Beyond the classic eicosanoids: Peripherally-acting oxygenated metabolites of polyunsaturated fatty acids mediate pain associated with tissue injury and inflammation.

Pain is a complex sensation that may be protective or cause undue suffering and loss of function, depending on the circumstances. Peripheral nociceptor neurons (PNs) innervate most tissues, and express ion channels, nocisensors, which depolarize the cell in response to intense stimuli and numerous substances. Inflamed tissues manifest inflammatory hyperalgesia in which the threshold for pain and the response to painful stimuli are decreased and increased, respectively. Constituents of the inflammatory milieu sensitize PNs, thereby contributing to hyperalgesia. Polyunsaturated fatty acids undergo enzymatic and free radical-mediated oxygenation into an array of bioactive metabolites, oxygenated polyunsaturated fatty acids (oxy-PUFAs), including the classic eicosanoids. Oxy-PUFA production is enhanced during inflammation. Pioneering studies by Vane and colleagues from the early 1970s first implicated classic eicosanoids in the pain associated with inflammation. Here, we review the production and action of oxy-PUFAs that are not classic eicosanoids, but nevertheless are produced in injured/ inflamed tissues and activate or sensitize PNs. In general, oxy-PUFAs that sensitize PNs may do so directly, by activation of nocisensors, ion channels or GPCRs expressed on the surface of PNs, or indirectly, by increasing the production of inflammatory mediators that activate or sensitize PNs. We focus on oxy-PUFAs that act directly on PNs. Specifically, we discuss the role of arachidonic acid-derived 12S-HpETE, HNE, ONE, PGA2, iso-PGA2 and 15d-PGJ2, 5,6-and 8,9-EET, PGE2-G and 8R,15S-diHETE, as well as the linoleic acid-derived 9-and 13-HODE in inducing acute nocifensive behavior and/or inflammatory hyperalgesia in rodents. The nocisensors TRPV1, TRPV4 and TRPA1, and putative Gαs-type GPCRs are the PN targets of these oxy-PUFAs.

"Comparable placebo treatment" and the ethics of deception.

Recent research, especially with functional brain imaging, demonstrated cases where the administration of a placebo produces objective effects in tissues that are indistinguishable from those of the real therapeutic agents. This phenomenon has been shown in treatments of pain, depression, Parkinsonism, and more. The main ethical complaint against placebo treatment is that it is a kind of deception, where supposedly we substitute what works just psychologically for a real drug that actually works on the tissue level. We claim that the scientific findings bring to a new level the seeming deconstruction of the distinction between "placebo" and "real" drugs, and that instances of placebo treatment which fulfill this criterion should be recognized as a unique category-we call it "comparable placebo treatment" (CPT). The paper uses an analysis of the notion of deception to argue that CPT does not amount to deception; that it can preserve patient autonomy; and that it is therefore morally legitimate.

Impact of a nutritional formula enriched in fish oil and micronutrients on pressure ulcers in critical care patients.

BACKGROUND: Pressure ulcers are an important source of morbidity and suffering for patients and a formidable burden on caregivers. OBJECTIVES: To assess the impact of a feeding formula enriched with fish oil on healing of preexisting pressure ulcers and serum levels of C-reactive protein in critical care patients. METHODS: Adult patients with pressure ulcers grade II or higher were randomly allocated to receive either a formula enriched with fish oil or an isocaloric control formula. Wound healing was assessed by using the Pressure Ulcer Scale for Healing tool on days 7, 14, and 28. Blood levels of C-reactive protein were measured on days 0, 7, and 14. RESULTS: Baseline demographics did not differ between the study (n = 20) and the control (n = 20) groups. The mean score on the ulcer healing tool increased significantly (P = .02) from day 0 to day 28 in the control group (from 9.25 [SD, 2.12] to 10.75 [SD, 3.41]) compared with the study group (from 9.10 [SD, 2.84] to 9.40 [SD, 3.72]). Mean levels of C-reactive protein decreased significantly (P= .02) from day 0 to day 14 in the study group (from 191 [SD, 104.4] mg/L to 111.7 [SD, 97.8] mg/L) compared with the control group (from 145 [SD, 90] mg/L to 139 [SD, 62] mg/L). CONCLUSION: Administration of a feeding formula enriched with fish oil was associated with decreased progression of pressure ulcers and a decrease in blood concentrations of C-reactive protein.

