Critical in Resolving Inflammation: A Review of the Emerging Roles of Eicosanoids in Diabetes Mellitus

Fernando H. G. Tessaro,¹Thais S. Ayala,¹and Joilson O. Martins¹

Academic Editor: Carlos Artério Sorgi

Received13 Jul 2014

Revised27 Oct 2014

Accepted27 Oct 2014

Published19 Mar 2015

Abstract

The biosynthesis pathway of eicosanoids derived from arachidonic acid, such as prostaglandins and leukotrienes, relates to the pathophysiology of diabetes mellitus (DM). A better understanding of how lipid mediators modulate the inflammatory process may help recognize key factors underlying the progression of diabetes complications. Our review presents recent knowledge about eicosanoid synthesis and signaling in DM-related complications, and discusses eicosanoid-related target therapeutics.

1. Introduction

Eicosanoids are biologically active lipid mediators that regulate inflammation [1] and that include prostaglandins (PGs), prostacyclins, thromboxanes (TX), leukotrienes (LT), and lipoxins (LX) (Figure 1) [2–4]. They may amplify or reduce inflammation, which coordinates cytokine production, antibody formation, cell proliferation and migration, and antigen presentation [2, 5, 6]. To prevent great tissue damage, eicosanoids also control the inflammatory resolution and tissue repair process [7, 8]. Imbalances in eicosanoid synthesis have been reported to drive chronic inflammation [1, 9], which deregulates signaling pathways and/or cellular events leading to abnormal immune functions [6, 10]. In particular, circulating and local mediators, such as eicosanoids, interleukin- (IL-) 1β, tumor necrosis factor- (TNF-) α, IL-6, IL-8, macrophage migration inhibitory factor (MIF), and free radicals, create a state of low-chronic inflammation in diabetic patients [5, 10, 11]. Inflammation may lead to diabetes progression, including damage to the kidneys (diabetic nephropathy), eyes (diabetic retinopathy), nerves (diabetic neuropathy), and cardiovascular system [12] (Figure 2).

Figure 1

Eicosanoid synthesis pathways. After cell stimulation, arachidonic acid (AA) can be metabolized by three enzymes: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP 450). COX catalyzes AA in (prostaglandin) PGG₂ and PGH₂, and these are converted into PGD₂, PGE₂, PGF_2α, PG₁₂, , and . The LOX pathway catalyzes AA into hydroxyeicosatetraenoic acids (HETEs) and diverse hydroperoxyeicosatetraenoic acids (HPETEs). This pathway involves four enzymes: 5-LOX, 8-LOX, 12-LOX, and 15-LOX. 5-LOX interacts with a 5-LOX-activating protein (FLAP), enhancing the interaction of 5-LOX to AA. LTA₄ hydrolases convert LTA₄ into LTB₄, and LTC₄ synthase can convert LTA₄ to LTC₄, whereupon it is then metabolized to LTD₄ and LTE₄. 5-LOX synthetizes LXA₄ and LXB₄ using 15-HETE. The pathway of CYP-450 leads to the conversion of HETEs, including 16-, 17-, 18-, 19-, and 20-HETE and epoxyeicosatrienoic acids (EETs): 5,6-, 8,9-, 11,12-, and 14,15-EET.

Figure 2

Eicosanoid compounds affect different organs in diabetes complications. Diabetic nephropathy, one of the most common complications in diabetes, shows low PGE₂ levels and altered glomerular hemodynamics. This dilates arteries and increases microvascular permeability. In normal conditions PGE₂ downregulates TNF-α production and upregulates IL-10 production through EP2 and EP4 receptor signaling. However, a proinflammatory environment leads to cell permeabilization, low concentrations of PGE₂, and mesangial cell proliferation. Diabetic retinopathy is another common complication in diabetes. In diabetes, the environment in the retina has a particular lipid profile, with higher COX-2 and abnormal production of PG. LTA₄ and LTB₄ are enhanced in addition to IL-8. Diabetic peripheral neuropathy is correlated with high COX-2 and PGE₂. In a diabetic’s cardiovascular system, PGE₂ has an important role in microvascular permeability, and 12-HETE and 20-HETE lower the activity of endothelial progenitor cell (EPC) function.

In this review, we summarize the role of eicosanoids on the pathogenesis and progression of diabetes. In addition, we review drugs used to treat diabetic complications by acting on compounds of the eicosanoid pathway and speculate on possible future targets to treat diabetes complications.

2. The Role of Eicosanoids in Diabetes

The level of inflammation severity in diabetes is associated with hemoglobin A1 levels [13]. Increased PGE₂ levels are related to dysfunction in insulin-regulated glycogen synthesis and gluconeogenesis in the liver [14, 15]. 12- as well as 15-hydroxyeicosatetraenoic acid (HETE) increases inflammatory cytokine expression, such as IL-6, TNF-α, and MCP-1, inducing chronic inflammation and the infiltration of inflammatory cells in adipose tissue [16–18]. In addition, 12-lipoxygenase (LOX) metabolites impair insulin action in adipocytes and can downregulate glucose transport, both of which may lead to insulin resistance [18, 19]. Nimesulide and metformin improved acute inflammation and impaired glucose metabolism [20], suggesting that impairing functions of prostaglandin synthesis are mediated by altered glucose levels [21].

2.1. Diabetic Nephropathy

Diabetic nephropathy is the major cause of diabetes-related death [22]. Renal disorders associated with diabetic nephropathy consist of modifications in renal hemodynamics, glomerular hypertrophy, mesangial cell proliferation, matrix accumulation, and proteinuria [23]. In normal conditions, PGE₂ is the major PG in the kidneys and acts in renal physiology, glomerular filtration, and renin release [24, 25]. PGE₂ activates kidney EP receptors, such as EP1, EP2, EP3, and EP4 in the collecting duct (except for EP2 whose mRNA has been localized to the outer and inner medulla of the kidney and EP4 which can also be expressed in the glomerulus) [25, 26]. Interactions between resident renal cells and macrophages change the microenvironment to a proinflammatory state, contributing to tissue damage and scarring [27, 28]. Macrophages and T cells infiltrate the glomeruli and interstitium, contributing to chronic renal failure in diabetic patients [27, 29–31].

