Ординатура / Офтальмология / Английские материалы / Handbook of Nutrition and Ophthalmology_Semba_2007

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role in inflammation by inducing the production of acute phase proteins, including fibrinogen and CRP, and by contributing to lymphocyte activation, leukocytosis, thrombocytosis, fever, and a general shift toward catabolism in metabolic pathways (16). IL-6 also appears to limit the extent of an inflammatory response by downregulating the release of TNF-α and IL-1β and promoting the release of IL-1Ra and soluble TNF-RI (17). NFκB plays a major role as a transcription factor for IL-6 (16). The receptor complex that mediates the activity of IL-6 consists of an 80-kDa receptor subunit and a 130-kDa sig- nal-transducing element, gp130 (18). Soluble IL-6 receptor (sIL-6R) consists of the 80 kDa subunit, and sIL-6R forms a stimulatory complex with IL-6 that regulates cellular events through direct activation of gp130 in a process known as trans signaling (18). Only few cell types have a complete IL-6 receptor on their surface, but because gp130 is ubiquitous, the presence of sIL-6R may make many cell types sensitive to the effects of IL-6. Elevated circulating IL-6 levels were independently associated with the progression of age-related macular degeneration in the Progression of Age-Related Macular Degeneration Study (19). Elevated plasma IL-6 levels were associated with macular edema in a study of 159 patients with diabetic retinopathy (20). No significant differences in serum IL-6 levels were found between 62 patients with less severe vs 31 patients with severe diabetic retinopathy (21). The same study described significant elevations in two chemokines in serum, regulated on activation, normal T-cell expressed and secreted (RANTES) and stromal cell-derived factor (SDF)-1α, in patients with severe compared with less severe retinopathy (21).

2.4. Interleukin-18

IL-18 is a pleiotropic proinflammatory cytokine that is produced by a variety of cells, including macrophages, adipocytes, lymphocytes, and endothelial cells (22,23). IL-18 regulates T-helper immune responses, induces IFN-γ production, and is considered to be an important mediator of atherosclerosis (23). IL-18 amplifies the inflammatory cascade by inducing the expression of cytokines, chemokines, and adhesion molecules, and both redox balance and TNF-α induce IL-18 through NF-κB activation (24). Elevated IL-18 levels were associated with elevated serum triglycerides (25), insulin resistance (26), the metabolic syndrome (27), obesity (28), and diabetes (29). Consumption of high-fat meals (30) and hyperglycemia (31) induced elevations in serum IL-18 levels. Elevated IL-18 was an independent predictor of unstable angina and cardiovascular death in adults with coronary artery disease (32) and of coronary events in healthy, middle-aged men (33). Studies of IL-18 gene polymorphisms support the idea that IL-18 plays a causal role in atherosclerosis and related complications (34).

2.5. C-Reactive Protein

CRP is a plasma protein that is largely produced by hepatocytes after an inflammatory stimulus (35). CRP is a pattern recognition molecule that binds to sites that are exposed during cell death or on the surfaces of pathogens and is considered part of the innate immune response (35). The expression of CRP is mostly regulated by IL-6 and IL-1β (35), but we recently demonstrated that leptin can stimulate the production of C-reactive protein, independent of IL-6 (36). Elevated CRP is associated with an increased risk of coronary heart disease (37–39), stroke and cognitive impairment (40). Elevated levels of plasma CRP were associated with anemia in the InChianti study (41) and in the Valsartan

Heart Failure Trial (42). Elevated circulating CRP levels were independently associated with the progression of age-related macular degeneration in the Progression of AgeRelated Macular Degeneration Study (19), but no association between CRP and age-related macular degeneration was found in the Cardiovascular Health Study (43).

2.6. Fibrinogen

Fibrinogen, the major plasma protein coagulation factor, is produced by hepatocytes. Fibrinogen serves as the precursor of fibrin and is an important determinant of platelet aggregation and blood viscosity (44). Fibrinogen is an acute-phase protein, and elevated fibrinogen is a risk factor for cardiovascular disease (45,46) and is an independent predictor of mortality (47–49). Fibrinogen was inversely correlated with hemoglobin among adults with anemia of chronic inflammation (50). In the Diabetes Control and Complications Trial (DCCT), elevated fibrinogen was associated with an increased risk of progression of diabetic retinopathy (51,52). Higher plasma fibrinogen levels have been described in diabetic patients with retinopathy compared with healthy controls (53,54). Fibrinogen was not correlated with the severity of retinopathy in the DCCT/Epidemiology of Diabetes Inverventions and Complications (EDIC) study (55). The EURODIAB Prospective Complications Study, among 1215 people with type 1 diabetes, fibrinogen was associated with the incidence of retinopathy over 7.3 yr of follow-up (56). Fibrinogen was no longer associated with incident retinopathy after adjusting for other risk factors such as hemoglobin A1c, fasting triglyceride levels, waist-to-hip ratio, and duration of diabetes (56). In a study of 150 adults with type 2 diabetes, elevated fibrinogen and duration of diabetes were independently associated with diabetic retinopathy in multiple regression analyses (57). In the Blue Mountains Eye Study, elevated fibrinogen was independently associated with risk of age-related macular degeneration (58).