The atypical chemokine receptor D6 controls macrophage efferocytosis and cytokine secretion during the resolution of inflammation.

The resolution of acute inflammation is hallmarked by the apoptotic death of inflammatory polymorphonuclear (PMN) cells, followed by their clearance by macrophages. In turn, resolution-phase macrophages exert reduced proinflammatory cytokine production, termed immune silencing. In this study, we found that the atypical chemokine receptor D6 plays an important and chemokine scavenging-independent role in promoting macrophage-mediated resolution. D6(-/-) mice displayed increased numbers of macrophages (2.2-fold increase), but not neutrophils, in their peritonea during the resolution of murine zymosan A-initiated peritonitis, in comparison to D6(+/+) animals. Moreover, D6-deficient macrophages engulfed higher numbers of apoptotic PMN cells in vivo (1.6-fold increase), and secreted higher amounts of TNF-α, CCL3, and CCL5 ex vivo than their wild-type (WT) counterparts. In addition, D6 was found to be expressed on apoptotic neutrophils from healthy humans and rodents. Moreover, the immune silencing of LPS-stimulated macrophages following their incubation with senescent PMN cells ex vivo (in terms of TNF-α, IL-1ß, and CCL5 secretion) was diminished (50-65% decrease) when D6(-/-) PMN cells were applied. Accordingly, the adhesive responses induced by macrophage interactions with senescent PMN cells were reduced with D6-deficient PMN cells. Thus, our results indicate a novel mode of action for D6 during the resolution of inflammation that is instrumental to the shaping of resolving macrophage phenotypes and the completion of resolution.

Fish oil attenuates surgery-induced immunosuppression, limits post-operative metastatic dissemination and increases long-term recurrence-free survival in rodents inoculated with cancer cells.

BACKGROUND & AIMS: Omega-3 fatty acids (ω-3FA) attenuate postoperative immunosuppression vis-à-vis infection. Since immune-surveillance targets metastasizing cancer cells, we assessed the effect of ω-3FA consumption on 1) early post-operative Natural Killer cell (NK) cytotoxicity and metastases and 2) long-term recurrence-free survival, in two rodent models of surgery-promoted metastases. METHODS: C57BL/6J mice were fed standard, ω-3FA-enriched, or ω-6FA-enriched chow, beginning one week before subcutaneous footpad implantation of syngeneic melanoma cells. When tumors reached the volume of 110 µl, the tumor-bearing footpad was amputated, and long-term recurrence-free survival was assessed. Also, F344 rats were fed ω-3FA or ω-6FA for a month before undergoing or not undergoing laparotomy, and were intravenously inoculated with radio-labeled syngeneic adenocarcinoma cells. Marginating-pulmonary (MP)-leukocytes were harvested, and lung tumor retention (LTR) of metastases was assessed. RESULTS: ω-3FA consumption did not affect the growth of footpad tumors, but significantly enhanced post-amputation recurrence-free survival in mice. Surgery had a deleterious effect on NK cell activity and LTR whereas ω-3FA had large beneficial effects in non-operated rats and an even greater impact in operated rats. CONCLUSIONS: ω-3FA feeding attenuates or even overcomes postoperative NK cell suppression, increases resistance to experimental and spontaneous metastasis, and enhances recurrence-free survival following excision of metastasizing primary tumors. These findings warrant clinical studies of ω-3FA-based nutrition in patients undergoing resection of a primary tumor.