During inflammation, macrophages release IL-1B and TNF-α, inducing endothelial cell permeability, altering glomerular hemodynamics, and decreasing PGE₂ production by mesangial cells [32]. Normal levels of PGE₂ suppress Th1 immune responses [33] and downregulate TNF-α production and upregulate IL-10 production through EP2 and EP4 receptor signaling, ending nonspecific inflammation [33–35]. Through an IL-10-dependent mechanism, PGE₂ regulates IL-12 secretion by selectively inhibiting IL-12p70 production and stimulating IL-12p40 release [36, 37]. However, PGE₂ is reduced in diabetic nephropathy, and this plays an essential role in the evolution of diabetic renal injury, strengthening the conclusion that inflammatory mechanisms have a significant role in both diabetic nephropathy development and progression [38–40]. Knockout podocyte-specific mice are protected against diabetes-induced nephropathy and albuminuria, showing the importance of COX-2 metabolites in the establishment of diabetic nephropathy [41].

2.2. Diabetic Retinopathy

Estimates done between 2005 and 2008 suggest that 28.5% of diabetics over the age of 40 in the United States had diabetic retinopathy and vision-threatening problems [42]. Low-grade chronic inflammation has been implicated in the pathogenesis of diabetic retinopathy [43]. The retina of diabetic individuals has a particular lipid profile [44]. COX-2 increases in the retina of diabetic animals, which contributes to abnormal production of PG [45].

5-LO-derived 5-HETE is the major proinflammatory eicosanoid, being five times higher in the vitreous of diabetics versus nondiabetics patients [46]. Mice null for the 5-LO gene demonstrated a minor inflammatory reaction [47–49]. Mice deficient in 5-LO had significantly less degeneration of retinal capillaries induced by diabetes, less superoxide generation, and less nuclear factor (NF)-kB expression [50]. Therefore, the generation of LTs could contribute to chronic inflammation and retinopathy in diabetes [51].

In addition, a hyperglycemic environment causes the release of 5-LO metabolites, LTA₄ and LTB₄. Retinas from both nondiabetic and diabetic mice are unable to produce LT or 5-LO mRNA. However, it was demonstrated that transcellular delivery of LTA₄, from bone marrow-derived cells to retinal cells, results in the generation of LTB₄/LTC₄ [52]. LTC₄ induces vascular permeability after binding with the retinal microvascular endothelial cells, and LTB₄ coordinates proinflammatory pathways and superoxide generation, which may contribute to endothelial cell death and capillary degeneration, in turn contributing to chronic inflammation and diabetic retinopathy development [53].

2.3. Diabetic Peripheral Neuropathy

Estimates suggest 50% of diabetic patients have diabetic peripheral neuropathy, which affects the sensorimotor and autonomic parts of the peripheral nervous system [54–56]. Few studies describe the involvement of the eicosanoid pathway in DPN. In streptozotocin-induced rats, the intrathecal administration of COX-2 inhibitors, but not of COX-1 or COX-3 inhibitors, had an antihyperalgesic effect, supporting the importance of spinal COX-2 in DPN [57]. Pain may be attributed to the action of PGE₂ on peripheral sensory neurons and on central sites within the spinal cord and the brain [58].

2.4. Diabetic Cardiovascular System

Impaired endothelial function is described in diabetes [59–61]. COX-2 expression and dilator prostaglandin synthesis increase in the coronary arterioles of diabetic patients [62]. Venous smooth muscle cells express more COX-2 and release more PGE₂ when stimulated by a mix of inflammatory cytokines [63]. PGE₂ causes pyrexia, hyperalgesia, and arterial dilation [58, 64]. PGE₂ may act as a mediator of active inflammation, promoting first local vasodilatation, then the recruitment and activation of neutrophils, macrophages, and mast cells [65–68]. Deregulation of PGE₂ synthesis leads to a wide range of pathological conditions [69]. In a normal cardiovascular system, PG₁₂ acts as a potent vasodilator and TXA₂ as a vasoconstrictor [70, 71]. The presence of both PGI₂ and TXA₂ maintains the normal physiology of the circulatory system [72]. In addition, the myocardium of diabetic and healthy rats does not differ in PG₁₂ and PGE₂ [73].

CYP-450-derived eicosanoids 12-HETE and 20-HETE, along with other inflammatory components in diabetic patients, lower the activity of endothelial progenitor cell function. Diabetic vascular complications are associated with reduced vascular regenerative potential and nonfunctional endothelial progenitor cell [79].

In sum, imbalanced levels of eicosanoids can induce modification of the microenvironment in the kidneys, eyes, nerves, and cardiovascular system and contribute to the progression of diabetes pathogenesis. Eicosanoid compounds have been studied as targets for drug development to control diabetes progression (Table 1). Thus, we reviewed drugs based on lipid mediators that are involved in diabetes complications.

3. Lipid Mediators in Modulation of Diabetes Complications

When celecoxib, a COX-2 inhibitor, was administered as therapy for diabetic nephropathy in a type 1 diabetes (T1DM) population, COX-2-dependent factors neutralized the angiotensin II effect in the renal microcirculation; further, this effect was greater in women with uncomplicated T1DM than in men [74]. These gender differences could be explained by higher plasma prostanoid found in female animals, an effect that may be estrogen mediated [80–83].

