Oxidative stress occurs when there is an imbalance between reactive oxygen species (ROS) and antioxidants, leading to cellular damage. ROS are generated through normal metabolic processes and environmental exposures like cigarette smoke and air pollution. They play roles in signaling but can cause harm in excess. Antioxidants like superoxide dismutase and glutathione normally counteract ROS. In respiratory diseases like asthma, emphysema, and pulmonary fibrosis, oxidative stress is elevated due to increased ROS and/or depleted antioxidants, contributing to airway inflammation and tissue injury. This oxidative damage may be a therapeutic target through antioxidants or reducing environmental oxidant exposures.
Reactive Oxygen Species in Signal Transduction and its applicationsMostafa Mohamed
Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling
Applications for Drugs Targeted to Increase ROS in Cancer Treatment
During favorable conditions, the level of reactive spices in the cell is limited to what is required for normal cellular activities. They act as important components of signaling pathways. Plants control some important processes such as defense, hormonal signaling and development by using them as signaling molecules. And An equilibrium is steblished between antioxidant system and ros formation. But when plant feels an external stress like, drought,cold, salt etc. the level of reactive specease increases above the basal level a situation that we call oxidative stress. These reactive molecules during oxidative stress, they react with biomolecules like as carbohydrates, unsaturated lipids, proteins, nucleic acids. Proteins are the most abundant cellular targets of the oxidative species, more than DNA and lipids, making up 68% of the oxidized molecules in the cell. Ros reacts with proteins which results in protein modification called redox PTMs.
Reactive Oxygen Species in Signal Transduction and its applicationsMostafa Mohamed
Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling
Applications for Drugs Targeted to Increase ROS in Cancer Treatment
During favorable conditions, the level of reactive spices in the cell is limited to what is required for normal cellular activities. They act as important components of signaling pathways. Plants control some important processes such as defense, hormonal signaling and development by using them as signaling molecules. And An equilibrium is steblished between antioxidant system and ros formation. But when plant feels an external stress like, drought,cold, salt etc. the level of reactive specease increases above the basal level a situation that we call oxidative stress. These reactive molecules during oxidative stress, they react with biomolecules like as carbohydrates, unsaturated lipids, proteins, nucleic acids. Proteins are the most abundant cellular targets of the oxidative species, more than DNA and lipids, making up 68% of the oxidized molecules in the cell. Ros reacts with proteins which results in protein modification called redox PTMs.
Oxidative stress is the main metabolic process that causes mitochondrial dysfunction. In this presentation we show different oxidative stress pathways and the main solutions to prevent mitochondrial damage by using non enzymatic antioxidants and boosting antioxidant enzymatic systems.
Just regarded to those who trying to learn somethings.. . thanks to those who read this slide... Just pray for me , for my parents and for my teachers...
in this presentation, the light is focused on discussing the Reactive oxygen species, oxidative stress, how it forms, how it affects the body and what are the diseases that correlate with oxidative stress.
nevertheless, how it can be balanced by the antioxidants and what is their role in oxidative stress.
Oxygen is an essential and fundamental term for life. Cells use oxygen to
produce energy for normal cell activities, Free radicals are normal
consequence of ATP production in the mitochondria. These by-products
are in general reactive oxygen species (ROS) and reactive nitrogen
species (RNS). These two species are referred collectively as ROS/RNS.
The phrases "free radicals" and "reactive oxygen species" (ROS) are
frequently used interchangeably although this is not always correct. The
physiological state of increased steady-state ROS level along with certain
physiological effects has been called oxidative stress. These species play
a dual role. As benefit compounds at low or moderate levels. And as toxic
compounds at high concentrations by generation of oxidative stress .The
delicate balance between their two antagonistic effects is clearly an
important aspect of life [1-5]. Free radicals are, by definition, species
which contain an odd number of electrons. They may be positively
charged, negatively charged, or neutral and all three types are important
Free radicals in human diseases and the roleMohammed Sakr
Free radicals reactive oxygen species and reactive nitrogen species are generated by our body by various endogenous systems, exposure to different physiochemical conditions or pathological states. A balance between free radicals and antioxidants is necessary for proper physiological function. If free radicals overwhelm the body's ability to regulate them, a condition known as oxidative stress ensues. Free radicals thus adversely alter lipids, proteins, and DNA and trigger a number of human diseases. Free radicals are a main cause of cardiovascular diseases, cancer, aging and immune defense disorders. Foods like berries and carrot protect us against free radicals.
