Exposure of different exogenous agents as chemicals in working environment for a long time may influence the physiological and biochemical metabolism. It may influence the prostate gland, the principal that such chemicals can alter the enzymatic activity has been established.[34
] Moreover, animal studies demonstrated that prostate tumors can be induced by administration of chemicals.[36
] Furthermore, many studies suggest various exogenous chemicals may affect hormone levels which may in turn, affect estrogen levels and androgenic stimulation of the prostate.[37
] This study was conducted in densely populated north-Indian region to evaluate the association of various modes of tobacco consumption with inflammation in prostate cancer patients by measuring the serum IL-18 pro-inflammatory levels. Our study provides evidence that tobacco chewing and smoking may be important contributors for inflammation. The patients who were involved in tobacco smoking alone and smoking in combination with other mode as chewing and alcohol drinking showed significant increase in inflammation in carcinoma patients than non-users. The subjects who were involved in tobacco chewing alone and in combination with smoking with alcohol also showed significantly increased in inflammatory levels but slightly lower than smokers.
IL-18 and IL-6 are important in the recruitment and activation of inflammatory cells. The reason for the aggravation and induction of these pro-inflammatory mediators is probably due to the activation of redox-sensitive transcription factor NF-kB.[41
] This transcription factor has been shown to be activated by a wide variety of agents including stress, cigarette smoke, viruses, bacteria, inflammatory stimuli, cytokines and free radicals.[43
] Tobacco smoke is a heterogeneous mixture that contains approximately 4,000 chemical compounds, including 40 different substances classified as carcinogenic to humans or animals.[45
Indices of increased local and systemic oxidative stress have been shown in cigarette smokers.[46
] Several studies showed that both the gas and particulate fractions of cigarette smoke are rich sources of radicals, but the former are short lived.[47
] Exposure to toxic agents in chewers can be estimated from biological markers. Some perceive hookah is not harmful[49
] because of the belief that the smoke gets filtered in the water.[52
One study suggested that regular smoking of marijuana and/or tobacco by young adults is associated with a high frequency of central airway inflammation. This injury is visually evident by bronchoscopy and is sometimes quite striking. At the microscopic level, there is evidence of airway inflammation in almost all smokers. These changes occur even in the absence of any symptoms or physiologic evidence of injury. The evidence for small airways inflammation was less striking in smokers of marijuana or tobacco alone, but quite prevalent in combined marijuana tobacco smoke. Collectively, these findings strongly suggest that smoking marijuana and/or tobacco has significant injurious effects on the central and peripheral airways, even in young and otherwise asymptomatic adults.[53
] Many studies have found that there is a synergic effect of cigarette smoking, alcoholic consumption and betel quid chewing in carcinogenesis of oral cavity mucosa.[54
] Bidis contain tobacco and also contain other chemicals like hydrogen cyanide and ammonia. Bidis deliver more nicotine and contains more N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in comparison to cigarettes. Furthermore, compared to cigarettes, the mainstream smoke of bidi contains a higher concentration of several toxic and mutagenic substances, including hydrogen cyanide, carbon monoxide, volatile phenols and carcinogenic hydrocarbons such as benz[a]anthracene and benzo[a]pyrene in greater amounts than found in regular cigarettes.[57
] Bidis could actually be worse than cigarettes due to a lot many reasons. They contain less tobacco but more nicotine than regular cigarettes. They pose the same risks for cancer, emphysema, heart diseases, etc. as cigarettes. Also, to keep bidis lit, smokers have to take more frequent and deeper puffs as compared to cigarettes. So, smokers may end up inhaling more smoke and taking it deeper into lungs. Also, due to the misconception that bidis are herbal and, therefore less harmful. Thus, it may be the reason of increased pro-inflammatory levels than cigarette smokers. A recent study by the Canadian government found that cannabis smoke contained more toxic substances than tobacco smoke. The study determined that marijuana smoke contained 20 times more ammonia and five times more hydrogen cyanide and nitrogen oxides than tobacco smoke.[58