Lower modified levels of PGE₂ relate to changes in the kidney microenvironment and the progression of diabetic nephropathy; thus, PGE₂ and its action are also important targets for drug development [84]. The PGE₂-EP4 pathway contributes to the progression of tubule interstitial fibrosis, and the chronic administration of EP4-agonist in mice, exacerbated inflammation via IL-6, and consequently albuminuria and fibrosis [85]. Additionally, EP4-agonist mediates hyperfiltration in the glomerulus in the early stages of diabetes [86, 87]. Diabetes inflammatory state and chemokine production also increased when mice (T1DM model) were treated with an EP4 agonist [85] and upregulated the development of immune responses Th1 and Th17 [88]. On the other hand, EP receptor antagonists inhibited Th1 and Th17 response [89, 90]. In summary, the activation of the EP4 receptor exacerbates albuminuria levels, inflammation, and fibrosis. COX-2 inhibition reduces albuminuria in renal disease in rats [91]. Recently, using PGE₁ in diabetic nephropathy patients in different disease stages decreased proteinuria and albuminuria [92].

Treating diabetic rats with 50 mg/Kg of aspirin plus 2 mg/Kg of meloxicam (a COX-2 inhibitor) reduced leukocyte adhesion and suppression of the blood-retinal barrier breakdown. This combined dose also reduced retinal ICAM-1 expression, and aspirin alone reduced the expression of C11a, CD11b, and CD18. Together, aspirin and meloxicam reduced the level of TNF-α [93]. Among diabetic patients, 330 mg of aspirin significantly slowed the development of retinal microaneurysms in diabetic retinopathy [75]. Another controlled trial showed that celecoxib reduced vascular leakage in diabetic patients with diabetic retinopathy [76].

Topical administration of nonsteroidal anti-inflammatory drugs (NSAIDs) compared to nontopical administration minimizes systemic exposure to the drug, such that topical NSAIDs can help enhance intraocular penetration. Diabetic patients exhibited elevated plasma IL-8 and elevated vitreous PGE₂ and IL-8 [78, 94]. Exposure to PGE₂ induces IL-8 gene transcription in human T cells [95]. The binding of IL-1β, TNF-α, and IFN-γ also stimulates human retinal pigment epithelial cells to express IL-8 [96]. One study provides direct clinical evidence that topical ocular ketorolac tromethamine (0.45% NSAID) reduces vitreous IL-8 in patients with proliferative diabetic retinopathy [97].

One study found that latanoprost (a PGF_2α agonist) used topically significantly reduced dilation of retinal arterioles in type I diabetes patients with diabetic retinopathy, whereas topical diclofenac had no significant effect [77]. In diabetic rats, celecoxib lowered the synthesis of PGE₂ in the retina (a result attributed to selective COX-2 inhibition, since COX-1 inhibitor did not have this effect) [98]. In addition, another COX inhibitor, nepafenac, inhibits increased retinal PG production and leukocyte adhesion in the retinal vessels of diabetes-induced rats [51].

In peripheral arterial diseases, the goal of treatment is to improve symptoms and prevent cardiovascular events [99]. Beraprost sodium is an analogue active PG₁₂ with antiplatelet and vasodilating properties [100, 101]. Oral administration of beraprost sodium to diabetic patients improved sensations described as burning/hot, electric, sharp, achy, and tingling [100]. Beraprost improves symptoms by dilating peripheral vessels and increasing blood flow to the skin [102], and it can also improve painful peripheral neuropathy over a period of 8 weeks [103].

4. Future Perspectives on Eicosanoids

Components of the eicosanoid pathway have a fundamental role in the development of inflammation. As seen in this review, several studies have established that they participate in the progression of diabetes and its complications. Eicosanoids may act as pro- or anti-inflammatory. Currently, PG agonist and COX-1 and/or COX-2 inhibitors are the most promising tools to control diabetes complications, showing good results and promise for the future. Future studies should aim to unveil the function of specific receptors and enzymes acting in more specific targets available only in certain organs, such as the kidneys, eyes, vessels, or nerves.

Conflict of Interests

The authors declare that there is no conflict of interests that would prejudice the impartiality of this scientific work.

Acknowledgments

We thank Sabrina S. Ferreira for assistance with Figure 2. The authors are supported by grant 2010/02272-0 from São Paulo Research Foundation (FAPESP), grant 470523/2013-1 from National Counsel of Technological and Scientific Development (CNPq, Projeto Universal 2013), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Pró-reitoria de Pesquisa da Universidade de São Paulo (PRP/USP, Projeto I and Novos Docentes), Brazil. The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.

