**1. Introduction**

#### **1.1 Involvement of oxidative stress in rheumatoid arthritis**

Rheumatoid arthritis (RA) is the most common inflammatory rheumatic disease, affecting almost 1–2% of the world's population. Most of patients present rheumatoid factors, which are autoantibodies directed to the Fc fraction of immunoglobulin G and antibodies reacting with citrullinated peptides [1, 2]. The pathogenesis of RA is understood incompletely. Until now, there is a lack of optimal therapy against this disease. The disease is characterized by immunological dysfunction and chronic inflammation which results in synovial joint deformity and destruction. In the course of RA, the synovial membrane of diarthrodial joints is inflamed, and articular tissue is damaged which leads to severe functional disarrangement of the entire joint. The initial stages of RA synovitis are characterized by proliferation of the microvasculature and secondary edema. Eventually, this process matures into a progressive infiltration of immune cells, including B cells, T cells, and monocytes from the bloodstream. These immune cells are activated in the joint and differentiate and acquire mature phenotypes. The influx of immune cells is also associated with phenotypic changes in synoviocytes, the typical resident cells. Both fibroblast- and monocyte-derived synoviocytes proliferate extensively and participate in inflammatory process. Synovial proliferation, neovascularization, and leukocyte extravasation transform the normal synovium into an invasive tumor-like "pannus." The architecture of the microvasculature is highly dysregulated, and thus efficiency of oxygen supply to the synovium is poor [3]. This, alongside with increased metabolic turnover of the expanding synovial pannus, leads to oxidative stress (OS), altered cellular bioenergetics, and a hypoxic microenvironment, which further promotes synovial invasiveness and abnormal cell function within the joint [4]. Free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) have distinct contribution to the destructive, proliferative synovitis of RA and play a prominent role in cell-signaling events (**Figure 1**).

However, few studies had clarified the role of free radicals in the etiopathogenesis of RA. Significant higher serum levels of ROS and RNS in RA patients in comparison with healthy subjects were described. Furthermore, strong positive correlation between ROS, RNS, and the clinical and biochemical markers of RA was observed [5]. In another study glycated, oxidized, and nitrated proteins and amino acids were detected in synovial fluid (SF) and plasma of arthritic patients with characteristic patterns found in early and advanced RA, with respect to healthy control [6]. Combination of estimates of oxidized, nitrated, and glycated amino acids with hydroxyproline and anti-cyclic citrullinated peptide antibody status in plasma provided a biochemical test of relatively high sensitivity and specificity for early-stage diagnosis and typing of arthritic disease. Advanced oxidation protein products (AOPPs) have been confirmed to accumulate in RA patients. A study of Ye et al. [7] demonstrated that AOPPs induce apoptosis of human chondrocyte via ROS-related mitochondrial dysfunction and endoplasmic reticulum stress pathways. These data implicate that AOPPs may represent a novel pathogenic factor that contributes to RA progression. Further it seems that an accurate redox balance is necessary to sustain an immune state that both prevents the development of overt autoimmunity and minimizes collateral tissue damage [8]. The inflamed joint

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*The Role of Endogenous Antioxidants in the Treatment of Experimental Arthritis*

is profoundly hypoxic, with evidence of oxidative damage and impaired mitochondrial dysfunction, as a result of abnormal angiogenesis and increased energy demands of the expanding synovial pannus [9]. In this hypoxic-inflammatory microenvironment, synovial cells adapt in order to survive through altering their cellular metabolism, which activates complex cross talk of key signaling pathways in the inflamed joint which further exacerbates inflammation. Thus, understanding the underlying mechanisms mediating hypoxia-induced pathways, OS, and subsequent cellular inflammation may provide a basis for novel therapies. It is well documented that ROS can activate different signaling pathways having a vital

1.To verify the hypothesis that per oral supplementation of CoQ10 could affect inflammation in arthritic rats by regulating endogenous antioxidants and OS

2.To verify the hypothesis that hyaluronan per oral administration can restore the redox balance under the conditions of experimental arthritis. OS has been monitored in erythrocytes and in plasma. The effect of three different molecu-

