The Occurence of Inflammation and Oxidative Stress in Lung Diseases

Interstitial lung diseases (ILD) include various chronic lung disorders such as sarcoidosis and idiopathic lung fibrosis (IPF). In the Netherlands the incidence of sarcoidosis is approximately 20-25 per 100.000 inhabitants whereas that of IPF is approximately 1000-1500 new cases each year. In short, three different stages in the development of ILD can be discerned. Firstly, the lung tissue is damaged. In sarcoidosis this damage is thought to be antigen-driven, multisystemically and leading to the formation of granuloma. Moreover, it is suggested that genetic factors play an important role in the genesis of sarcoidosis. In IPF the exact etiology of this damage is unknown, but it has been speculated to be inflicted by an unidentified stimulus that produces repeated episodes of acute lung injury Secondly, the walls of the air sacs in the lung become inflamed as a reaction to the caused damage. This results in the activation of inflammatory cells like macrophages that cause the expression of pro-inflammatory cytokines, especially interleukin-10 and tumour necrosis factor (TNF)-alpha, in the lungs. Finally, scarring (or fibrosis) begins in the interstitium (or tissue between the air sacs) and the lung becomes stiff, causing an irreversible loss of the tissue's ability to transfer oxygen. It is well-known that inflammation plays a key-role in the occurrence and progression of ILD, although the long-lasting hypothesis that inflammation alone leads to fibrosis is being questioned at the moment. Conventional treatment of ILD comprises nonspecific anti-inflammatory agents such as glucocorticoids (prednisone) and other immune-suppressing medication such as cyclophosphamide, methotrexate and gamma-interferon. However, all these therapies fail to be completely efficacious, suggesting that inflammation alone is indeed not solely responsible for the occurrence and progression of ILD. Paradoxically, anti-TNF-α agents such as infliximab and thalidomide have recently shown some beneficial effects in sarcoidosis. A pivotal role for reactive oxygen species (ROS) in all three stages has also been proposed. Various biomarkers of oxidative stress, i.e. exhaled ethane and both 8-isoprostane and oxidized proteins in the bronchoalveolar fluid, are elevated in ILD patients of different clinical stages. However, only little is known about the effect of this elevated oxidative stress on the endogenous antioxidant levels present in ILD. Interestingly, clinical administration of an antioxidant, i.e. N-acetylcysteine (NAC), to IPF patients has recently demonstrated that this slows the deterioration of vital capacity and carbon monoxide diffusing capacity (DLCO) at 12 months. This supports the hypothesis that oxidative stress is involved in ILD and proofs the principle of antioxidant treatment in ILD. It is well-known that oxidative stress and inflammation are intertwined and that the pro-inflammatory cytokine TNF-alpha is capable of stimulating oxidative stress in various cells and tissues. As a result, the preliminary beneficial effects of anti-TNF-alpha agents combined with the preliminary beneficial effects of antioxidants in ILD may indicate that a new strategy of treatment of ILD should ideally combine the reduction of both the oxidative stress and the inflammation occurring in these diseases. Recently, much attention has been given to the potential health-beneficial properties of flavonoids, natural occurring polyphenolic compounds, and to quercetin, the most commonly occurring flavonoid, in particular. Quercetin is known to be a powerful antioxidant and to possess some anti-inflammatory effects. It is therefore tempting to speculate that quercetin could exert positive effects in ILD. Since the anti-oxidative and inflammatory changes in ILD are still not exactly known, the aim of the present study is to determine both the anti-oxidant and the inflammatory status in ILD, i.e. sarcoidosis and fibrosis. Furthermore, the possible anti-inflammatory effect of antioxidants on LPS-induced cytokine production, exemplified with the flavonoid quercetin, will be examined.