References

C. N. Serhan, “Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not?” The American Journal of Pathology, vol. 177, no. 4, pp. 1576–1591, 2010.
View at: Publisher Site | Google Scholar
S. G. Harris, J. Padilla, L. Koumas, D. Ray, and R. P. Phipps, “Prostaglandins as modulators of immunity,” Trends in Immunology, vol. 23, no. 3, pp. 144–150, 2002.
View at: Publisher Site | Google Scholar
G. Levin, K. L. Duffin, M. G. Obukowicz et al., “Differential metabolism of dihomo-γ-linolenic acid and arachidonic acid by cyclo-oxygenase-1 and cyclo-oxygenase-2: implications for cellular synthesis of prostaglandin E₁ and prostaglandin E₂,” Biochemical Journal, vol. 365, no. 2, pp. 489–496, 2002.
View at: Publisher Site | Google Scholar
M. Wada, C. J. DeLong, Y. H. Hong et al., “Enzymes and receptors of prostaglandin pathways with arachidonic acid-derived versus eicosapentaenoic acid-derived substrates and products,” The Journal of Biological Chemistry, vol. 282, no. 31, pp. 22254–22266, 2007.
View at: Publisher Site | Google Scholar
J. I. Odegaard and A. Chawla, “Alternative macrophage activation and metabolism,” Annual Review of Pathology: Mechanisms of Disease, vol. 6, pp. 275–297, 2011.
View at: Publisher Site | Google Scholar
H. Harizi, J.-B. Corcuff, and N. Gualde, “Arachidonic-acid-derived eicosanoids: roles in biology and immunopathology,” Trends in Molecular Medicine, vol. 14, no. 10, pp. 461–469, 2008.
View at: Publisher Site | Google Scholar
C. D. Russell and J. Schwarze, “The role of pro-resolution lipid mediators in infectious disease,” Immunology, vol. 141, no. 2, pp. 166–173, 2013.
View at: Publisher Site | Google Scholar
C.-M. Hao and M. D. Breyer, “Roles of lipid mediators in kidney injury,” Seminars in Nephrology, vol. 27, no. 3, pp. 338–351, 2007.
View at: Publisher Site | Google Scholar
K. Meirer, D. Steinhilber, and E. Proschak, “Inhibitors of the arachidonic acid cascade: interfering with multiple pathways,” Basic and Clinical Pharmacology and Toxicology, vol. 114, no. 1, pp. 83–91, 2014.
View at: Publisher Site | Google Scholar
D. T. Graves and R. A. Kayal, “Diabetic complications and dysregulated innate immunity,” Frontiers in Bioscience, vol. 13, no. 4, pp. 1227–1239, 2008.
View at: Publisher Site | Google Scholar
J. I. Odegaard and A. Chawla, “Connecting type 1 and type 2 diabetes through innate immunity,” Cold Spring Harbor Perspectives in Medicine, vol. 2, no. 3, 2012.
View at: Publisher Site | Google Scholar
International Diabetes Federation, IDF Diabetes Atlas, International Diabetes Federation, Brussels, Belgium, 6th edition, 2013, http://www.idf.org/diabetesatlas.
F. Cipollone, A. Iezzi, M. Fazia et al., “The receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control,” Circulation, vol. 108, no. 9, pp. 1070–1077, 2003.
View at: Publisher Site | Google Scholar
G. P. Puschel, C. Kirchner, A. Schroder, and K. Jungermann, “Glycogenolytic and antiglycogenolytic prostaglandin E₂ actions in rat hepatocytes are mediated via different signalling pathways,” European Journal of Biochemistry, vol. 218, no. 3, pp. 1083–1089, 1993.
View at: Publisher Site | Google Scholar
J. Henkel, F. Neuschäfer-Rube, A. Pathe-Neuschäfer-Rube, and G. P. Püschel, “Aggravation by prostaglandin E2 of interleukin-6-dependent insulin resistance in hepatocytes,” Hepatology, vol. 50, no. 3, pp. 781–790, 2009.
View at: Publisher Site | Google Scholar
Y. Wen, J. Gu, S. K. Chakrabarti et al., “The role of 12/15-lipoxygenase in the expression of interleukin-6 and tumor necrosis factor-α in macrophages,” Endocrinology, vol. 148, no. 3, pp. 1313–1322, 2007.
View at: Publisher Site | Google Scholar
Y. Wen, J. Gu, G. E. Vandenhoff, X. Liu, and J. L. Nadler, “Role of 12/15-lipoxygenase in the expression of MCP-1 in mouse macrophages,” The American Journal of Physiology—Heart and Circulatory Physiology, vol. 294, no. 4, pp. H1933–H1938, 2008.
View at: Publisher Site | Google Scholar
S. K. Chakrabarti, B. K. Cole, Y. Wen, S. R. Keller, and J. L. Nadler, “12/15-Lipoxygenase products induce inflammation and impair insulin signaling in 3t3-l1 adipocytes,” Obesity, vol. 17, no. 9, pp. 1657–1663, 2009.
View at: Publisher Site | Google Scholar
E. Alpert, A. Gruzman, H. Totary, N. Kaiser, R. Reich, and S. Sasson, “A natural protective mechanism against hyperglycaemia in vascular endothelial and smooth-muscle cells: role of glucose and 12-hydroxyeicosatetraenoic acid,” Biochemical Journal, vol. 362, part 2, pp. 413–422, 2002.
View at: Publisher Site | Google Scholar
E. Yapakçi, O. Uysal, H. Demirbilek, S. Olgar, N. Naçar, and H. Özen, “Hypoglycaemia and hypothermia due to nimesulide overdose,” Archives of Disease in Childhood, vol. 85, no. 6, p. 510, 2001.
View at: Publisher Site | Google Scholar
T. Coll, X. Palomer, F. Blanco-Vaca et al., “Cyclooxygenase 2 inhibition exacerbates palmitate-induced inflammation and insulin resistance in skeletal muscle cells,” Endocrinology, vol. 151, no. 2, pp. 537–548, 2010.
View at: Publisher Site | Google Scholar
B. Broumand, “Diabetes: changing the fate of diabetics in the dialysis unit,” Blood Purification, vol. 25, no. 1, pp. 39–47, 2006.