Enteral n-3 fatty acids and micronutrients enhance percentage of positive neutrophil and lymphocyte adhesion molecules: a potential mediator of pressure ulcer healing in critically ill patients.

n-3 Fatty acids are recognised as influencing both wound healing and immunity. We assessed the impact of a fish oil- and micronutrient-enriched formula (study formula) on the healing of pressure ulcers and on immune function in critically ill patients in an intensive care unit. A total of forty patients with pressure ulcers and receiving nutritional support were enrolled (intervention group, n 20, received study formula; and a control group, n 20, received an isoenergetic formula). Total and differential leucocyte count and percentage of adhesion molecule positive granulocyte and lymphocyte cells (CD11a, CD11b, CD18 and CD49b) were measured on days 0, 7 and 14. Percentage of positive lymphocytes for CD54, CD49b, CD49d and CD8 were also measured on days 0, 7 and 14. The state of pressure ulcers was assessed by using the pressure ulcer scale for healing tool score on days 7, 14 and 28 of treatment. No between-group differences in patient demographics, anthropometry or diagnostic class were observed. Patients who received the study formula showed significant increases in the percentage of positive CD18 and CD11a lymphocytes and of CD49b granulocytes as compared to controls (P < 0·05). While the severity of pressure ulcers was not significantly different between the two groups on admission, severity increased significantly over time for the control group (P < 0·05), but not for the study group. The present study suggests that a fish oil- and micronutrient-enriched formula may prevent worsening of pressure ulcers and that this effect may be mediated by an effect on adhesion molecule expression.

The tight calorie control study (TICACOS): a prospective, randomized, controlled pilot study of nutritional support in critically ill patients.

PURPOSE: To determine whether nutritional support guided by repeated measurements of resting energy requirements improves the outcome of critically ill patients. METHODS: This was a prospective, randomized, single-center, pilot clinical trial conducted in an adult general intensive care (ICU) unit. The study population comprised mechanically ventilated patients (n = 130) expected to stay in ICU more than 3 days. Patients were randomized to receive enteral nutrition (EN) with an energy target determined either (1) by repeated indirect calorimetry measurements (study group, n = 56), or (2) according to 25 kcal/kg/day (control group, n = 56). EN was supplemented with parenteral nutrition when required. RESULTS: The primary outcome was hospital mortality. Measured pre-study resting energy expenditure (REE) was similar in both groups (1,976 ± 468 vs. 1,838 ± 468 kcal, p = 0.6). Patients in the study group had a higher mean energy (2,086 ± 460 vs. 1,480 ± 356 kcal/day, p = 0.01) and protein intake (76 ± 16 vs. 53 ± 16 g/day, p = 0.01). There was a trend towards an improved hospital mortality in the intention to treat group (21/65 patients, 32.3% vs. 31/65 patients, 47.7%, p = 0.058) whereas length of ventilation (16.1 ± 14.7 vs. 10.5 ± 8.3 days, p = 0.03) and ICU stay (17.2 ± 14.6 vs. 11.7 ± 8.4, p = 0.04) were increased. CONCLUSIONS: In this single-center pilot study a bundle comprising actively supervised nutritional intervention and providing near target energy requirements based on repeated energy measurements was achievable in a general ICU and may be associated with lower hospital mortality.

Effects of polyunsaturated fatty acid consumption in diabetic nephropathy.