2.7. Transforming Growth Factor-β1

TGF-β an important regulator of cell proliferation and differentiation, is produced by T-lymphocytes and a variety of other cells (59). TGF-β belongs to a group of structurally related cytokines collectively known as the TGF-β superfamily, and the isoform TGF-β1 (generally referred to as TGF-β) is the first-described and best-studied member of the group (60). TGF-β inhibits monocyte/macrophage MHC class II expression, suppresses the proliferation and differentiation of T- and B-cells, and limits the synthesis of proinflammatory cytokines such as TNF-α (59). TGF-β has both proand anti-inflammatory effects, depending on the cellular context. The effects of TGF-β as an anti-inflammatory cytokine are suggested by TGF-β1 knockout mice, which show multifocal, severe inflammatory reactions (61). Reduced TGF-β activity is implicated in the pathogenesis of atherosclerosis (59).

2.8. IL-1 Receptor Antagonist

IL-1 Ra is produced by monocyte/macrophages, neutrophils, and other cells, and its main role is to block the proinflammatory activity of IL-1β by binding to the IL-1 receptor without initiating signal transduction (62). The balance between IL-1 and IL-1Ra may relate to the severity of rheumatoid arthritis, inflammatory bowel disease, and other inflammatory diseases (62). Serum IL-1Ra is elevated in response to inflammation (63), as it is produced by the liver as an acute-phase protein in amounts about 100-fold higher than serum IL-1 (64,65); greater levels of IL-Ra are needed to functionally inhibit IL-1 in target

cells (62). Thus, IL-1Ra is a strong marker for inflammation. The effects of IL-1Ra as an anti-inflammatory cytokine are suggested by IL-Ra knockout mice, which can develop an inflammatory arthritis or vasculitis, depending on genetic background (62). The recombinant form of IL-1Ra, anakinra, has been approved for clinical use in the treatment for rheumatoid arthritis (66).

2.9. Interleukin-10

IL-10 is a multifunctional anti-inflammatory cytokine that is produced by a variety of cells, including monocyte/macrophages and lymphocytes. The main function of IL-10 appears to be the limitation and termination of inflammatory responses (67). IL-10 suppresses the synthesis of proinflammatory cytokines such as TNF-α, IL-6, and IL-1β (67, 68) and reduces the production of chemotactic factors such as IL-8 or CC chemokines (69). Low serum IL-10 is associated with cardiovascular disease, such as unstable angina (70). Among patients with unstable angina, higher serum IL-10 was predictive of a decreased risk of cardiovascular events (71). Elevated serum IL-10 was associated with a more favorable prognosis among patients with acute coronary syndromes and elevated CRP levels (72). Regular physical activity increased serum IL-10 and reduced IL-6 in healthy older men (73) and in patients with coronary heart disease (74).

3. THE CYTOKINE NETWORK IN THE PROINFLAMMATORY STATE

Cytokines function as an integrated network and comprise a series of differentiated responses (1–3). The general dichotomy of proand anti-inflammatory mediators is useful conceptually but may oversimplify what is a complex network where the activity of different cytokines and inflammatory mediators probably depend on multiple factors. The inflammatory response is a plastic network composed of redundant signaling among several different mediators, and these mediators have a reciprocal relationship with other biological subsystems, including oxidative/anti-oxidant balance, hormone regulation, and the nervous system (75). Most studies have utilized single markers of inflammation, and much work remains to be done to characterize inflammatory phenotypes based on multiple markers of inflammation.

4. UPREGULATION OF THE PROINFLAMMATORY STATE

4.1. Reactive Oxygen Species

ROS are ubiquitous reactive derivatives of O2 metabolism that are found in all biological systems. ROS are formed as intermediates in reduction-oxidation (redox) processes that lead from oxygen to water, and ROS participate in cell signaling and regulation (76). The role of ROS and oxidative stress in the proinflammatory state are shown in Fig. 2. It is estimated that 5% of total oxygen metabolism of liver tissues results in the production of ROS (77). Excessive production of ROS that exceeds endogenous defense mechanisms can result in oxidative damage to DNA, protein, and lipids. In the classic definition of Helmut Sies, oxidative stress refers the condition in which the balance between oxidants and antioxidant defenses is upset and excess ROS cause oxidative damage to nucleic acids, proteins, and lipids (78). Among the major ROS are O2− (superoxide), H2O2 (hydrogen peroxide), OH• (hydroxyl radical), R-COO• (fatty acid peroxyl radical), nitric oxide (NO), and ONOO– (peroxynitrite). Many ROS have extremely short half-lives and are

Fig. 2. Reactive oxygen species and upregulation of inflammatory cytokines.