View at: Publisher Site | Google Scholar
M. E. Molitch, R. A. DeFronzo, M. J. Franz et al., “Diabetic nephropathy,” Diabetes Care, vol. 21, no. 1, pp. S50–S53, 1998.
View at: Google Scholar
M. D. Breyer, H. R. Jacobson, and R. M. Breyer, “Functional and molecular aspects of renal prostaglandin receptors,” Journal of the American Society of Nephrology, vol. 7, no. 1, pp. 8–17, 1996.
View at: Google Scholar
M. D. Breyer and R. M. Breyer, “Prostaglandin receptors: their role in regulating renal function,” Current Opinion in Nephrology and Hypertension, vol. 9, no. 1, pp. 23–29, 2000.
View at: Publisher Site | Google Scholar
B. L. Jensen, J. Stubbe, P. B. Hansen, D. Andreasen, and O. Skøtt, “Localization of prostaglandin E₂ EP2 and EP4 receptors in the rat kidney,” American Journal of Physiology—Renal Physiology, vol. 280, no. 6, pp. F1001–F1009, 2001.
View at: Google Scholar
A. K. H. Lim and G. H. Tesch, “Inflammation in diabetic nephropathy,” Mediators of Inflammation, vol. 2012, Article ID 146154, 12 pages, 2012.
View at: Publisher Site | Google Scholar
K. Shikata and H. Makino, “Microinflammation in the pathogenesis of diabetic nephropathy,” Journal of Diabetes Investigation, vol. 4, no. 2, pp. 142–149, 2013.
View at: Publisher Site | Google Scholar
F. Chow, E. Ozols, D. J. Nikolic-Paterson, R. C. Atkins, and G. H. Tesch, “Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury,” Kidney International, vol. 65, no. 1, pp. 116–128, 2004.
View at: Publisher Site | Google Scholar
C. K. Wong, C. C. Szeto, M. H. M. Chan, C. B. Leung, P. K. T. Li, and C. W. K. Lam, “Elevation of pro-inflammatory cytokines, C-reactive protein and cardiac troponin T in chronic renal failure patients on dialysis,” Immunological Investigations, vol. 36, no. 1, pp. 47–57, 2007.
View at: Publisher Site | Google Scholar
E. Galkina and K. Ley, “Leukocyte recruitment and vascular injury in diabetic nephropathy,” Journal of the American Society of Nephrology, vol. 17, no. 2, pp. 368–377, 2006.
View at: Publisher Site | Google Scholar
J. Pfeilschifter, W. Pignat, K. Vosbeck, and F. Marki, “Interleukin 1 and tumor necrosis factor synergistically stimulate prostaglandin synthesis and phospholipase A2 release from rat renal mesangial cells,” Biochemical and Biophysical Research Communications, vol. 159, no. 2, pp. 385–394, 1989.
View at: Publisher Site | Google Scholar
J. B. Stafford and L. J. Marnett, “Prostaglandin E₂ inhibits tumor necrosis factor-alpha RNA through PKA type I,” Biochemical and Biophysical Research Communications, vol. 366, no. 1, pp. 104–109, 2008.
View at: Publisher Site | Google Scholar
S. Shinomiya, H. Naraba, A. Ueno et al., “Regulation of TNFα and interleukin-10 production by prostaglandins I₂ and E₂: studies with prostaglandin receptor-deficient mice and prostaglandin E-receptor subtype-selective synthetic agonists,” Biochemical Pharmacology, vol. 61, no. 9, pp. 1153–1160, 2001.
View at: Publisher Site | Google Scholar
M.-T. Wang, K. V. Honn, and D. Nie, “Cyclooxygenases, prostanoids, and tumor progression,” Cancer and Metastasis Reviews, vol. 26, no. 3-4, pp. 525–534, 2007.
View at: Publisher Site | Google Scholar
P. Kaliriski, P. L. Vieira, J. H. N. Schuitemaker, E. C. de Jong, and M. L. Kapsenberg, “Prostaglandin E2 is a selective inducer of interleukin-12 p40 (IL-12p40) production and an inhibitor of bioactive IL-12p70 heterodimer,” Blood, vol. 97, no. 11, pp. 3466–3469, 2001.
View at: Publisher Site | Google Scholar
H. Harizi, M. Juzan, V. Pitard, J. F. Moreau, and N. Gualde, “Cyclooxygenase-2-issued prostaglandin E2 enhances the production of endogenous IL-10, which down-regulates dendritic cell functions,” Journal of Immunology, vol. 168, no. 5, pp. 2255–2263, 2002.
View at: Publisher Site | Google Scholar
K. R. Tuttle, “Linking metabolism and immunology: diabetic nephropathy is an inflammatory disease,” Journal of the American Society of Nephrology, vol. 16, no. 6, pp. 1537–1538, 2005.
View at: Publisher Site | Google Scholar
C. Mora and J. F. Navarro, “Inflammation and diabetic nephropathy,” Current Diabetes Reports, vol. 6, no. 6, pp. 463–468, 2006.
View at: Publisher Site | Google Scholar
G. S. Hotamisligil, “Inflammation and metabolic disorders,” Nature, vol. 444, no. 7121, pp. 860–867, 2006.
View at: Publisher Site | Google Scholar
H. Cheng, X. Fan, G. W. Moeckel, and R. C. Harris, “Podocyte COX-2 exacerbates diabetic nephropathy by increasing podocyte (pro)renin receptor expression,” Journal of the American Society of Nephrology, vol. 22, no. 7, pp. 1240–1251, 2011.
View at: Publisher Site | Google Scholar
X. Zhang, J. B. Saaddine, C.-F. Chou et al., “Prevalence of diabetic retinopathy in the United States, 2005–2008,” The Journal of the American Medical Association, vol. 304, no. 6, pp. 649–656, 2010.
View at: Publisher Site | Google Scholar
A. M. Joussen, V. Poulaki, M. L. Le et al., “A central role for inflammation in the pathogenesis of diabetic retinopathy,” The FASEB Journal, vol. 18, no. 12, pp. 1450–1452, 2004.
View at: Publisher Site | Google Scholar
