Negative Effects Of Direct And Second Hand Smoke On Health

Tobacco or cigarette smoke contains thousands of harmful toxins, carcinogens and chemicals that enter the bloodstream and thereby travel to every other organ in the body. The inhaled smoke progresses down through the windpipe and eventually into the bronchial tubes. The toxic smoke then slowly enters into the bronchioles, which contain the minuscule clusters of air sacs known as alveoli, where it begins to impact the thin delicate walls of the alveoli and further inhibits the physiological functioning of the lung. The toxins found in the smoke possess the ability to cause inflammation and cell damage. In chronic smokers, the leucocyte count in the blood is constantly high in order to fight against the consequential damage. The immune system of a smoker is weak and less efficient in counteracting the inflammatory response triggered by cigarette smoke. Prominent metabolic alterations and changes in morphological and morphometric parameters have been studied in the polymorphonuclear neutrophils of chronic smokers.

Over a period of time, the carcinogens present in tobacco and cigarette can lead to mutagenic and genotoxic effects. The passive smoker along with the habitual smoker is susceptible to DNA damage and subsequently is at the risk of tumor development and cancer. There are different types of toxicants found in tobacco and cigarettes including organic and inorganic chemicals such as Nicotine, hydrogen cyanide, carbon monoxide, formaldehyde, benzene, toxic metals, radioactive toxic metals, ammonia, and polycyclic aromatic hydrocarbons. These chemicals collectively exert their properties as they enter into the body via the bloodstream. Many of these substances can inflict serious health problems such as difficulty in breathing, bronchial asthma, fatigue, weakness, chronic bronchitis, severe irritation in the eyes, ears, nose and is the main cause of lung and throat cancer.

According to reports published by the World Health Organization, smoking is the foremost cause of Chronic obstructive pulmonary disease (COPD) and this includes smoke from cigarettes, cigars, and pipes as well as secondhand tobacco smoke exposure. The molecular mechanisms of these diseases include specific modifications in key biological structures such as alveolar epithelial cells, which are vital in the maintenance of normal alveolar architecture and function. Frequent exposure to cigarette smoke subsequently result in particular adjustments in the alveolar epithelial cells that stimulate a rapid increase in epithelial permeability, a decrease in surfactant production, and inappropriate production of inflammatory cytokines and growth factors, provoking an increased risk of lung cancer. Supposedly, Cell death was observed to be the most detrimental effect of cigarette smoke on alveolar epithelial cells such as either apoptosis or necrosis influenced by the immensity of cigarette smoke exposure. The toxic smoke-induced cell death mechanisms largely governs the enhancement of oxidative stress. This cigarette smoke contains carcinogens and generates free radical species that is destructive to the alveolar epithelial cells.

Recent experimental studies indicate that the apoptosis of alveolar epithelial cells and alveolar endothelial cells is involved in the pathogenesis of lung diseases such as pulmonary emphysema and asthma. Oxidative stress in Lung diseases Oxidative stress is the underlying cause for an imbalance between the systemic manifestation of ROS and the biological system's potentiality to swiftly detoxify the reactive intermediates and to restore the consequent damage. Under normal metabolism ROS are released in multiple biologic processes and signal cascades that include normal tissue homeostasis and cell signaling, however rapid changes to local and global levels of reactive species directly promote the development of several human diseases. The Reactive oxygen species (ROS) are chemically reactive chemical species produced in vivo by endothelial, inflammatory and immune cells by various cellular pathways as a byproduct of the metabolic processes and exhibit predominant roles in oxidative stress and tissue injury, along with its participation in redox signaling. These ubiquitous molecules include variant species, such as superoxide anion, hydrogen peroxides, alpha oxygen and hydroxyl radicals.