Oxidative stress is described as the imbalance between pro-oxidants (Reactive oxygen species) and antioxidants levels commonly called redox imbalance. It occurs in a discrete step-wise process of initiation, propagation, and termination stages via the generation of free radicals. These steps bring about effects that have contributed to hypertension through endothelial dysfunction, reduced bioavailability of Nitric oxide, atherosclerotic plaque formation, and reduction of toxic oxidants. Hence, oxidative stress mechanism is implicated in hypertension and thus, the daily intake of antioxidants-containing foods and products to supplement depleted endogenous antioxidants is recommended.
definition, properties, types of free radical, neurodegenerative disorder, cardiovascular disease, and cancer due to free radicals, importance of antioxidants and their role.
Oxidative stress is the main metabolic process that causes mitochondrial dysfunction. In this presentation we show different oxidative stress pathways and the main solutions to prevent mitochondrial damage by using non enzymatic antioxidants and boosting antioxidant enzymatic systems.
Just regarded to those who trying to learn somethings.. . thanks to those who read this slide... Just pray for me , for my parents and for my teachers...
in this presentation, the light is focused on discussing the Reactive oxygen species, oxidative stress, how it forms, how it affects the body and what are the diseases that correlate with oxidative stress.
nevertheless, how it can be balanced by the antioxidants and what is their role in oxidative stress.
Oxygen is an essential and fundamental term for life. Cells use oxygen to
produce energy for normal cell activities, Free radicals are normal
consequence of ATP production in the mitochondria. These by-products
are in general reactive oxygen species (ROS) and reactive nitrogen
species (RNS). These two species are referred collectively as ROS/RNS.
The phrases "free radicals" and "reactive oxygen species" (ROS) are
frequently used interchangeably although this is not always correct. The
physiological state of increased steady-state ROS level along with certain
physiological effects has been called oxidative stress. These species play
a dual role. As benefit compounds at low or moderate levels. And as toxic
compounds at high concentrations by generation of oxidative stress .The
delicate balance between their two antagonistic effects is clearly an
important aspect of life [1-5]. Free radicals are, by definition, species
which contain an odd number of electrons. They may be positively
charged, negatively charged, or neutral and all three types are important
Free radicals in human diseases and the roleMohammed Sakr
Free radicals reactive oxygen species and reactive nitrogen species are generated by our body by various endogenous systems, exposure to different physiochemical conditions or pathological states. A balance between free radicals and antioxidants is necessary for proper physiological function. If free radicals overwhelm the body's ability to regulate them, a condition known as oxidative stress ensues. Free radicals thus adversely alter lipids, proteins, and DNA and trigger a number of human diseases. Free radicals are a main cause of cardiovascular diseases, cancer, aging and immune defense disorders. Foods like berries and carrot protect us against free radicals.
Oxidative stress is described as the imbalance between pro-oxidants (Reactive oxygen species) and antioxidants levels commonly called redox imbalance. It occurs in a discrete step-wise process of initiation, propagation, and termination stages via the generation of free radicals. These steps bring about effects that have contributed to hypertension through endothelial dysfunction, reduced bioavailability of Nitric oxide, atherosclerotic plaque formation, and reduction of toxic oxidants. Hence, oxidative stress mechanism is implicated in hypertension and thus, the daily intake of antioxidants-containing foods and products to supplement depleted endogenous antioxidants is recommended.
definition, properties, types of free radical, neurodegenerative disorder, cardiovascular disease, and cancer due to free radicals, importance of antioxidants and their role.
A brief introduction about Pharmacology of free radicals, generation of free radicals, Antioxidants, Free radicals causing disorders such as cancer diabetes, neuro degenerative disorders such as Parkisonism's Disease
Free radical reactions are expected to produce progressive adverse changes that accumulate with age throughout the body. Such “normal” changes with age are relatively common to all.
However, superimposed on this common pattern are patterns influenced by genetics and environmental differences that modulate free radical damage.
These are manifested as diseases at certain ages determined by genetic and environmental factors.
Cancer and atherosclerosis, two major causes of death, are salient “free radical” diseases. Cancer initiation and promotion is associated with chromosomal defects and oncogene activation. It is possible that endogenous free radical reactions, like those initiated by ionizing radiation, may result in tumor formation.
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
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Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
2. INTRODUCTION
• Molecular oxygen is a prerequisite to life of all aerobic organisms.
