The Effect of Low-Grade Chronic Inflammation on the Pathogenesis of Metabolic Syndrome

It is well accepted that metabolic syndrome (MS) increases the risk for the development of cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), stroke and cancer [1] . Recently, the chronic inflammatory condition that often accompanies the MS has been implicated as a major factor both in the installation of the MS itself and its associated pathophysiological consequences [2] . However, the inflammatory state that accompanies the MS does not completely fit into the classical definition of acute or chronic inflammation, as it is not accompanied by infection; there is no massive tissue injury and the dimension of the inflammatory activation is also not large. So, it is often called low-grade chronic inflammation or meta-inflammation , meaning metabolically-triggered inflammation [3] . Several studies support the concept that a proinflammatory state is a component of the MS because of the strong association of elevated C-reactive protein (CRP) with MS-risk factors and high CRP levels impart risk for major coronary events beyond that imparted by the other metabolic risk factors. High-sensitivity CRP (hs-CRP) has been developed and used as a marker to predict coronary vascular diseases in the MS and it was recently used as a predictor for non-alcoholic fatty liver disease (NAFLD) in correlation with serum markers that indicated lipid and glucose metabolism. However, the reasons for a link between inflammation and MS are not fully understood. One explanation may be that adipose tissue in obese people with MS releases increased amounts of cytokines into the circulation which in turn accounts for a greater production of CRP by the liver. Another possibility is that insulin resistance (IRalone is responsible for higher production of cytokines. Regardless of the mechanism, the finding that patients with MS exhibit characteristics of a proinflammatory state provide a new and exciting connection between inflammation and metabolic processes.


Introduction 1
The Pathogenesis of Low-Grade Chronic Inflammation

Introduction
It is well accepted that the metabolic syndrome (MS) increases the risk for the development of cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), stroke and cancer [ 1 ] . Recently, the chronic inflammatory condition that often accompanies the MS has been implicated as a major factor both in the installation of the MS itself and its associated pathophysiological consequences [ 2 ] . However, the inflammatory state that accompanies the MS does not completely fit into the classical definition of acute or chronic inflammation, as it is not accompanied by infection; there is no massive tissue injury and the dimension of the inflammatory activation is also not large. So, it is often called 'low-grade chronic inflammation' or 'meta-inflammation', meaning metabolically-triggered inflammation [ 3 ] .
Several studies support to the concept that a proinflammatory state is a component of the MS because of the strong association of elevated C-reactive protein (CRP) with MS-risk factors and high CRP levels impart risk for major coronary events beyond that imparted by the other metabolic risk factors. High-sensitivity CRP (hs-CRP) has been developed and used as a marker to predict coronary vascular diseases in the MS and it was recently used as a predictor for non-alcoholic fatty liver disease (NAFLD) in correlation with serum markers that indicated lipid and glucose metabolism.
However, the reasons for a link between inflammation and MS are not fully understood. One explanation may be that adipose tissue in obese people with the MS releases increased amounts of cytokines into the circulation which in turn accounts for a greater production of CRP by the liver. Another possibility is that insulin resistance (IR) 3 alone is responsible for a higher production of cytokines. Regardless of the mechanism, the finding that patients with MS exhibit characteristics of a proinflammatory state provides a new and exciting connection between inflammation and metabolic processes [4] .

The Pathogenesis of Low-Grade Chronic Inflammation:
Chronic inflammation is also referred to as slow, long-term inflammation lasting for prolonged periods of several months to years. Low grade chronic inflammation can result from the following: -Failure of eliminating the agent causing an acute inflammation such as infectious organisms.
-Exposure to a low level of a particular irritant or foreign material that cannot be eliminated by enzymatic breakdown or phagocytosis in the body.
-An autoimmune disorder in which the immune system is sensitized to the normal component of the body and attacks healthy tissue giving rise to diseases.
-Recurrent episodes of acute inflammation.
-Inflammatory and biochemical inducers are causing oxidative stress and mitochondrial dysfunction [5] .
Inflammation consists of a tightly regulated cascade that is orchestrated by immune signaling molecules called cytokines. The first step of the inflammatory cascade involves identification of infection or damage (Figure 1b Further neutrophil recruitment is blocked by lipoxins and instead favor enhanced infiltration of monocytes which is important for wound healing [6] . TNF-α is one of the cytokines produced chiefly by activated macrophages. Natural killer cells, neutrophils, mast cells, eosinophils, neurons and CD4+ lymphocytes. It is primarily responsible for the regulation of the functions of immune cells. Studies reveal that in obese subjects its level increases in adipose tissue (visceral rather than subcutaneous) and reduces as weight decreases [6] . 5 C-Reactive Protein (CRP) is an acute-phase protein which increase by macrophages and T cells in response to inflammation following IL-6 secretion. Studies showed that the risk of hypertension, T2DM and CVD increased as its level increasing in human. Recent research suggests that patients with elevated basal levels of CRP are at an increased risk of T2DM, hypertension and CVD [6] .
Adiponectin (ApN) is produced by adipose tissue. Studies showed that circulating ApN is negatively correlated with the body mass index (BMI) and decreased in obesity, in patients with T2DM or CVD. Abnormal hormonal milieu together with the enhanced oxidative stress and pro inflammatory state may be the mechanisms involve in the down regulation of ApN during obesity and the metabolic syndrome [6]. 6 7 Figure 1: Primers of the inflammatory cascade [6] .