M. Tikhonenko, T. A. Lydic, Y. Wang et al., “Remodeling of retinal fatty acids in an animal model of diabetes: a decrease in long-chain polyunsaturated fatty acids is associated with a decrease in fatty acid elongases Elovl2 and Elovl4,” Diabetes, vol. 59, no. 1, pp. 219–227, 2010.
View at: Publisher Site | Google Scholar
A. M. Abu El-Asrar, L. Missotten, and K. Geboes, “Expression of cyclo-oxygenase-2 and downstream enzymes in diabetic fibrovascular epiretinal membranes,” British Journal of Ophthalmology, vol. 92, no. 11, pp. 1534–1539, 2008.
View at: Publisher Site | Google Scholar
M. L. Schwartzman, P. Iserovich, K. Gotlinger et al., “Profile of lipid and protein autacoids in diabetic vitreous correlates with the progression of diabetic retinopathy,” Diabetes, vol. 59, no. 7, pp. 1780–1788, 2010.
View at: Publisher Site | Google Scholar
X.-S. Chen, J. R. Sheller, E. N. Johnson, and C. D. Funk, “Role of leukotrienes revealed by targeted disruption of the 5-lipoxygenase gene,” Nature, vol. 372, no. 6502, pp. 179–182, 1994.
View at: Publisher Site | Google Scholar
C. D. Funk and X.-S. Chen, “5-Lipoxygenase and leukotrienes: transgenic mouse and nuclear targeting studies,” American Journal of Respiratory and Critical Care Medicine, vol. 161, no. 2, pp. S120–S124, 2000.
View at: Publisher Site | Google Scholar
J. Tang and T. S. Kern, “Inflammation in diabetic retinopathy,” Progress in Retinal and Eye Research, vol. 30, no. 5, pp. 343–358, 2011.
View at: Publisher Site | Google Scholar
R. A. Gubitosi-Klug, R. Talahalli, Y. Du, J. L. Nadler, and T. S. Kern, “5-Lipoxygenase, but not 12/15-lipoxygenase, contributes to degeneration of retinal capillaries in a mouse model of diabetic retinopathy,” Diabetes, vol. 57, no. 5, pp. 1387–1393, 2008.
View at: Publisher Site | Google Scholar
T. S. Kern, “Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy,” Experimental Diabetes Research, vol. 2007, p. 95103, 2007.
View at: Google Scholar
R. Talahalli, S. Zarini, N. Sheibani, R. C. Murphy, and R. A. Gubitosi-Klug, “Increased synthesis of leukotrienes in the mouse model of diabetic retinopathy,” Investigative Ophthalmology and Visual Science, vol. 51, no. 3, pp. 1699–1708, 2010.
View at: Publisher Site | Google Scholar
R. Talahalli, S. Zarini, J. Tang et al., “Leukocytes regulate retinal capillary degeneration in the diabetic mouse via generation of leukotrienes,” Journal of Leukocyte Biology, vol. 93, no. 1, pp. 135–143, 2013.
View at: Publisher Site | Google Scholar
A. J. M. Boulton, “Management of diabetic peripheral neuropathy,” Clinical Diabetes, vol. 23, no. 1, pp. 9–15, 2005.
View at: Publisher Site | Google Scholar
B. C. Callaghan, H. T. Cheng, C. L. Stables, A. L. Smith, and E. L. Feldman, “Diabetic neuropathy: clinical manifestations and current treatments,” The Lancet Neurology, vol. 11, no. 6, pp. 521–534, 2012.
View at: Publisher Site | Google Scholar
S. Tesfaye, A. J. Boulton, P. J. Dyck et al., “Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatment,” Diabetes Care, vol. 33, no. 10, pp. 2285–2293, 2010.
View at: Google Scholar
A. Matsunaga, M. Kawamoto, S. Shiraishi et al., “Intrathecally administered COX-2 but not COX-1 or COX-3 inhibitors attenuate streptozotocin-induced mechanical hyperalgesia in rats,” European Journal of Pharmacology, vol. 554, no. 1, pp. 12–17, 2007.
View at: Publisher Site | Google Scholar
C. D. Funk, “Prostaglandins and leukotrienes: advances in eicosanoid biology,” Science, vol. 294, no. 5548, pp. 1871–1875, 2001.
View at: Publisher Site | Google Scholar
C. G. Schalkwijk and C. D. A. Stehouwer, “Vascular complications in diabetes mellitus: the role of endothelial dysfunction,” Clinical Science, vol. 109, no. 2, pp. 143–159, 2005.
View at: Publisher Site | Google Scholar
A. Ceriello, “Basal insulin and cardiovascular and other outcomes,” The New England Journal of Medicine, vol. 367, no. 18, pp. 1762–1763, 2012.
View at: Google Scholar
Z. Guo, W. Su, S. Allen et al., “COX-2 Up-regulation and vascular smooth muscle contractile hyperreactivity in spontaneous diabetic db/db mice,” Cardiovascular Research, vol. 67, no. 4, pp. 723–735, 2005.
View at: Publisher Site | Google Scholar
T. Szerafin, N. Erdei, T. Fülöp et al., “Increased cyclooxygenase-2 expression and prostaglandin-mediated dilation in coronary arterioles of patients with diabetes mellitus,” Circulation Research, vol. 99, no. 5, pp. e12–e17, 2006.
View at: Publisher Site | Google Scholar
J. Y. T. Leung and C. C. Y. Pang, “Effects of nimesulide, a selective COX-2 inhibitor, on cardiovascular function in two rat models of diabetes,” Journal of Cardiovascular Pharmacology, vol. 64, no. 1, pp. 79–86, 2014.
View at: Publisher Site | Google Scholar
K. Boniface, K. S. Bak-Jensen, Y. Li et al., “Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling,” The Journal of Experimental Medicine, vol. 206, no. 3, pp. 535–548, 2009.
View at: Publisher Site | Google Scholar
Y. Yu and K. Chadee, “Prostaglandin E₂ stimulates IL-8 gene expression in human colonic epithelial cells by a posttranscriptional mechanism,” The Journal of Immunology, vol. 161, no. 7, pp. 3746–3752, 1998.