The respiratory system primarily provides abundant supply of oxygen (O2) to all the tissues, in order to corroborate normal oxygen homeostasis and organ functions. In the lung, constant exposure to gaseous oxygen and ROS, are quelled by nonenzymatic and enzymatic antioxidant defenses, such as glutathione (GSH), superoxide dismutase, and catalase. However, the available large surface area for gas exchange makes the pulmonary system particularly susceptible to oxidative stress-mediated injury including high environmental O2 concentration in the lung and exogenous pollutants such as cigarette and tobacco smoke inhaled through the breath subsequently provoke the production of pro-oxidant reactive oxygen species (ROS) and reactive nitrogen species (RNS).

The antioxidant defense system becomes overwhelmed and fails to effectively counteract the stress mechanisms, leading to the development of various pulmonary diseases. In particular, chronic inflammation-induced production of ROS in the lung predisposes an individual to lung damage and cancer development. The generation of reactive species is not restricted to pathogen defence. These molecules are essential in mitochondrial respiration as part of the electron transport chain. During the reaction in which electrons rapidly shift from donors to acceptors, they influence the transfer of protons across membranes. The role of ROS in multiple intracellular signaling pathways occurs on the macromolecular level, whereby proteins interacting with proteins, ligands with receptors, with shape and surface charge being key to specificity. One such example is protein tyrosine phosphatases (PTPs) which can be inactivated in the presence of hydrogen peroxide and is reversible with glutathione along with other thiols. The intracellular release of ROS is able to potentially regulate tyrosine phosphorylation, and therefore kinase mediated signaling in multiple pathways. This may result in the progression of COPD where the particular PTP domain containing protein, phosphatase and tensin homolog (PTEN) plays a crucial role in the activation and migration of neutrophils, dynamically linked with COPD pathogenesis.

A complete understanding of the mechanisms of oxidant stress and the fundamental role of oxidants in lung disease pathogenesis paves the way to the development of improved therapeutic strategies. The reactive species trigger the pathogenesis of various lung diseases, such as acute respiratory distress syndrome, COPD, asthma, interstitial pulmonary fibrosis and lung cancer. Exposure to cigarette and tobacco smoke majorly contributes to about 80%-90% of the COPD and lung cancer cases.

In the past few decades, protease/antiprotease imbalance and inflammatory processes have been proposed to act as downstream effectors of the lung destruction following persistent tobacco and cigarette smoking. It is believed that apoptosis is a major step occurring in the alveolar cells that result in prominent lung damage. A Recent study highlighted the significant production and time-dependent increase in the proportion of apoptotic cells in bronchial, bronchiolar epithelium and also of alveolar macrophages in those rats chronically exposed to cigarette smoke. Another study has reported the manifestaton of oxidative stress, apoptosis and excessive proteolytic injury in cigarette smoke induced human lung fibroblasts as well as epithelial cells in vitro.

Oxidative Stress markers

In the lungs of several smoke induced pulmonary disease patients, reactive oxygen species (ROS) and reactive nitrogen species (RNS) are rapidly released from the inflamed leukocytes and macrophages. These reactive species have the potentiality to cause oxidative damage to DNA, lipids, carbohydrates and proteins, and thereby initiate an array of downstream processes that promote the development and progression of chronic pulmonary diseases (COPD). They rapidly interact with the resident cells in the lung, particularly epithelial cells and alveolar macrophages, to activate and trigger the chemotactic molecules that recruit additional inflammatory cells such as neutrophils, monocytes and lymphocytes into the lung, which in turn enhances the intensity of oxidative stress in the lung.

Precisely, all these events together lead to a vicious cycle of insistent inflammation, accompanied by chronic oxidative stress, which lead to prolonged interference in the protease-antiprotease balance, disruption in the tissue repair mechanisms, enhanced apoptosis and accelerated autophagy in lung cells, which collectively hasten the pathophysiological events of COPD. An experimental study investigated the significant relationship between the level of urinary excretion rate of the oxidized nucleoside 8-hydroxydeoxyguanosine (8-OHdG) and prevailing clinical factors in lung cancer patients. It has been reported that cigarette and tobacco smoking possess the ability to accelerate the urinary excretion rate of 8-OHdG, further more resulting in destructive oxidative DNA modifications.

