PATHOGENESIS OF CIGARETTE SMOKING: ROLE OF INFLAMMATORY MEDIATORS AND OXIDATIVE STRESS IN RELEVANCE TO MULTIPLE SCLEROSIS

Abstract

Cigarette smoking (CS), as a leading cause of morbidity worldwide, has been shown to play an important role in aetiology of chronic inflammatory and autoimmune diseases including multiple sclerosis (MS). CS can lead to those diseases through several mechanisms contributing to an increased disease susceptibility, all of which can have immunomodulatory effects in humans, including, but not limited to, genetic modifications, oxidative stress, increased susceptibility to infections and others. Due to the evidence suggesting the role of oxidative stress in MS pathogenesis, it has been postulated that higher levels of uric acid (UA), a natural peroxynitrite scavenger and endogenous antioxidant, could reduce or influence the disease progression. In the first part of this thesis, the aim was to determine quantitively the effect of smoking on serum UA levels before and after smoking cessation among people with MS, and further to determine the possible correlation between serum UA levels and both disability progression and disease severity. We found that smoker MS patients had a significant lower serum UA levels than non-smoker patients and this reduction was recovered by smoking cessation. However, UA levels were not correlated with the level of disability or disease severity.

In the second part, we sought to determine, in vitro, how cigarette smoke extract (CSE) and nicotine influence peripheral blood CD4+ and CD8+ T cells and NK cells, as well as how they impact their responses and the signalling pathways involved in relevance to MS. Mainly, we found for the first time, that cigarette smoke exposure can induce a distinct subset of T helper cells (TH-GM) and cytotoxic ones (Tc-GM), which were found to be regulated by IL-2/IL- 2Rα/STAT5 and MAPK ERK1/2 signalling pathways and predominantly express GM-CSF. Further, NK cells were activated indirectly and found to be potent inducers of TNFα, IL-2 and GM- CSF. In addition, these CS-induced inflammatory mediators were shown already to have a role in autoimmunity induction. In conclusion, these findings increase our understanding of the modifiable crucial role of cigarette smoking in relevance to MS and other chronic inflammatory and autoimmune diseases. In addition, the work confirms uric acid, a natural anti-oxidant, as a potential indicator of smoking cessation.