• High concentrations of oxygen or its metabolites, referred to as reactive
oxygen species (ROS), have the potential to cause cellular injury and
contribute to disease pathogenesis.
• The most damaging forms of ROS are free radicals.
• A free radical, by definition, refers to any chemical species containing one
or more unpaired electrons in their atomic or molecular orbitals.
• Unpaired electron(s) give considerable reactivity to free radical species,
which can trigger chemical reactions that damage cellular constituents of
living organisms.
3. • O2 can form the superoxide anion radical (O2
- ) upon addition of an electron;
thus, overcoming this restraint and making it a highly reactive species.
• When two free radicals share their unpaired electrons, nonradical species of
lower reactivity are generated.
• Thus, ROS constitute both free radicals and nonradicals
4. NITRIC OXIDE
• Nitric oxide (NO•) is another small gaseous molecule that serves as an
important signaling molecule in diverse physiological processes, including
vasorelaxation and immune regulation during chronic inflammation in the
lung.
• The regulated production of NO• by lung cells is critical for homeostasis of
the lung
• The reaction of NO• with (O2
- ) to form reactive nitrogen species (RNS),
such as peroxynitrite (ONOO–), may contribute to the pathophysiology of
chronic lung diseases.
5. • ROS and RNS together play important roles in regulation of cell
proliferation, differentiation, and survival
• ROS/RNS can inactivate enzymes including antiproteases, induce
apoptosis, regulate cell proliferation, and modulate the immune-
inflammatory system in the lungs and other tissues
• ROS/RNS have been implicated in initiating inflammatory responses in the
lungs through the activation of transcription factors, protein kinase
pathways, chromatin remodeling, and gene expression of
proinflammatory mediators.
• Under normal physiological conditions, the balance between generation
and elimination of ROS/RNS maintains the functional integrity of redox-
sensitive signaling cascades regulating cellular phenotypes.
6. • Redox homeostasis of cells/tissues is maintained by the regulated balance
of oxidant production and antioxidant systems, both enzymatic and
nonenzymatic
• An increase in oxidant generation in excess of the capacity of
cells/tissues to detoxify or scavenge reactive species leads to OXIDATIVE
STRESS
• Oxidative stress typically causes damage to cellular components in an
indiscriminant manner.
• Such states are accelerated in the presence of transition metals, such as
iron and copper, and/or specific monooxygenases or oxidases.
7. An imbalance between reactive oxygen species and antioxidants can lead to elevated
stress. A, Normally, there are sufficient antioxidants in the respiratory tract such that the
production of a small amount of reactive oxygen species is inconsequential.
B, If either antioxidants are diminished or production of reactive oxygen species is
increased (eg, during an asthma exacerbation), the balance of antioxidants and reactive
oxygen species is tipped toward oxidative stress.
8.
9. SOURCES OF ROS/RNS
• The primary ROS include superoxide anion (O2
- ), hydrogen peroxide
(H2O2), and hydroxyl radical (•OH), which can be generated from both
enzymatic and nonenzymatic sources.
• Normal metabolic processes in all cells are the major source of reactive
oxygen species.
• The human lung is constantly exposed to ambient air, which may contain
environmental toxins capable of inducing ROS generation.
• ROS may also be generated by electron transfer reactions in the
mitochondria and endoplasmic reticulum (ER), from xenobiotics, and a
range of metabolic enzymes that catalyze oxidation reactions
10. • Additional major sources of superoxide include the membrane oxidases,
such as the cytochrome P450 and b5 families of enzymes in the
endoplasmic reticulum2 and the reduced nicotin- amide adenine
dinucleotide phosphate oxidases of phagocytic cells.
• Direct exposure to environmental air is an additional source of reactive
oxygen species exposure that is unique to the airways
• For instance, cigarette smoke inhalation results in increased exposure to
both superoxide and hydrogen peroxide.
• Cigarette smoke–mediated lung damage might also be a result of
increased exposure to nitric oxide and nitrites.
11. • Other sources of environmental oxidants include air
pollution, which contains ozone.
• Ionizing radiation is an efficient method of producing
reactive oxygen species in the laboratory but is a minor
contributor to reactive oxygen species in vivo
14. ENZYMATIC SOURCES OF RNS
• An important RNS in the lung is NO•, which is endogenously generated by
specific nitric oxide synthases (NOSs).