Smokers have increased rates of many cancers, especially those arising in the lung, head and neck, bladder and cervix and rare research on prostate cancer. It contains 1,014-1,016 free radicals/puff, which include reactive aldehydes, quinines and benzo(a)pyrene.[59
] Many of these are relatively long lived, such as tar-semiquinone, ROS has been implicated in initiating inflammatory responses in the lungs through the activation of transcription factors, such as nuclear factor NF-kB and activator protein (AP)-1 and other signal transduction pathways, such as mitogen-activated protein (MAP) kinases and phosphoinositide-3-kinase (PI-3K), leading to enhanced gene expression of pro-inflammatory mediators.[60
] Recently, it has been shown that oxidative stress and the redox status of the cells can also regulate nuclear histone modifications, such as acetylation, methylation and phosphorylation, leading to chromatin remodelling and recruitment of basal transcription factors and RNA polymerase II leading to the induction of proinflammatory mediators.[60
] Among these, NF-kB has been reported to play an important role in mediating cell survival and the up-regulation of many cytokines and pro-inflammatory mediators essential to the host and ERK1/2 has been reported to mediate transcription of proteases and cytokines in response to a variety of stimuli, including cigarette smokes.[62
In experimental systems, exposure to chewable tobacco products was associated with the generation of reactive oxygen species, modulation of inflammatory mediators and inhibition of collagen synthesis and impairment of DNA repair capacity.[63
] This study also showed an unique trends of IL-18 expression in subjects with prostate cancer, betel chewers alone and betel chewers with alcohol drink showed only slight increase in inflammatory levels as compared to non-users. This could be because of the anti-oxidant properties of betel as shown previously by researchers.[64
] Similarly, areca nut or seed is consumed simultaneously with betel and gutkha chewing which also has a strong antioxidant activity[66
] but slight increase may be due to tobacco use with it.
Mechanistic studies on murine model showed a concentration dependent decrease in the extracellular production of nitric oxide in peritoneal macrophages. This decrease in the generation of reactive nitrogen species was mediated by the down-regulating transcription of inducible nitric oxide synthase in macrophages with concomitant decrease in the expression of interleukin-12. This study indicates the ability of betel leaf to down-regulate T-helper 1 pro-inflammatory responses.[67
] Another reason of difference in level of IL-18 during chewing and smoking may be due to its way of exposure as it may comes quick contact in blood through smoking via lungs and chewing take quite more time and it acted by several enzymes of gastro-intestinal tract.
In this study, the difference in Interleukin-18 levels in various modes may be due to processed and unprocessed tobacco or its products in its chewing form and smoking form. Our study does not prove that tobacco is an etiological factor for cancer prostate. Our study however, shows that the levels of inflammation (as measured by IL-18) are higher in man with prostate cancer who are smokers, gutkha users and combined tobacco and alcohol users. In our previous study, we demonstrated that the levels of serum IL-18 were well correlated with disease progression (TNM staging) of various groups and elevated in patients of carcinoma prostate as compared to controls.[14
The current novel pro-inflammatory markers of IL-18 is also documented with its higher expression in various other carcinoma as gastric,[29
] and oesophageal carcinoma.[31
] The pathways for IL-18 production are well documented but its clear mode of action in patients with prostate carcinoma is not well documented. The IL-18 performs its various biological activities via its capacity of stimulating innate immunity and both Th1 and Th2-mediated responses.[68
] It can also be speculated that IL-18 production by the normal adjacent prostate cells may reflect the degree of defense mechanism against tumor growth and dissemination of prostate carcinoma.[69
] This study may become more imperative if larger sample size included and some parameters like various occupational exposures may be included, but we try to reduce biases and confounding as patients from all occupational sites included, who come for treatment during study time. Strongest point of this study is this novel pro-inflammatory marker (IL-18) is measured first time in tobacco exposed group and with various modes and stratified manners. This type of study will definitely solve the puzzle of tobacco exposure in development of various untreated disease like cancers.