Abstract: The significance of airway inflammation in asthma has been completely understood. Oxidative stress also appears to play an important role in the pathophysiology of asthma. Lycopene as a potent antioxidant and anti-inflammatory agent is considered to inhibit airway inflammation in the asthmatics. The aim of current study is to review, the latest evidences regarding the implication of lycopene in airway inflammation. For this purpose, published researches in U.S. National Library of Medicine-National Institutes of Health (Pubmed) were reviewed. Evidences showed that lycopene can protect cells from inflammation via its redox-based property on suppression of Nuclear Factor- kappa B (NF-κB) which is a key nucleic factor that facilitates the production of inflammatory biomarkers. Therefore, it has been suggested that consuming fresh vegetables and fruits (especially tomato) as the sources of lycopene can help asthmatics to decrease airway inflammation.

INTRODUCTION

As antioxidants are reported to decrease the inflammation in the human body, it is aimed to review the latest evidences about the effects of lycopene on the inflammation in airway epithelial cells, especially in some inflammatory situations such as asthma. On the other hand, correlation among asthma, inflammation and oxidative stress was studied.

Inflammation is considerably increased in asthma: However, asthma is characterized by variable and reversible obstruction of airflow; it is considered as a chronic inflammatory disease (Cullinan and Taylor, 2003). It has been shown that even in the newly diagnosed asthmatics; there is an increased inflammation in the airways which has been defined as increased number of inflammatory cells such as eosinophils, mast cells and macrophages (Barnes et al., 1998). Inflammation is a complex process which initiated by tissue damage. Regardless of the type of tissue damage, multiple substances are released by the injured tissues causing dramatic secondary changes which worsen the disease (Guyton and Hall, 2000). A wide range of mediators and immune cells are involved in the pathophysiology of asthma (Macdowell and Peters, 2007). Many studies have confirmed an increased number of inflammatory cells including eosinophils, mast cells, T lymphocytes (T cells), neutrophils and macrophages in the Bronchoalveolar Lavage (BAL) of asthmatics (Douwes et al., 2002). The role of these cells in chronic airway inflammation is well known, specifically their ability to produce inflammatory biomarkers which may affect the airways (Barnes et al., 1998; Chung and Barnes, 1999). However, the precise mechanism by which inflammatory cells and their mediators cause airway hyperresponsiveness in asthma remains unclear. Figure 1 shows the pathways of innate and acquired immunity which are involved in the pathophysiology of asthma. The key role of neutrophils has recently been understood in the eosinophilic asthma (Douwes et al., 2002). Eosinophils are one of the inflammatory cells which found in the epithelial and submucosal layers. It has been reported that 50% of asthmatic patients are attributed to the eosinophilic airway inflammation (Douwes et al., 2002).

Activated eosinophils produce cytokines which result in further production of cytokines by epithelial cells (Chung and Barnes, 1999). It has been shown that mast cells are increased in the bronchoalveolar lavage of asthmatics and they associate with severity of asthma (Barnes et al., 1998). It has also been reported that mast cells are immunoreactive to the some inflammatory biomarkers such as Interleukin (IL)-3, Interleukin (IL)-4, Interleukin (IL)-5, Interleukin (IL)-6 and Granulocyte-macrophage Colony-Stimulating Factor (GM-CSF) (Forsythe and Ennis, 1999). It has recently been found that increased mast cells are located within airway smooth muscles (Forsythe and Ennis, 1999).

Fig. 1:	Pathways of innate and acquired immunity (the first pathway describes eosinophilic asthma and the second pathway shows neutrophilic asthma)

Furthermore, it has been proposed that airway inflammation can be induced by exposure to the Reactive Oxygen Species (ROS). On the other hand, ROS can be produced by epithelial cells, macrophages and/or neutrophils during inflammatory periods (Wright et al., 1994).

Oxidative stress is increased in the airway epithelial cells during asthma: Studies suggest that acute exacerbations of asthma are associated with increased oxidative stress (Nadeem et al., 2005). In asthma; ROS are produced by the inflammatory cells such as neutrophils and eosinophils when they are stimulated by triggers like allergens, viruses and air pollution (Wood et al., 2003). Moreover, it has been reported that in asthma, oxidative stress is overwhelmed antioxidants (Rahman et al., 1996). Reactive oxygen species increase epithelial shedding, contraction of smooth muscle cells, functional impairment of β-adrenoceptors, pulmonary vasoconstriction and the vascular permeability in the airway structures (Godard et al., 1987).

ROS may also result in some pathological changes such as hardening of the airways; bronchial hyperreactivity and inflammation (Godard et al., 1987). Catalase and glutathione peroxidise (GSH-Px) activities are decreased in asthma (Novak et al., 1991). Indicators of free radical activity are also increased in the asthmatic children and adults. Therefore, there is an evidence for imbalance oxidants and antioxidants equilibrium in the patients with chronic and acute asthma (Rahman et al., 1996).

Antioxidants may decrease inflammation: The nutritional status plays an important role in the susceptibility of body to the inflammation (Beck et al., 2000). There are many findings about effects of antioxidants on nuclear factor-kappa B. This factor can increase the expression of selected cytokines and chemokines including IL-6 and IL-8 and eventually promotes inflammation in the body (Kim et al., 2004).