In yet another extensive study, the consequential role of four oxidative stress markers have been implicated in the pathogenesis of cigarette smoke induced lung cancer. The oxidative stress biomarkers such as pH, 8-isoprostane, Hydrogen peroxide concentration and antioxidant capacity between lung cancer patients and healthy are found to cause mutational changes in the genome of cells and have been detected in high levels in the exhaled breath of smokers. Tobacco smoke is one of the most important causative factors of lung cancer as it leads to chronic airway inflammation and activation of cells, which directly result in the production of high levels of nitric oxide and its metabolites interact with reactive oxygen species (ROS) and trigger the generation of other reactive products with potential carcinogenicity.

A recent experimental study examined the prospective function of two specific oxidative stress markers in the pathological process of lung cancer. Supposedly, urinary metabolites such as 8hydroxyguanosine (8OHG) and 8hydroxy 2deoxyguanosine (8OHdG) were identified as biomarkers of oxidative DNA and RNA damage as well as markers of cancer growth and development. The nitric oxide molecules regulates modifications in tumor necrosis factor alpha (TNFα). They sensitize the lung tumor cells to TNFα-mediated cytotoxicity via inhibition of NF-κB activation and increase the occurrence of oxidative damage. They are primarily responsible for cytogenetic changes in the lung and increased cell proliferation.

Researchers have examined and quantified the presence of various metabolites in urine, blood and breath which significantly unveil reliable information on human exposure to carcinogens in tobacco and cigarettes. Marina Sarkele et al (2014) conducted an extensive study to analyze the association between the level of oxidative stress biomarkers to the consequential effects in patients with acute respiratory distress syndrome. They investigated the variance between oxidants and antioxidants in the initiation of acute respiratory distress syndrome. Lipid peroxidation provokes intracellular death and particulary modify the proteins and DNA. The main goal of the study was to measure the level of oxidative stress related molecules such as malondialdechyde and 4-hydroxinonenal as well as antioxidative molecules including superoxiddismutase, glutathionperoxidase, tocopherol and analyze their clinical significance.

Antioxidant Defense system

The antioxidant defense system contains a complex system of substances that detains, inhibits or eliminates oxidative damage to a target molecule. The human body contains an enzymatic and non-enzymatic antioxidant defense system which is a highly interconnected network that depends on the dietary intake of antioxidants as well as the endogenous production of antioxidative compounds such as glutathione. These free radical scavengers can act at distinct levels and by multiple mechanisms in the oxidative sequence. Antioxidants can be categorized into a number of diverse groups such as Antioxidant enzymes: Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GSR) Antioxidative proteins: Hemoglobin, ceruloplasmin, transferrin, albumin, lactoferrin Small-molecular-weight compounds inclusive of ascorbic acid (vitamin C), tocopherols (vitamin E), glutathione (GSH), uric acid, selenium, bilirubin, glucose Ubiquinone (coenzyme Q-10), Flavonoids , Protein sulfhydryl (SH) groups (thiols). Among the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx or GSH-Px) play a crucial role. These enzymes are proteins which catalyze several important reactions to prevent damage from the reactive species. Studies have mentioned the function of SOD and CAT in the cell cytoplasm and in the line of defense against various harmful oxidants, e.g. superoxide anion and hydrogen peroxide. There are numerous different isoforms of SOD which exist with multifold active metals in the center and different amino acid constituency. Studies have found that there are three different forms of SOD such as acytosolic-CuZn-SOD, mitochondrial Mn-SOD, and extracellular SOD in humans. These scavengers primarily convert the free radical superoxide species into either ordinary molecular oxygen (O2) or hydrogen peroxide (H2O2) which are further catalyzed into by-products.