View at: Google Scholar
T. Nakayama, N. Mutsuga, L. Yao, and G. Tosato, “Prostaglandin E2 promotes degranulation-independent release of MCP-1 from mast cells,” Journal of Leukocyte Biology, vol. 79, no. 1, pp. 95–104, 2006.
View at: Publisher Site | Google Scholar
X. S. Wang and H. Y. A. Lau, “Prostaglandin E2 potentiates the immunologically stimulated histamine release from human peripheral blood-derived mast cells through EP1/EP3 receptors,” Allergy: European Journal of Allergy and Clinical Immunology, vol. 61, no. 4, pp. 503–506, 2006.
View at: Publisher Site | Google Scholar
C. L. Weller, S. J. Collington, A. Hartnell et al., “Chemotactic action of prostaglandin E₂ on mouse mast cells acting via the PGE₂ receptor 3,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 28, pp. 11712–11717, 2007.
View at: Publisher Site | Google Scholar
D. F. Legler, M. Bruckner, E. Uetz-von Allmen, and P. Krause, “Prostaglandin E2 at new glance: Novel insights in functional diversity offer therapeutic chances,” International Journal of Biochemistry and Cell Biology, vol. 42, no. 2, pp. 198–201, 2010.
View at: Publisher Site | Google Scholar
P. M. Vanhoutte, H. Shimokawa, E. H. C. Tang, and M. Feletou, “Endothelial dysfunction and vascular disease,” Acta Physiologica, vol. 196, no. 2, pp. 193–222, 2009.
View at: Publisher Site | Google Scholar
P. M. Vanhoutte, “COX-1 and vascular disease,” Clinical Pharmacology and Therapeutics, vol. 86, no. 2, pp. 212–215, 2009.
View at: Publisher Site | Google Scholar
J.-I. Kawabe, F. Ushikubi, and N. Hasebe, “Prostacyclin in vascular diseases—recent insights and future perspectives,” Circulation Journal, vol. 74, no. 5, pp. 836–843, 2010.
View at: Publisher Site | Google Scholar
T. Przygodzki, M. Talar, and C. Watala, “COX-2-derived prostaglandins do not contribute to coronary flow regulation in diabetic rats: distinct secretion patterns of PGI2 and PGE 2,” European Journal of Pharmacology, vol. 700, no. 1–3, pp. 86–92, 2013.
View at: Publisher Site | Google Scholar
D. Z. I. Cherney, J. W. Scholey, R. Nasrallah et al., “Renal hemodynamic effect of cyclooxygenase 2 inhibition in young men and women with uncomplicated type 1 Diabetes mellitus,” American Journal of Physiology: Renal Physiology, vol. 294, no. 6, pp. F1336–F1341, 2008.
View at: Publisher Site | Google Scholar
The Damad Study Group, “Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinopathy. A multicenter randomized controlled clinical trial,” Diabetes, vol. 38, no. 4, pp. 491–498, 1989.
View at: Publisher Site | Google Scholar
E. Y. Chew, J. Kim, H. R. Coleman et al., “Preliminary assessment of celecoxib and microdiode pulse laser treatment of diabetic macular edema,” Retina, vol. 30, no. 3, pp. 459–467, 2010.
View at: Publisher Site | Google Scholar
K. K. Tilma and T. Bek, “Topical treatment for 1 week with latanoprost but not diclofenac reduces the diameter of dilated retinal arterioles in patients with type 1 diabetes mellitus and mild retinopathy,” Acta Ophthalmologica, vol. 90, no. 8, pp. 750–755, 2012.
View at: Publisher Site | Google Scholar
S. D. Schoenberger, S. J. Kim, J. Sheng, K. A. Rezaei, M. Lalezary, and E. Cherney, “Increased prostaglandin E2 (PGE2) levels in proliferative diabetic retinopathy, and correlation with VEGF and inflammatory cytokines,” Investigative Ophthalmology & Visual Science, vol. 53, no. 9, pp. 5906–5911, 2012.
View at: Publisher Site | Google Scholar
Y. Issana, E. Hochhausera, A. Guod et al., “Elevated level of pro-inflammatory eicosanoids and EPC dysfunction in diabetic patients with cardiac ischemia,” Prostaglandins & Other Lipid Mediators, vol. 100-101, pp. 15–21, 2013.
View at: Publisher Site | Google Scholar
M. A. Bayorh, R. R. Socci, D. Eatman, M. Wang, and M. Thierry-Palmer, “The role of gender in salt-induced hypertension,” Clinical and Experimental Hypertension, vol. 23, no. 3, pp. 241–255, 2001.
View at: Publisher Site | Google Scholar
D. Eatman, M. Wang, R. R. Socci, M. Thierry-Palmer, N. Emmett, and M. A. Bayorh, “Gender differences in the attenuation of salt-induced hypertension by angiotensin (1–7),” Peptides, vol. 22, no. 6, pp. 927–933, 2001.
View at: Publisher Site | Google Scholar
J. M. Orshal and R. A. Khalil, “Gender, sex hormones, and vascular tone,” The American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 286, no. 2, pp. R233–R249, 2004.
View at: Google Scholar
J. C. Sullivan, J. M. Sasser, D. M. Pollock, and J. S. Pollock, “Sexual dimorphism in renal production of prostanoids in spontaneously hypertensive rats,” Hypertension, vol. 45, no. 3, pp. 406–411, 2005.
View at: Publisher Site | Google Scholar
V. Sreeramkumar, M. Fresno, and N. Cuesta, “Prostaglandin e 2 and T cells: friends or foes,” Immunology and Cell Biology, vol. 90, no. 6, pp. 579–586, 2012.
View at: Publisher Site | Google Scholar
R. Mohamed, C. Jayakumar, and G. Ramesh, “Chronic administration of EP4-selective agonist exacerbates albuminuria and fibrosis of the kidney in streptozotocin-induced diabetic mice through IL-6,” Laboratory Investigation, vol. 93, no. 8, pp. 933–945, 2013.