As above, some of the antioxidants have an influential effect on NF-κB. Lycopene (Kim et al., 2004), vitamin C and vitamin E (Cindrova-Davies et al., 2007) are shown to decrease the inflammation via their probable redox-based effect on NF-κB. On the other hand, studies have shown that inflammation considerably affects the level of some nutrients in blood serum (Stephensen and Gildengorin, 2000). During inflammation, the concentrations of vitamin A, vitamin E and carotenoids are decreased (Stephensen and Gildengorin, 2000).

It has also been reported that the concentrations of serum α-carotene, β-carotene and lycopene are in the lowest phase in inflammatory situations (Boosalis et al., 1996). In one study, it has been suggested that dietary supplementation with lycopene may be an effective approach to reduce the oxidative stress and improve the inflammatory status of colitis (Reifen et al., 2001). It has also been found that circulating levels of antioxidant nutrients have an inverse correlation with IL-6 and C-Reactive Protein (CRP) concentrations (Boosalis et al., 1996; Reifen et al., 2001). It was previously reported by corresponding researchers that lycopene decreases release of IL-6 and Interferon gamma-induced Protein 10 kDa (IP-10) (IP-10 is increased in viral infections) in cultured airway epithelial cells (Saedisomeolia et al., 2009a). Probably, this effect of nutrients on inflammation is not exclusively restricted to the antioxidants as the researchers reported that Docosahexaenoic Acid (DHA) which is an Ω3 fatty acid can decrease the release of some inflammatory biomarkers (Saedisomeolia et al., 2009b).

Lycopene; a potent antioxidant: The antioxidant activity of carotenoids can be ranked as follows: lycopene >α-carotene>β-cryptoxanthin>zeaxanthin = β-carotene> lutein (Stahl et al., 1998). Therefore, lycopene is the most powerful antioxidant among carotenoids (Stahl et al., 1998). Lycopene is a key antioxidant in tomatoes and tomato products (Tyssandier et al., 2004). Studies have reported that higher plasma lycopene concentrations are associated with increased activities of antioxidant enzymes such as Superoxide Dismutase (SOD) and glutathione peroxidase and have also decreased lipid peroxidation biomarkers such as Malondialdehyde (MDA) (Pan et al., 2003).

It has been shown that lycopene via its redox-based property, prevents cutaneous damage and nephrotoxicity due to gentamicin (Tyssandier et al., 2004). Some studies have shown that consumption of processed tomato products enhances plasma lycopene concentrations in association with reduced lipoprotein sensitivity to oxidative damage (Hadley et al., 2003).

It has been proposed that other components in tomato have a synergistic effect with lycopene (Stacewicz-Sapuntzakis and Bowen, 2005). Ahmad Sacdisomeolia previously reported that lycopene usage is increased while cultured airway epithelial cells faced to lipid peroxidation (Saedisomeolia et al., 2008). Lycopene scavenges peroxyl radicals via special processes including electron transfer, allylic hydrogen abstraction and addition (Polyakov et al., 2001). Following equations show these mechanisms:

Lycopene and inflammation: Lycopene as an anti-inflammatory agent (Reifen et al., 2001) reduces inflammatory biomarkers in vivo (Jacob et al., 2007) and in vitro (Kim et al., 2004).

The researchers previously reported that lycopene decreases the production of two inflammatory biomarkers (IL-6 and IP-10) which may attribute to its redox-based activity (Saedisomeolia et al., 2009a, b). As mentioned before, studies have shown that lycopene supple- mentation may reduce oxidative stress and improve inflammatory status in colitis (Reifen et al., 2001). It has also been reported that lycopene diminishes inflammatory signals in the lateral prostate lobes (Herzog et al., 2005) and inhibits the expression of inflammatory agents in hyperhomocysteinemic rats (Liu et al., 2007). The mechanism by which carotenoids decrease the inflammation is related to their redox-based action on suppression of NF-κB.

NF-κB has an essential role in expression of many inflammatory biomarkers (Blackwell and Christman, 1997). It has been found that β-carotene can inhibit NF-κB activity in the exposed cells (Kim et al., 2004).

Furthermore, it has been shown that lycopene can suppress NF-κB via decreased nuclear translocation of p65 subunit in Lipopolysaccharide (LPS)-stimulated dendritic cells (Kim et al., 2004).

Applicable dietary approaches to decrease airway inflammation: Circulating levels of lycopene are in the lowest phase in asthmatics compared to healthy people (Stahl et al., 1998). Lycopene can reduce production of inflammatory biomarkers by cells via its antioxidant activity. Redox-based effect of antioxidants on suppression of NF-κB establishes an important link between antioxidants and inflammation (Stahl et al., 1998). Many studies showed the beneficial effect of antioxidant rich foods such as fruits and vegetables on prevalence rate of asthma.

For example in one study has been shown that there is a negative association between the intake of fresh fruits and asthma in adults (Butland et al., 1999). It has been found that consumption of fresh fruits and vegetables in childhood may decrease the risk of asthma in adults (Nja et al., 2005).

Therefore, it seems that consuming a balanced diet can diminish inflammation and oxidative stress in airway cells of asthmatics. It is clear that this approach is not a substitute for patient’s medication which is prescribed by physician. Actually, scientists and researchers need to investigate more about the effects of different foods on inflammatory situations.

CONCLUSION

As inflammation is increased in asthma, consumption of potent dietary anti-inflammatory antioxidants such as lycopene is suggested in this disorder.

NOMENCLATURE