• NOS enzymes metabolize L-arginine to NO• and L-citrulline via a five
electron oxidation reaction which requires a dimeric enzyme, oxygen,
NADPH and the cofactors, flavin adenine dinucleotide (FAD), flavin
mononucleotide (FMN), tetrahydrobiopterin (BH4), calmodulin, and iron
protoporphyrin.
• There are three different NOS forms, all of which are expressed in the
lung, the inducible form iNOS or NOS2, neuronal NOS or NOS1, and the
endothelial NOS enzyme NOS3
15. • The NOS1 and NOS3 enzymes are calcium dependent and produce
picomolar levels of NO, while nanomolar levels are generated by the
calcium-independent iNOS.
• NO• synthesis by iNOS is regulated by the availability of the substrate L-
arginine and cofactor BH4.
• Uncoupling of NOS enzymes can contribute to the formation of the O2
- .
• It has also been reported that iNOS can specifically bind to cyclooxgenase-
2 (COX-2) and S-nitrosylate COX-2, upregulate its catalytic activity and
enhance prostaglandin E2 production.
• RNS may also mediate lipid peroxidation, protein oxidation and nitration,
enzyme inactivation, or even cell necrosis.
16. SUPEROXIDE DISMUTASES
• It participates in the generation of other reactive metabolites, H2O2, •OH,
and ONOO–.
• SODs represent a key defense against reactive species generated during
normal metabolism or inflammatory states.
• SODs are ubiquitous enzymes that catalyze the dismutation of O2
- radical
to the weaker oxidant, H2O2.
• EC-SOD normally protects the lungs against fibrosis by preventing
oxidative degradation of the matrix and by binding type I and type IV
collagen via its heparin/matrix binding domain.
17. • Three mammalian SOD isozymes:
1. The intracellular copper-zinc SOD (CuZn-SOD)
2. The mitochondrial manganese SOD (Mn-SOD)
3. Extracellular SOD (EC-SOD)
18.
19. Reactive oxygen species and antioxidant enzymes in airways. A, Environmental sources include
ozone (O3) and hydrogen peroxide (H2O2) from air pollution and cigarette smoke. Intracellular
sources include mitochondrial respiration, xanthine oxidase (XO), and P450 and cytochrome b5
enzymes; hydrogen peroxide is a product of superoxide dismutases (SOD), such as Cu,Zn SOD
and mitochondrial DOS (Mn- SOD), as well as other oxidases, such as those found in
peroxisomes. Extracellular sources of reactive oxygen species include membrane oxidases
(Mox) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases of
eosinophils (EOS) and neutrophils (PMN).
20. Antioxidants found in airways include the SODs, glutathione peroxidase (Gpx)
and catalase (Cat), thrioredoxin (Trx), and the low-molecular-weight
antioxidants glutathione (GSH), vitamin C (ascorbate), and vitamin E (α-
tocopherol
21. The major endogenous ROS/RNS and the primary mechanisms for their
generation are summarized
23. IMMUNE SOURCES AND ROS/RNS
REGULATION
1. IMMUNE CELLS
• NO• participates in pathogen killing by macrophages.
• It also delays fusion of phagosomes with lysosomes to form a functional
phagolysosome, which enhances antigen processing/presentation of
macrophages.
• Macrophages scavenge endogenous dying cells.
• Phagocytosis of dying cells requires the secretion of alarmins by dying cells
to attract and preactivate phagocytes; these signals by dying cells ensures
specific recognition and phagocytosis/efferocytosis, all of which involve
redox regulation.
24. 2. ENDOTHILIAL CELLS
• The importance of ECs in inflammation-induced vascular dysfunction is
dependent on their ability to produce and respond to ROS and RNS.
• Targeting ROS-quenching enzymes catalase and SOD , it alleviates toxic
effects of excessive ROS and suppresses proinflammatory mechanisms,
including endothelial cytokine activation and barrier disruption.
• Pulmonary EC-derived ROS play a pivotal role in EC activation and
function.
• Alterations in EC phenotype contribute to vascular tone, permeability, and
inflammatory responses and, thus, have been implicated in lung diseases,
including pulmonary hypertension, ischemia-reperfusion (IR) injury, and
adult respiratory distress syndrome.
25. 3. FIBROBLASTS
• Fibroblasts and fibroblast-like mesenchymal cells participate in innate
immunity and in tissue repair.
• Epithelial-to-mesenchymal transition (EMT) is a process regulating cell
plasticity, which allows epithelial cells to lose their polarity and specialized
junctional structures, to undergo cytoskeletal reorganization, and to
acquire morphological and functional features of mesenchymal like cells.