The complex metabolic, vascular and inflammatory perturbations that characterize diabetes mellitus often lead to progressive albuminuria, renal injury and dysfunction (diabetic nephropathy [DN]), and diabetes is the leading cause of end-stage renal disease in the US and Europe. Diet has an important role in cardiometabolic disorders and its potential influence on DN is of interest. Fatty acids are a major source of energy, but in excess, fatty acids (particularly saturated fatty acids) can induce lipotoxicity. Omega-3 polyunsaturated fatty acids (PUFAs) confer protection against cardiovascular disease-the major cause of death in patients with DN-by virtue of their antihyperlipidemic, antihypertensive, anti-inflammatory and other properties. Omega-6 PUFAs are also cardioprotective. However, a significant proportion of adults consume insufficient quantities of these essential nutrients. This Review describes the role of omega-3 and omega-6 PUFAs in nutrition and metabolism, with a focus on experimental, epidemiologic and clinical studies that have investigated their renoprotective effect in patients with diabetes. Results from a number of studies suggest, but do not firmly establish, that long-chain omega-3 PUFAs (found in fish oil) reduce albuminuria in the setting of DN. Intake of omega-6 fatty acids is associated with reduced albuminuria in experimental settings and in epidemiologic studies of DN. Although PUFAs do not seem to attenuate glomerular dysfunction, insufficient evidence exists to rule out such an effect. We feel that further research is needed into the potential of PUFA consumption and supplementation in DN.

The therapeutic potential of long-chain omega-3 fatty acids in nonalcoholic fatty liver disease.

OBJECTIVES: The pharmacologic approach to disease management has not (as of yet) demonstrated safety and efficacy in nonalcoholic fatty liver disease (NAFLD). The current article introduces the long-chain omega-3 polyunsaturated fatty acids (LC-ω3s), and reviews the evidence and mechanisms by which their increased intake or supplementation may ameliorate NAFLD. METHODS: A literature search was performed through Ovid Medline, using such terms as NAFLD, NASH, nonalcoholic, steatosis, polyunsaturated fatty acids, fish oil and omega-3. RESULTS: The LC-ω3s display pleiotropic properties that are of benefit in cardiovascular disease. Deficiency of omega-3 fatty acids results in hepatic steatosis, whereas fish oil displays powerful hypotriglyceridemic properties. Intake and/or metabolism of omega-3 fatty acids are commonly impaired in NAFLD patients. A number of pre-clinical and clinical studies have demonstrated an ameliorative effect of supplemental fish oil, seal oil and purified LC-ω3s in reducing hepatic lipid content in NAFLD. There is less evidence that hepatic inflammation and fibrosis are safely reduced by LC-ω3s. CONCLUSIONS: Supplementation of LC-ω3s appears to safely reduce nutritional hepatic steatosis in adults. Whether other histopatholgic features of NAFLD also respond to LC-ω3s is being addressed by clinical trials. Any recommendation for omega-3 supplementation in NAFLD/NASH is contingent on these results.

Macrophages, meta-inflammation, and immuno-metabolism.

Current research depicts specific modes of immunity and energy metabolism as being interrelated at the molecular, cellular, organ and organism level. Hence, whereas M2 (alternatively-activated) macrophages dominate insulin-sensitive adipose tissue in the lean, M1-skewed (classically-activated) macrophages accumulate in parallel to adiposity in the obese, and promote inflammation and insulin resistance, that is, meta-inflammation. The latest frontier of immuno-metabolism explores the coregulation of energy metabolism and immune function within hematopoietic cells. M1-skewed macrophages are sustained in edematous, hypoxic tissues by anaerobic glycolysis, whereas mitochondrial biogenesis and respiration dominates in M2 cells. We review the underlying mechanisms and the consequences of the transition from M2 to M1 predominance in adipose tissue, as well as the extracellular signals and transcription factors that control macrophage phenotypes and impose distinct metabolic modes.

Inhaled aerosolized insulin: a "topical" anti-inflammatory treatment for acute lung injury and respiratory distress syndrome?