One of the most well recognized adaptive antioxidant defense system in the body is the thiol and glutathione complex. It functions as a conventional redox buffer against the toxic free radicals for maintenance of cellular homeostasis and function. Most living organisms produce glutathione which is a tripeptide containing a glutamate side chain with an amine group of cysteine at its carboxylate side which in turn is attached to a peptide glycine. GSH is a nonprotein sulphydryl in the cells and efficiently contributes to the maintenance of the cellular redox status. The oxidation/ reduction potential is described as a measure of correlation of the concentration of oxidizing equivalents to that of reducing equivalents . Extensive research has determined the multifold properties of glutathione such as the protective defense mechanism against oxidants, cell proliferation, catalytic and metabolic functions, protein synthesis and transport.

The primary role of GSH is inducing the detoxification of lipid peroxidation products and protect against radiation-induced cell damage and other adverse events. There are different forms of glutathione such as the reduced and disulfide (GSSG) form, mixed disulfides combined with various proteins, leukotrienes, and other metabolites. GSH and GSSH participate in a range of cellular processes including cellular signaling apoptosis and gene expression. This defence system is one of the most efficient, particularly in association with GSH peroxidase (GPX), GSH reductase (GSR), and the hexose monophosphate shunt system. These antioxidant enzymes play a substantial role in the maintenance of the cellular reductive potential. While several other enzymes/proteins participate in the redox system of the cell and their genes, including manganese superxide dismutase, glutamate cysteine ligase, glutathione peroxidase, thioredoxin reductase, and metallothionein. They are stimulated by various manipulation mechanisms of the cellular GSH/GSSG levels in reaction to various oxidative stresses, including hyperoxia and inflammatory mediators, such as tumor necrosis factor (TNF)-α and lipopolysaccharide (LPS), in lung cells. Glutathione plays a critical role in the Nrf2-inducible glutathione-S-transferase system that catalyzes the specific fusion of GSH with endogenous and exogenous electrophilic compounds. These Glutathione-fused electrophiles can be exported from cells through multidrug resistance–associated proteins (MRPs). Additionally, the genes that encode the MRPs also have an antioxidant response element in their 5′-flanking region that is triggered by binding to Nrf2.

Overall, the Antioxidant scavenging system can be precisely enhanced by altering the nutrition intake , particularly vitamins, trace elements and important amino acids that have either direct antioxidant effects, or serve as precursors / cofactors for antioxidant enzymes. Cigarette smoke inhalation is the molecular link between oxidative stress and development of several lung diseases. Chronic cigarette smokers suffer from recurrent inflammation, cell damage, protease – antiprotease imbalance, loss of interstitial matrix, and alveolar wall cell death. Collectively, these events lead to necrosis, apoptosis and anoikis death by detachment from extracellular matrix. The protective mechanisms of the respiratory system consisting of the epithelial mucus layer and the mucociliary escalator act as a barrier between the epithelial cells and toxic particles such as microorganisms and allergens. Researchers have investigated a decrease in the vascular endothelial growth factor (VEGF) and the VEGF receptor R2 protein in several smoke induced pulmonary diseases which subsequently lead to an increased epithelial and endothelial cell death. Improvement of several antioxidant based strategies help in overcoming the destructive effects of toxic free radicals in the system.

Summary and Conclusion

There is now considerable evidence supporting an increased risk of lung diseases including lung cancer in chronic cigarette or tobacco smokers.

Millions of people all over the world suffer tremendously due to the direct usage of tobacco and owing to the exposure to second hand smoke. According to WHO reports, smoking generates a staggering amount of 7 million deaths annually. Chronic smoking is majorly responsible for most of the lung diseases as they are found to cause morphological changes to the respiratory tract. The numerous toxic chemicals present in the smoke directly damage the first line of defense in the upper respiratory tract and further more lead to reduced cell viabilty, enhanced inflammatory processes and induction of apoptosis in the respiratory hair cells. There exists a definite complex relationship between duration of smoking, oxidative stress and onset of pulmonary diseases.