View at: Publisher Site | Google Scholar
R. Nasrallah, S. J. Robertson, and R. L. Hébert, “Chronic COX inhibition reduces diabetes-induced hyperfiltration, proteinuria, and renal pathological markers in 36-week B6-Ins2^Akita mice,” American Journal of Nephrology, vol. 30, no. 4, pp. 346–353, 2009.
View at: Publisher Site | Google Scholar
D. Sakata, C. Yao, and S. Narumiya, “Prostaglandin E₂, an immunoactivator,” Journal of Pharmacological Sciences, vol. 112, no. 1, pp. 1–5, 2010.
View at: Publisher Site | Google Scholar
C. Yao, D. Sakata, Y. Esaki et al., “Prostaglandin E2-EP4 signaling promotes immune inflammation through TH1 cell differentiation and TH17 cell expansion,” Nature Medicine, vol. 15, no. 6, pp. 633–640, 2009.
View at: Publisher Site | Google Scholar
C. Chizzolini, R. Chicheportiche, M. Alvarez et al., “Prostaglandin E₂ synergistically with interleukin-23 favors human Th17 expansion,” Blood, vol. 112, no. 9, pp. 3696–3703, 2008.
View at: Publisher Site | Google Scholar
Q. Chen, K. Muramoto, N. Masaaki et al., “A novel antagonist of the prostaglandin E 2 EP 4 receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models,” British Journal of Pharmacology, vol. 160, no. 2, pp. 292–310, 2010.
View at: Publisher Site | Google Scholar
J. L. Wang, H. F. Cheng, S. Shappell, and R. C. Harris, “A selective cyclooxygenase-2 inhibitor decreases proteinuria and retards progressive renal injury in rats,” Kidney International, vol. 57, no. 6, pp. 2334–2342, 2000.
View at: Publisher Site | Google Scholar
P.-F. Li, Y.-R. Mu, Y. Xin, Y. Qu, and L. Liao, “Therapeutic effect of prostaglandin E1 on diabetic nephropathy: a one-year follow-up study,” Journal of Southern Medical University, vol. 30, no. 3, pp. 482–485, 2010 (Chinese).
View at: Google Scholar
A. M. Joussen, V. Poulaki, N. Mitsiades et al., “Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-α suppression,” The FASEB Journal, vol. 16, no. 3, pp. 438–440, 2002.
View at: Google Scholar
M. Funk, G. Schmidinger, N. Maar et al., “Angiogenic and inflammatory markers in the intraocular fluid of eyes with diabetic macular edema and influence of therapy with bevacizumab,” Retina, vol. 30, no. 9, pp. 1412–1419, 2010.
View at: Publisher Site | Google Scholar
S. Caristi, G. Piraino, M. Cucinotta, A. Valenti, S. Loddo, and D. Teti, “Prostaglandin E2 induces interleukin-8 gene transcription by activating C/EBP homologous protein in human T lymphocytes,” Journal of Biological Chemistry, vol. 280, no. 15, pp. 14433–14442, 2005.
View at: Publisher Site | Google Scholar
V. M. Elner, M. A. Burnstine, R. M. Strieter, S. L. Kunkel, and S. G. Elner, “Cell-associated human retinal pigment epithelium interleukin-8 and monocyte chemotactic protein-1: immunochemical and in-situ hybridization- analyses,” Experimental Eye Research, vol. 65, no. 6, pp. 781–789, 1997.
View at: Publisher Site | Google Scholar
S. D. Schoenberger, S. J. Kim, R. Shah, J. Sheng, and E. Cherney, “Reduction of interleukin 8 and platelet-derived growth factor levels by topical ketorolac, 0.45%, in patients with diabetic retinopathy,” JAMA Ophthalmology, vol. 132, no. 1, pp. 32–37, 2014.
View at: Publisher Site | Google Scholar
S. P. Ayalasomayajula and U. B. Kompella, “Retinal delivery of celecoxib is several-fold higher following subconjunctival administration compared to systemic administration,” Pharmaceutical Research, vol. 21, no. 10, pp. 1797–1804, 2004.
View at: Publisher Site | Google Scholar
J. R. Vane and R. M. Botting, “Pharmacodynamic profile of prostacyclin,” American Journal of Cardiology, vol. 75, no. 3, pp. 3A–10A, 1995.
View at: Publisher Site | Google Scholar
P. Nony, P. Ffrench, P. Girard et al., “Platelet-aggregation inhibition and hemodynamic effects of beraprost sodium, a new oval prostacyclin derivative: a study in healthy male subjects,” Canadian Journal of Physiology and Pharmacology, vol. 74, no. 8, pp. 887–893, 1996.
View at: Publisher Site | Google Scholar
J.-L. Demolis, A. Robert, M. Mouren, C. Funck-Brentano, and P. Jaillon, “Pharmacokinetics and platelet antiaggregating effects of beraprost, an oral stable prostacyclin analogue, in healthy volunteers,” Journal of Cardiovascular Pharmacology, vol. 22, no. 5, pp. 711–716, 1993.
View at: Publisher Site | Google Scholar
H. S. Yoon, W. J. Choi, I. H. Sung, H. S. Lee, H. J. Chung, and J. W. Lee, “Effects of Beraprost Sodium on subjective symptoms in diabetic patients with peripheral arterial disease,” Clinics in Orthopedic Surgery, vol. 5, no. 2, pp. 145–151, 2013.
View at: Publisher Site | Google Scholar
S. Shin, K. J. Kim, H.-J. Chang et al., “The effect of oral prostaglandin analogue on painful diabetic neuropathy: a double-blind, randomized, controlled trial,” Diabetes, Obesity and Metabolism, vol. 15, no. 2, pp. 185–188, 2013.
View at: Publisher Site | Google Scholar

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Copyright © 2015 Fernando H. G. Tessaro et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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