difficult to measure directly in humans, however, the oxidative damage generated by ROS is usually used as a marker for oxidative stress (Subheading 7.2.). Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, membrane-associated enzymes that catalyze the one electron reduction of oxygen using NADH or NADPH as the electron donor, are major sources of superoxide (79). Superoxide is also produced by xanthine oxidase, an enzyme that catalyzes two terminal steps of purine metabolism (80), by mitochondrial respiratory chain complexes (81), cyclooxygenase, and cytochrome p450 (76). Endothelial nitric oxide synthase (eNOS) is a cytochrome p450 reductase-like enzyme that cata-

Fig. 3. Advanced glycoxidation end products (AGEs) in selected meat, poultry, and fish, per serving. (Adapted from ref. 87.)

lyzes flavin-mediated electron transport from the electron donor NADPH to a prosthetic heme group (82). In the absence of L-arginine, eNOS can become uncoupled and produce superoxide and hydrogen peroxide (82). NO produced by nitric oxide synthase in combination with superoxide can generate peroxynitrite (83). External sources of ROS include cigarette smoke (84), heavy alcohol use (85), and ultraviolet light exposure (86).

4.2. Advanced Glycation End Products

Advanced glycation end products (AGEs) are a heterogenous group of macromolecules that are formed by the non-enzymatic glycation of proteins, lipids, and nucleic acids (87,88). AGEs can be produced by lipid peroxidation and are also produced by glucose during hyperglycemia (89). AGEs can modify native molecules by cross-linking and by binding to several cellular receptors, including the receptor for advanced glycation end products (RAGE) (88). AGEs have been implicated in some chronic diseases and conditions such as diabetes, inflammation, renal disease, and Alzheimer disease (87). The binding of AGEs to RAGE results in activation of NF-κB and upregulation of inflammatory cytokines (88). In animal models, dietary AGE restriction resulted in reduced circulating AGEs levels and decreased progression of atherosclerosis (90) and diabetes (91). Proliferative diabetic retinopathy has been recently associated with upregulation of RAGE and its ligands (92).

Commonly consumed foods also contain AGEs in varying amounts, with much higher levels of AGEs found in fatty and fried foods and low levels found in fruits and vegetables (87) (Figs. 3 and 4). The highest AGE levels per serving were found in frankfurters, fried chicken, roast beef, hamburgers, chicken nuggets, French fries, cream cheese, butter, and processed cheese (87). In an intervention study involving a crossover design in 24 diabetic subjects, a diet high in AGEs was associated with increased markers of inflammation (93). A recent pilot study has shown that a meal high in saturated fats (hamburger, French fries) is followed by large elevations in serum IL-6 concentrations (Luigi Ferrucci, personal communication). These studies are consistent with the idea that dietary AGEs can increase systemic inflammation and potentially contribute to chronic diseases. Further work is needed to characterize the relationship between AGEs and eye diseases.

Fig. 4. Advanced glycoxidation end products (AGEs) in snack foods, fruits, and vegetables per serving. (Adapted from ref. 87.)

5. ANTIOXIDANT DEFENSE MECHANISMS

Antioxidant defense mechanisms include antioxidant enzymes such as superoxide dismutase, catalase, thioredoxin, and glutathione peroxidase, and extrinsic compounds such as carotenoids, tocopherols, ascorbate, selenium, and plant polyphenols, including flavonoids.

5.1. Antioxidant Enzymes

Superoxide dismutase (SOD) is an enzyme that catalyzes the breakdown of superoxide into hydrogen peroxide. Several types of SOD are known, including copperand zinccontaining superoxide dismutase (Cu,ZnSOD), the major intracellular form, and man- ganese-containing SOD (MnSOD), a form that is located primarily in the mitochondria matrix (94). Extracellular SOD (EC-SOD) is the predominant SOD in plasma, lymph, and the extracellular matrix of tissues (94). Catalase and thioredoxin are enzymes that catalyze the breakdown of hydrogen peroxide to oxygen and water (95). Glutathione peroxidase is a selenoenzyme that plays an important role in the reduction of H2O2 and lipid hydrogen peroxides (96).

5.2. Carotenoids

Carotenoids are pigmented compounds found in the flesh of fruits and vegetables, and carotenoids can quench singlet oxygen and reduce peroxyl and alkoxyl radicals (97). Major dietary carotenoids include α-carotene, β-carotene, β-cryptoxanthin, lutein, zeaxanthin, and lycopene. The biochemistry, metabolism, and role of carotenoids as antioxidants are presented in detail in Chapter 3 (Subheading 5.4.). In the Women’s Health and Aging Study, a population-based study of the causes of disability among older women living in the community in Baltimore, Maryland, low serum carotenoids were a strong independent predictor of subsequent rises in IL-6 (98). Low serum carotenoids were independent predictors of frailty (99), severe walking disability, and all-cause mortality (100). Low selenium was also an independent predictor of all-cause mortality (100). Serum carotenoids are considered the best biological markers for consumption of fruits and vegetables by the Food and Nutrition Board of the Institute of Medicine (101).