Free mainly composed of nicotine Their findings

Free radicals produced during the
hypersensitive response to pathogens have interesting implications for many
research fields. A number of immune cells including neutrophils eosinophils and
Macrophages have been shown to be an important component of host defense
against tumor1 as well as microbial killing. However, Cytotoxic
nature of phagocytes is thought to occur through a variety of effectors
pathways primarily through, the production of reactive oxygen species (ROS) and
reactive nitrogen species (RNS)2, generally known as Oxidative
burst.

For instance, one of the study showing role
of free radical in microbial killing and the study tells us that both the NADPH
phagocyte oxidase and iNOS contribute to the ability of macrophages to inhibit
or kill S. typhimurium. Analysis of murine peritoneal macrophages
reveals a temporally coordinated action of ROS and RNS. Rapid bacterial killing
coinciding with production of O2 by the NADPH phagocyte oxidase is followed by
a prolonged period of inhibition of bacterial growth associated with the
production of iNOS-derived nitrosative species.3 in another study chronic granulomatous disease
(CGD), where the respiratory burst is absent was studied that CGD cells are
essentially normal both morphologically and constitutionally except that
they lack a functional very low potential cytochrome b (b?245)9 which
is a component of the oxidase system responsible for the respiratory burst of
normal cells that decrese the potential of microbial killing4

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Research prove the role of efficient
microbial killing mainly by process of oxidative burst if the enzymes of
oxidative burst and phagocytosis process are suppressed experimentally then the
microbial killing will not be efficient the study conducted on use of cigarette
smoke mainly composed of nicotine Their findings
may partially explain the known increase in susceptibility to bacterial
infection and neutrophil-associated destructive inflammatory diseases in
individuals chronically exposed to nicotine.5

Our current
understanding of potential mechanisms of ROS damage comes primarily from
studies in Escherichia coli that have,
importantly, focused on cytoplasmic ROS/damage. Superoxide and hydrogen
peroxide (H2O2) are produced
inadvertently in the cytoplasm and kill the bacteria effectively.6 In contrast, if we talk about
salmonella infection, reactive oxygen species
are critical weapons in the phagocyte arsenal. In theory, O2- and nitric
oxide can combine to form highly reactive peroxynitrite (ONOO-). But both are temporally and genetically separable
during Salmonella infection, suggesting that ONOO- is irrelevant when combating this pathogen7.
Studies by Aussel et al,
reported in this volume, provide important information regarding Salmonella resistance to the ROS produced by
Phagocyte oxidase, and suggest that Salmonella relies
less on blocking ROS formation than on scavenging8.

Other studies suggested that the process of
oxidative burst can lead to efficient killing of bacteria, regardless of the
antigen specificity of the antibody. H2O2 production by antibodies alone was
found to be not sufficient for bacterial killing. Their study suggested that
the antibody-catalyzed water-oxidation pathway produced an additional molecular
species with a chemical signature similar to that of ozone. This species is
also generated during the oxidative burst of activated human neutrophils and
during inflammation. These observations suggest that alternative pathways may
exist for biological killing of bacteria that are mediated by potent oxidants
previously unknown to biology.

Overall,
variety of soluble and particulate stimuli induces extracellular superoxide
production. Most of the oxygen consumed can be accounted for as hydrogen
peroxide, which is formed from dismutation of the superoxide radical. However, hydrogen peroxide is
bactericidal only at high concentrations, and exogenously generated superoxide
does not kill bacteria directly. Therefore, a variety of secondary oxidants
have been proposed to account for the destructive capacity of neutrophils
(Fig 1). provides a summary of their properties.10

Fig. 1. Possible
oxidant generating reactions with stimulated neutrophils. NOS, nitric oxide
synthase; MPO, myeloperoxidase. (Hampton,etal)

NO
and ROS have a number of complementary, synergistic, and overlapping functions
in plants. This balance is achieved in a highly complicated network of
reciprocal regulation, The same mechanisms also affect important components of
the signal transduction cascade leading to disease resistance, such as kinases
and phosphatases, and expand its functions to the modulation of transcription
factor activity, and thus, of gene expression. The global picture of ROS-NO
interactions is far from being complete, but it already has been revealed as a
fascinating cross talk of mechanisms able to fine tune resistance responses.11

Indeed,
many chronic diseases could be the consequence of imbalance in free redical
production and elimination of infection. This imbalance or over proction of
reactive oxygen and nitrogen species eventually develop the inflammaotory
disease and cancer. Patients with chronic kidney disease (CKD) show a high
cardiovascular morbidity and mortality. This seems to be consequence of the
cardiovascular risk factor clustering in CKD patients. Non traditional risk
factors such as oxidative stress and inflammation are also far more prevalent
in this population than in normal subjects. Renal disease is associated with a
graded increase in oxidative stress markers even in early CKD. This could be
consequence of an increase in reactive oxygen species as well as a decrease in
antioxidant defence. This oxidative stress can accelerate renal injury
progression 12