**1.2 Role of antioxidant systems and endogenous antioxidants in remission of** 

Epidemiological studies have shown that RA occurs in previously healthy subjects who had low levels of circulating antioxidants [11], implying a pathogenic role of increased OS in the development of RA. Patients with RA have been reported to have lower serum levels of a variety of antioxidants, including vitamin E, vitamin C, β-carotene, selenium, and zinc, in comparison with healthy individuals [12]. In order to prevent the damaging effect of prooxidants, the body has an antioxidant defense system that protects cellular systems from oxidative damage [13]. Some common enzymes that are involved in the neutralization of free radicals are endogenous enzymatic antioxidants such as superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), glutathione reductase (GR), and peroxiredoxins. These enzymes neutralize hydrogen peroxide, yielding water (CAT, GPx) and oxygen (CAT) molecules. The nonenzymatic endogenous antioxidants taking part in the first line of defense belong to preventive antioxidants, and in blood plasma they are represented by metal-binding proteins as ceruloplasmin, ferritin, lactoferrin, transferrin, and albumin. These proteins inhibit the formation of ROS by binding with transition metal ions (e.g., iron and copper). Also, metallothionein plays an essential role in the prevention against ROS. The second line of defense against ROS involves nonenzymatic antioxidants that are represented by molecules characterized by the ability to rapidly inactivate radicals and oxidants. The third line of defense consists of repair mechanisms against damage caused by free radicals. This form of protection is provided by enzymatic antioxidants, which can repair damaged DNA and proteins, fight against oxidized lipids, stop chain propagation of peroxyl lipid radicals, and repair damaged cell membranes and molecules [14]. Dietary antioxidants (vitamins C and E, carotenoids, polyphenols, and biogenic elements) can affect the activity of endogenous antioxidants. Endo- and exogenous antioxidants may act synergistically to maintain or re-establish redox homeostasis. The major endogenous nonenzymatic low-molecular-mass antioxidants include glutathione, uric acid, melatonin, coenzyme Q, bilirubin, and polyamines.

Considering the mechanism of antioxidant protection, the endogenous substances

with detailed analysis performed in plasma and skeletal muscles.

lar weights of polysaccharides has been evaluated.

*DOI: http://dx.doi.org/10.5772/intechopen.85568*

importance in the pathophysiology of RA [10]. Our chapter is focused on two main aims:

**rheumatoid arthritis**

**Figure 1.** *Pathological changes in arthritic joint induced by oxidative stress.*

#### *The Role of Endogenous Antioxidants in the Treatment of Experimental Arthritis DOI: http://dx.doi.org/10.5772/intechopen.85568*

is profoundly hypoxic, with evidence of oxidative damage and impaired mitochondrial dysfunction, as a result of abnormal angiogenesis and increased energy demands of the expanding synovial pannus [9]. In this hypoxic-inflammatory microenvironment, synovial cells adapt in order to survive through altering their cellular metabolism, which activates complex cross talk of key signaling pathways in the inflamed joint which further exacerbates inflammation. Thus, understanding the underlying mechanisms mediating hypoxia-induced pathways, OS, and subsequent cellular inflammation may provide a basis for novel therapies. It is well documented that ROS can activate different signaling pathways having a vital importance in the pathophysiology of RA [10].

Our chapter is focused on two main aims:

*Antioxidants*

disarrangement of the entire joint. The initial stages of RA synovitis are characterized by proliferation of the microvasculature and secondary edema. Eventually, this process matures into a progressive infiltration of immune cells, including B cells, T cells, and monocytes from the bloodstream. These immune cells are activated in the joint and differentiate and acquire mature phenotypes. The influx of immune cells is also associated with phenotypic changes in synoviocytes, the typical resident cells. Both fibroblast- and monocyte-derived synoviocytes proliferate extensively and participate in inflammatory process. Synovial proliferation, neovascularization, and leukocyte extravasation transform the normal synovium into an invasive tumor-like "pannus." The architecture of the microvasculature is highly dysregulated, and thus efficiency of oxygen supply to the synovium is poor [3]. This, alongside with increased metabolic turnover of the expanding synovial pannus, leads to oxidative stress (OS), altered cellular bioenergetics, and a hypoxic microenvironment, which further promotes synovial invasiveness and abnormal cell function within the joint [4]. Free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) have distinct contribution to the destructive, proliferative synovitis of RA and play a prominent role in cell-signaling events (**Figure 1**). However, few studies had clarified the role of free radicals in the etiopathogenesis of RA. Significant higher serum levels of ROS and RNS in RA patients in comparison with healthy subjects were described. Furthermore, strong positive correlation between ROS, RNS, and the clinical and biochemical markers of RA was observed [5]. In another study glycated, oxidized, and nitrated proteins and amino acids were detected in synovial fluid (SF) and plasma of arthritic patients with characteristic patterns found in early and advanced RA, with respect to healthy control [6]. Combination of estimates of oxidized, nitrated, and glycated amino acids with hydroxyproline and anti-cyclic citrullinated peptide antibody status in plasma provided a biochemical test of relatively high sensitivity and specificity for early-stage diagnosis and typing of arthritic disease. Advanced oxidation protein products (AOPPs) have been confirmed to accumulate in RA patients. A study of Ye et al. [7] demonstrated that AOPPs induce apoptosis of human chondrocyte via ROS-related mitochondrial dysfunction and endoplasmic reticulum stress pathways. These data implicate that AOPPs may represent a novel pathogenic factor that contributes to RA progression. Further it seems that an accurate redox balance is necessary to sustain an immune state that both prevents the development of overt autoimmunity and minimizes collateral tissue damage [8]. The inflamed joint

**150**

**Figure 1.**

*Pathological changes in arthritic joint induced by oxidative stress.*