Syndrome:
Although a pivotal response to infection and tissue injury, inflammation has also been associated with many pathological processes. Overt acute inflammation leads to tissue damage and non-resolving inflammation causes chronic tissue malfunction, suggesting an evolutionary trade-off between the rapid and effective response to perturbations in tissue homeostasis and the collateral damage on tissue function.
Obesity, raised fasting plasma glucose, high cholesterol and hypertension a cluster, is considered as a most dangerous risk factors are so-called metabolic syndrome [7] . Reactive oxygen species [ROS] have been implicated in characteristics of MS, including, hypertension, atherosclerosis, diabetes and even obesity itself [8] .
Aside from cytokines, the action of NF-κB can also be affected by insulin, free fatty acid [FFA] and glucose levels in circulation, all of which are elevated in MS. Elevated FFAs are thought to increase oxidative stress due to increased β-oxidation and mitochondrial uncoupling which can increase ROS production. While hyperglycemia has been shown to increase NF-κB activation, insulin acts to decrease its activation.
However, due to the insulin resistance that accompanies MS, the insulin is unable to have its anti-inflammatory effects, resulting in NF-κB activation. Insulin resistance results in both hyperglycemia and increased circulating FFAs and seems to be one of the 8 promoting agents for low grade chronic inflammation in MS. Thus, inflammation may be the underlying factor connecting Type 2 diabetes and cardiovascular disease in MS.
Within adipose tissue, associated macrophages account for nearly all of the TNF-α production and both TNF-α and mRNA production increase in the adipose tissue of obese individuals. TNF-α is a pro-inflammatory cytokine as it activates NF-κB, leading to increased oxidative stress and further cytokine production in peripheral tissues. It has also been associated with an increase in liver and muscle   [8] .
TNF-α has been implicated in endothelial dysfunction as it has been shown to increase leukocyte adhesion to the endothelium, activate NF-κB dependent inflammatory pathways, induce endothelial cell expression of VCAM-1, induce smooth muscle expression of metalloproteinases contributing to plaque destabilization and suppress the expression of nitric oxide synthase leading to decreased capacity to vasodilate vessels.
TNF-α also stimulates the production of IL-6 stimulates hepatic CRP production. Antagonistic to TNF-α action is adiponectin which is present in decreased levels in MS.
The underlying mechanism of vascular dysfunction, at endothelium and smooth muscle levels, appears to be secondary to the excessive ROS generated which seems to be wall. An unstable plaque is prone to rupture leading to thrombus formation and vessel wall occlusion [8] . to atherosclerotic lesions and cardiac events [8] .
The pathogenesis of atherosclerosis is a process that requires a complex and Severity of atherosclerosis is elevated as plasma concentrations of IL-1β and IL-18 are elevated [9] .
Gout is a disease associated with high concentrations of uric acid. The prevalence of gout increases in the population. Moreover, the prevalence has also increased affecting 21% of the adult population. The pathogenesis of gout is piloted by the accumulation and deposition of crystals of uric acid in the joints and as such these crystals are 11 activating inflammasome. Clinical studies on gout shows that blockage of IL-1β significantly reduce severity of disease [10] .

Prevention of Inflammation:
Chronic inflammation can have a deleterious effect on the body and is a key factor causing almost all chronic degenerative diseases. Some of the most effective ways to prevent chronic inflammation are: -Increased uptake of anti-inflammatory foods as; whole grains, natural foods, vegetables and fruits which are helpful in defeating inflammation.
-Avoiding use of antibiotics, antacids, and non-steroidal anti-inflammatory drugs (NSAIDs) as the cause inflammation in intestinal walls which in turn release toxins and trigger chronic, body-wide inflammation.
-Regular exercise is helpful in controlling weight as well as decreasing the risk of CVD and strengthening the heart, muscles, and bones.
-Avoiding stress as chronic psychological stress is linked to greater risk for depression, heart disease and body losing its ability to regulate the inflammatory response and normal defense as it is associated with an increase in cortisol levels which in turns leads to the suppression of the immune system [5] .

Conclusion:
Inflammation is a tissue-destroying process that involves the recruitment of blood-derived products. Rapidly destroy or isolate the underlying source of the 12 disturbance, removes damaged tissue and restore tissue homeostasis is the primary function of inflammation. Inflammatory and chronic metabolic alterations that together are termed metabolic syndrome. The risk of developing serious pathological conditions such as (CVD) and T2DM is significantly associated with inflammation and its concurrent multi-organ abnormalities which represent a great burden upon societies, as they require significant resources from health care systems. Thus, understanding the tissue-specific pathogenic processes that lead to disease progression is required for the development of more effective therapeutic approaches. 13