Among the many pathogenic mechanisms for
parkinsons disease thought to contribute to the demise of neuronal cells,
dopamine-dependent oxidative stress has classically taken center stage due to
extensive experimental evidence showing that dopamine-derived reactive oxygen
species and oxidized dopamine metabolites are toxic to nigral neurons.13 Other study suggested that oxidative stress, inflammation and
arterial hypertension participate in a self-perpetuating cycle which, if not
interrupted, can lead to progressive cardiovascular disease and renal
complications.14

Cancer initiation and
progression has been linked to oxidative stress, a condition in which the balance
between production and disposal of reactive oxygen or nitrogen species is
altered. Oxidative stress has several pro tumorigenic effects, such as
increasing DNA mutation rate or inducing DNA damage, genome instability and
cell proliferation.15 However, one study revealed that increased
levels of DNA base oxidation products such as 8OHdg
(8-hydroxy-2?-deoxyguanosine) do not always lead to malignancy, although
malignant tumors often show increased levels of DNA base oxidation. Hence
additional actions of Reactive Species must be important, possibly their
effects on p53, cell proliferation, invasiveness and metastasis. Chronic
inflammation predisposes to malignancy, but the role of Reactive Species in
this is likely to be complex because RS can sometimes act as anti-inflammatory
agents.16

Cancer stem cells (CSCs) are
cancer cells that have the ability to generate tumors through the processes of
self-renewal and differentiation into multiple cells. Several studies have
found that tumors promote a constant influx of myelomonocytic cells that
express inflammatory mediators supporting pro-tumoral functions. Myelomonocytic
cells are key orchestrators of cancer-related inflammation associated with
proliferation and survival of malignant cells, subversion of adaptive immune
response, angiogenesis, stroma remodeling, and metastasis formation17 

Additionally,
two studies showed that CD133+ Cancer Stem Cells conferred chemoresistance to
cisplatin and doxorubicin (known ROS generators) in ovarian cancer cells18
and hepatocellular carcinoma19, respectively. These studies further
indicate that redox status may be important in maintaining CSC survival. Oxygen radicals may
augment tumor invasion and metastasis by increasing the rates of cell
migration. During transformation into invasive carcinoma, epithelial cells
undergo profound alterations in morphology and adhesive mode, resulting in a
loss of normal epithelial polarization and differentiation, and a switch to a
more motile, invasive phenotype. For example, treatment of mammalian carcinoma
cells with hydrogen peroxide prior to intravenous injection into mice enhances
lung metastasis formation, indicating that an important function for ROS is the
seeding of metastatic tumor cells 20. This might be due to a
decreased attachment of tumor cells to the basal lamina, or alternatively be
due to the increased activity or expression of proteins that regulate cellular
motility. For instance, oxidative stress regulates the expression of intercellular
adhesion protein-1 (ICAM-1), a cell surface protein in endothelial and
epithelial cells 21. On the other hand, it is believed that the
matrix metalloproteinases (MMPs) play the central role, and their increased
expression reportedly is associated with the invasion and metastasis of
malignant tumors 22 and  Oxidative
stress may also modulate MMP expression by activation of the rat sarcoma viral
oncogene (RAS), or direct activation of the MAPK family members
extracellular-signal regulated kinase 1/2 (ERK1/2), p38, and JNK, or
inactivation of phosphatases that regulate these proteins 23.

 

Fig 2: Model of the
sensitivity of normal cells versus cancer cells to reactive oxygen species
Reuter. S etal

Normal cells are
hypersensitive to ROS if not adequately protected by anti-oxidant mechanisms,
which may lead to cancer formation. Cancer cells, on the other hand, have
upregulated antioxidant mechanisms (glutathione, SOD, catalase, and others)
that will protect them against ROS, as can be observed in, for example, the
case of radioresistance.(fig 2) 24

Additionally the role is
free redical is also established for aging process.  Aging is a physiologic state in which a
progressive decline of organ functions is accompanied with the development of
age-related diseases. The causes of aging remain unknown, probably being
related to a multifactorial process. To date, the free radical and
mitochondrial theories seem to be the 2 most prominent theories on aging and
have survived the test of time. Such theories claim that oxidative stress
within mitochondria can lead to a vicious cycle in which damaged mitochondria
produce increased amounts of reactive oxygen species, leading in turn to
progressive augmentation in damage. If aging results from oxidative stress, it
may be corrected by environmental, nutritional and pharmacological strategies 25