Acute lung injury (ALI) and the more severe acute respiratory distress syndrome (ARDS) are forms of pulmonary edema that result from robust local and systemic inflammatory states, such as sepsis. The morbidity and mortality associated with ALI and ARDS are significant and the treatment of these conditions presents a formidable challenge. Controlling hyperglycemia with insulin is a core component of patient management in the critically ill. Insulin treatment also exerts beneficial metabolic effects beyond glucose control, as well as non-metabolic effects, in insulin-resistant states. For instance, insulin inhibits NF-kappaB--dependent synthesis of pro-inflammatory factors and attenuates production of ROS. Indeed, intravenous administration of insulin ameliorates pulmonary injury and dysfunction in the LPS model of ALI. Most recently, an inhalable insulin formulation was shown to effectively reduce glucose concentrations with minimal impact on long-term pulmonary function. We propose that administering inhalable insulin to hyperglycemic ALI/ARDS patients could directly reduce alveolar inflammation while reducing circulating glucose levels.

Polyphenols in the prevention and treatment of sepsis syndromes: rationale and pre-clinical evidence.

Sepsis is the overwhelming systemic response to infection of a normally sterile body compartment. Despite advances in elucidating its pathophysiology, severe sepsis remains a leading cause of death in the critically ill. Polyphenols are a family of chemicals found in food and beverages derived from plants, such as cocoa, green tea, turmeric, and soya, as well as in medicinal herbs. These phytochemicals exhibit anti-inflammatory and vasculoprotective properties in clinical and preclinical studies. The oral or systemic administration of polyphenols protects rodents from endotoxinemia and microbial sepsis. Under these circumstances, polyphenols reproducibly attenuate microvascular hyperpermeability, tissue infiltration by leukocytes, oxidative and nitrosative stress, tissue injury, organ dysfunction, shock and vasoplegia, lactate production, and mortality. Importantly, efficacy is maintained in some cases even when treatment is initiated hours after the onset of sepsis. The inhibition of nuclear factor-kappaB activation and subsequent expression of inducible nitric oxide synthase, adhesion molecules, and tumor necrosis factor-alpha by polyphenols is operative in ameliorating the sequelae of sepsis. Enhancement of the endogenous antioxidant capacity probably also contributes to the effectiveness of the polyphenols. Because several of the polyphenols reviewed in this article appear to be safe and to exert anti-inflammatory effects in humans, clinical trials assessing their efficacy in the critically ill are indicated. Whether delivered alone or in combination with nutritional formulas, polyphenols may help to prevent and treat sepsis.

Enteral omega-3 in acute respiratory distress syndrome.

PURPOSE OF REVIEW: The acute respiratory distress syndrome (ARDS) is a severe illness that is often the cause of death in ICU patients. A safe and effective intervention for this condition is lacking. Fish oil-based enteral nutrition [rich in n-3 polyunsaturated fatty acids (PUFAs) and antioxidants] improved clinical outcomes in a previous trial on ARDS patients but was ineffective, or even harmful in other studies utilizing different fish oil formulae (rich in n-3 PUFAs and arginine) in severely ill ICU patients. Until most recently, consistent evidence that enteral n-3 PUFA is therapeutic in ARDS was lacking. RECENT FINDINGS: In ARDS, an overwhelming inflammatory response damages the endothelial-alveolar units, reducing oxygen diffusion and increasing pulmonary workload. n-3 PUFA targets this inflammatory response. In two recent randomized, controlled studies, the fish oil formula that was previously shown to be effective was administered to patients with ARDS/acute lung injury (in which hypoxia is less severe) and to patients with severe sepsis and hypoxia, respectively. n-3 PUFA feeding improved oxygenation, and a meta-analysis of the three studies demonstrated that enteral fish oil reduces mortality, complications and length of ICU stay. SUMMARY: Enteral administration of fish oil, antioxidants and physiologic amounts of arginine improve oxygenation and clinical outcomes in ICU patients with impaired oxygenation. Whether n-3 PUFA per se produces such benefit is the subject of an ongoing clinical study.

Anti-inflammatory properties of omega-3 fatty acids in critical illness: novel mechanisms and an integrative perspective.

