LA EXPULSIÓN DE LOS CORRUPTOS

Obesity is an inflammatory condition, often associated with the development of adipose tissue inflammation, resulting in metabolic dysfunction and an increased risk for developing multiple chronic diseases.217 In addition to excess fat storage in adipose tissue, obesity is also associated with fat storage in other tissues including liver and

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skeletal muscle, which may lead to insulin resistance and stimulate inflammation.218 On the other hand, obesity changes the type of chemicals that fat cells secrete which include several pro-inflammatory mediators, produced by macrophages resident in the adipose tissue.218 It has been demonstrated that healthy obese subjects have increased circulating levels of pro-inflammatory cytokines such as IL-6, TNF-α and CRP.219,220_{Weight loss by}

hypocaloric diets or surgery reduced CRP levels in healthy middle-aged221 and postmenopausal obese women222 and obese men.223

Chronic diabetic wounds are trapped in a persistent inflammatory state with elevated levels of pro-inflammatory cytokines and proteases together with impaired expression of growth factors.224 _{Recent data have demonstrated that the plasma}

concentration of inflammatory mediators, such as TNF-α and IL-6, are increased in the insulin-resistant states of obesity and type-2 diabetes. The first molecular link between inflammation and insulin resistance was established by observing the insulin resistance in obese mouse can be reduced through neutralization of TNF-α by soluble TNF- α

receptors.225_{In the Women’s Health Study, elevatedCRP levels were associated with a}

four-fold increased risk to develop diabetes among healthy middle-aged women after follow up of 4 years.226 In addition, Dandona et al. demonstrated that insulin has an anti- inflammatory effect that may inhibit atherogenesis in the long term.227

Cigarette smoking has been shown to augment the production of pro-

inflammatory cytokines such as IL-1, IL-6 and IL-8 and to decrease the levels of anti- inflammatory cytokines such as IL-10.228 One of the key mechanisms behind smoking- induced inflammation activation is through the NF-kB pathway. In response to

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intracellular inhibitor (IkB) is activated by phosphorylation of IkB, which leads to the poly-ubiquitination and subsequent degradation of IkB. Degradation of IkB induces transcription of various genes involved in immune regulation and inflammation.229 The pro-inflammatory impact of smoking on increased level of various inflammatory cytokines was confirmed in several epidemiological studies. The associations between cigarette smoking, years since quitting smoking and inflammatory markers were investigated among 2,920 British men and the result showed that current smokers had higher levels of the acute phase CRP compared to never smokers.230 Reduced levels of inflammatory markers were found in subjects who quit smoking for 5 years, and the levels of inflammatory markers were reverted to those found in never smokers only in subjects who quit smoking for 20 years or more.230Serum levels of the key pro- inflammatory mediator TNF-α were found to be highest among healthy subjects who smoked more than one pack of cigarettes per day, followed by smokers who smoked less than one pack per day and lowest in healthy nonsmokers, demonstrating a positive relationship between cigarette smoke and serum level of TNF-α.231 _{Also, significantly}

higher serum levels of IL-1β was found in healthy active smokers compared with nonsmokers.232 In a recent multi-ethnic study of atherosclerosis cohort of 6814 adults without prior CDV, a monotonic association was found between higher pack-year quartiles and increasing inflammatory markers including high sensitivity CRP (hsCRP), IL-6 and fibrinogen.233

NSAIDs which include aspirin, indomethacin, piroxicam, sulindac, ibuprofen and other COX-2 inhibitors, are a diverse group of similarly acting compounds that are used to treat the signs and symptoms of inflammation by primarily inhibiting the activity of the

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COX enzymes and thereby affecting the synthesis of the prostaglandin signaling molecules, which are involved in a wide range of inflammation-related process.234

NSAIDs have shown the ability to alter systemic inflammation, reduce tumor recurrence and improve moderate cancer cachexia (a multifactorial syndrome affecting almost 50% of all cancer patients, characterized by skeletal muscle wasting with or without loss of fat mass and is often associated with psychological distress and fatigue).235A large body of evidence supports aspirin’s protective effect of reducing cancer incidence and cancer mortality. The beneficial effects are particularly large and consistent for colorectal, esophageal and gastric cancers, with smaller reductions seen on breast, prostate and lung cancer. 236 _{Data from 51 randomized controlled trials (RCTs) showed that aspirin use at} doses between 75 and 100 mg/day reduced overall cancer incidence by 12%. This benefit was only noted apparently with a 24% reduction observed after 3 years of follow-up and beneficial effect became larger with increasing follow-up. The benefit was most evident in patients with a scheduled treatment duration of 5 years or longer.237 Reductions in cancer incidence were similar in men and women.237 _{Data from multiple RCTs showed} that aspirin use can reduce total cancer death by 20% and the protective effect was only observed after 5 years of use. The magnitude of benefit became larger with longer duration of aspirin use, and it had similar benefit in men and women.238

2.4 Risk factors for pancreatic cancer