Harman originally proposed
the “free-radical theory” of aging in the mid-1950s. He suggested that free
radicals produced during aerobic respiration have deleterious effects on cell
components and connective tissues, causing cumulative damage over time that
ultimately results in aging and death 26

Foods such as blueberries,
spinach, and spirulina, a blue-green algae with high oxygen radical absorbance
capacity 27 have also been studied extensively for neuroprotective
actions. For example, in the cerebellum there is a correlation between the loss
of function of ?-adrenergic receptors in the aged brain and a loss in the
ability to learn complex motor skills 28. Feeding aged F344 rats a
diet rich in spinach improves cerebellar ?-adrenergic receptor function and
improves motor learning that is associated with a decrease in oxidized
glutathione and the pro-inflammatory cytokine TNF? 29, 30

Several antioxidant defense mechanisms
have evolved to protect cell components from the attack of oxidative stress and
associated oxidative damage. These mechanisms include antioxidant enzymes, such
as SOD, superoxide reductases, catalase, glutathione peroxidases (Gpx), and
many heat-shock proteins. The hypothesis that lifespan can be enhanced by
increasing antioxidant defenses has been controversial because of conflicting
results in several aging models. For example, many studies have shown that
endogenous levels of antioxidant enzymes in the brain and other tissues do not
decrease during aging 31,32. Moreover, studies in mammals in which
levels of antioxidants are experimentally increased have shown that maximum
longevity is not affected33, 34. Experiments with Drosophila
melanogaster have shown that overexpression of MnSOD increased
lifespan35, while overexpression of CuZn-SOD had only minor
incremental effects on lifespan36.

Increasing evidence
associates aging and age-related diseases with inflammation 37-39.
The key cellular event signaling ongoing inflammation in the brain is the
accumulation of reactive microglia in the degenerative areas 40,41.
Microglia are the resident immune cells of the central nervous system; they
constitutively express surface receptors that trigger or amplify the innate
immune response. These include complement receptors, cytokine receptors,
chemokine receptors, major histocompatibility complex II, and others 42.
In the case of cellular damage, they respond promptly by inducing a protective
immune response, which consists of a transient upregulation of inflammatory
molecules as well as neurotrophic factors 43. This innate immune
response usually resolves potential pathogenic conditions. However, when
chronic inflammation occurs, prolonged activation of microglia triggers a
release of a wide array of neurotoxic products 44 and
proinflammatory cytokines such as interleukin-1 (IL-1?), interleukin-6 (IL-6),
tumor necrosis factor alpha (TNF?), and many others. Elevated protein levels of
IL-1?, TNF? and IL-6 have been found in the brains of aged animals 45,46

 

 

 

 

Fig 3: Oxidative
stress in brain cells Gemma C etal 49

It has been proposed
that the increase in brain microglial activation may be one of the early events
that leads to oxidative damage. Activated microglia are indeed the most
abundant source of free radicals in the brain and release radicals such as
superoxide and nitric oxide47. Microglia-derived radicals, as well
as their reaction products hydrogen peroxide and peroxynitrite, can harm cells
and these products have been shown to be involved in oxidative damage and
neuronal cell death in neurological diseases. It also should be noted that
microglial cells have efficient antioxidative defense mechanisms. These cells
contain high concentrations of glutathione, the antioxidative SOD enzymes,
catalase, glutathione peroxidase, and glutathione reductase, as well as
NADPH-regenerating enzymes 48. Though, oxygen is imperative for
life, imbalanced metabolism and excess reactive oxygen species (ROS) generation
end into a range of disorders such as Alzheimer’s disease, Parkinson’s disease,
aging and many other neural disorders. Toxicity of free radicals contributes to
proteins and DNA injury, inflammation, tissue damage and subsequent cellular
apoptosis. Antioxidants are now being looked upon as therapeutic against many
diseases, as they have capability to combat by neutralizing free radicals. Diet
is major source of antioxidants, as well as medicinal herbs are catching
attention to be commercial source of antioxidants at present. Recognition of
upstream and downstream antioxidant therapy to oxidative stress has been proved
an effective tool in alteration of any free radical related cell damage as well
as free radical scavenging so as to prevent cell damage in post-oxidative
stress scenario. 

Conclusion

This review clearly implicates the role of Reactive
oxygen species in different phases of diseases like chronic inflammation,
cancer and aging beside its role in bacterial killing. Therefore, targeting
redox-sensitive pathways and inhibiting the free radical generation by any
means can be of great promise for prevention and therapy of such vulnerable
diseases