INTRODUCTION: Fish oil-based nutrition is protective in severe critical care conditions. Regulation of the activity of transcription factor NF-kappaB is an important therapeutic effect of the major omega-3 fatty acids in fish oil, eicosapentaenoic and docosahexaenoic acid (EPA and DHA). METHODS AND RESULTS: Using the articles obtained by a Pubmed research, this article reviews three aspects of NF-kappaB/inflammatory inhibition by fish oil. (1) Inhibition of the NF-kappaB pathway at several subsequent steps: extracellular, free omega-3 inhibits the activation of the Toll-like receptor 4 by endotoxin and free saturated fatty acids. In addition, EPA/DHA blocks the signaling cascade between Toll-like/cytokine receptors and the activator of NF-kappaB, IKK. Oxidized omega-3 also interferes with the initiation of transcription by NF-kappaB. (2) The altered profile of lipid mediators generated during inflammation, with production of the newly identified, DHA-derived inflammation-resolving mediator classes (in addition to the formation of less pro-inflammatory eicosanoids from EPA). Resolvin D1 and Protectin D1 are potent, endogenous, DHA-derived lipid mediators that attenuate neutrophil migration and tissue injury in peritonitis and ischemia-reperfusion injury. Their production is increased in the later stages of an inflammatory response, at which time they enhance the removal of neutrophils. (3) Modulation of vagal tone with potential anti-inflammatory effects: vagal fibers innervating the viscera down-regulate inflammation by activating nicotinic receptors upon infiltrating and resident macrophages. Stimulation of the efferent vagus is therapeutic in experimental septic shock. Fish oil supplementation increases vagal tone following myocardial infarction and in experimental human endotoxinemia. CONCLUSION: It remains to be shown whether these pleiotropic actions of EPA/DHA contribute to fish oil's therapeutic effect in sepsis.

Prevention of liver cirrhosis in rats by curcumin.

BACKGROUND AND AIM: Curcumin, the major polyphenolic compound in turmeric, has been shown to attenuate hepatic damage in several animal models of liver injury. The aim of the present study was to examine the efficacy of curcumin in preventing thioacetamide-induced cirrhosis and to unravel the mechanism of curcumin's effect on hepatic fibrosis in rats. METHODS: Liver cirrhosis was induced by thioacetamide (TAA; 200 mg/kg, i.p.) twice weekly for 12 weeks. One group of rats concomitantly received curcumin (300 mg/kg/day, by gavage for 12 weeks); the control group received the solvent at identical amounts and duration. RESULTS: TAA administration induced liver cirrhosis, which was inhibited by curcumin. Liver histopathology, hydroxyproline levels and spleen weights were significantly lower in the rats treated with TAA+curcumin compared with TAA only (P<0.001). Immunohistochemical studies and in situ hybridization demonstrated inhibition of hepatic stellate cell (alpha smooth muscle actin-positive) activation and collagen alpha1 (I) gene expression in the livers of the TAA+curcumin-treated rats. Curcumin reduced oxidative stress as shown by the decreased hepatic nitrotyrosine staining in the curcumin+TAA-treated rats. Curcumin treatment had no effect on pre existing liver cirrhosis. As determined by in vitro studies using the rat HSC-T6 cell line, curcumin had no direct inhibitory effect on collagen alpha1 (I) messenger RNA expression. Further studies in these cells using reverse transcriptase-polymerase chain reaction demonstrated that curcumin had no effect on the expression of PDGF-induced TIMP-1 and TIMP-2, TGFbeta1, TGFbeta2 and MCP-1 but significantly inhibited tumor necrosis factor alpha expression. Curcumin had no effect on hepatic stellate cells proliferation. Zymography showed that curcumin had no effect on matrix metalloproteinase-2 activity. CONCLUSIONS: Curcumin inhibited the development of TAA-induced liver cirrhosis mainly due to its anti-inflammatory activities and not by a direct anti-fibrotic effect. As curcumin ingestion is safe in humans, it may be reasonable to assess in clinical studies the beneficial effect of curcumin in slowing the development of liver cirrhosis.