• Myofibroblasts are the primary “effector” cells in tissue remodeling and
pulmonary fibrosis.
• Activation of the NADPH oxidase isoform, NOX4, mediates generation of
H2O2, myofibroblast differentiation, contractility, and ECM production in
response to TGF-β1.
27. 1. ASTHMA
• ROS and RNS have been implicated in the pathogenesis of asthma.
• Dysregulation in pathways that lead to oxidative stress or its defense may
contribute to the initiation and severity of asthma.
• Leukocyte activation with induction of NADPH oxidase and production of
O2
- and H2O2 correlate negatively with FEV1 in asthmatic subjects.
• An increase in ROS production is inversely correlated with FEV1.
• Airway inflammation-associated oxidative stress in asthma may induce
oxidative modifications of proteins or lipids.
• Increased numbers of eosinophils and neutrophils in association with
higher expression of peroxidases and other markers of eosinophil
activation are found in bronchoalveolar lavage fluid (BAL) and bronchial
tissues of asthmatics
28. • ROS can decrease β-adrenergic function in lungs and sensitize airway
smooth muscle to acetylcholine-induced contraction.
• H2O2 activates mitogen-activated kinases in tracheal myocytes and
stimulates contraction of tracheal smooth muscle cells.
• ROS also stimulates mucin secretion, contributes to Th2 cell
differentiation, and promotes T cell proliferation via arginase and NADPH
oxidase pathways.
• Proinflammatory cytokines are elevated during airway inflammation,
which activate oxidases leading to increases in ROS, the targets of which
include receptor kinases, phosphatases, phospholipids, or nonreceptor
tyrosine kinases
29. • Exhaled NO• is increased in asthmatics and is associated with airway
inflammation.
• It is primarily iNOS that contributes to exhaled NO•.
• Induction of iNOS is observed at both transcriptional and translational
levels principally in steroid-naïve patients.
• Following antigen challenge, levels of NO• decrease, while nitrate
increases without perturbing levels of nitrite and SNO(S-nitrosothiols).
• Persistent increases in ROS and NO• lead to RNS formation and
subsequent oxidation and nitration of proteins, which contributes to the
dysregulation of airway inflammation in asthma
• High levels of ROS may overwhelm antioxidant defenses, causing
significant loss of antioxidant activity in asthma
30. • Global loss of SOD activity, due to SOD deficiency, loss of circulating SOD
activity, or inactivation of SOD via oxidative modification reflects the increased
oxidative stress in asthmatic patients.
• Oxidative modification-mediated reduction of catalase activity is also observed
in asthmatics.
• Although airway glutathione is increased in asthmatic patients, the ratio of
oxidized to reduced glutathione is elevated reflecting an oxidizing
microenvironment.
• Inhalation of exogenous ROS and RNS from exposures to environmental
pollutants including ozone, diesel exhaust particles, and oxidant components
of tobacco smoke, all contribute to additive oxidative stress, airway
hyperreactivity, and inflammation in asthma.
• Numerous cytokines, such as TNF-α, heparin-bound epidermal growth factor,
fibroblast growth factor 2, angiotensin II, serotonin, and thrombin, are found
in the lung during inflammation and activate oxidases that lead to increases in
reactive oxygen species in cell culture.
31. THERAPEUTIC IMPLICATIONS
• There are 2 strategies for treating oxidative stress asthma:
1. reducing exposure to reactive oxygen species
2. augmenting antioxidant defenses
• Reducing exposure to environmental oxidants, such as nitrites and ozone,
might decrease asthmatic exacerbations through the attenuation of the
activity of pulmonary inflammatory cells
• For instance, ozone decreases FEV1 by 12.5% compared with filtered air,
and children playing sports (hence more outdoor exposure) have a higher
prevalence of asthma in areas with high concentrations of environmental
ozone.
• Augmentation of existing antioxidant defenses with catalytic antioxidants
might also be useful in attenuating asthma and other respiratory disorders
32. 2.EMPHYSEMA
• Important contributing factors to the pathobiology of emphysema include
inflammation, alveolar epithelial cell injury/apoptosis, protease–
antiprotease and oxidant–antioxidant imbalances.
• Oxidative stress caused by cigarette smoke inhalation contributes to the
pathogenesis of emphysema.
• Cigarette smoke contains , •OH, and H2O2.
• ROS are also generated by the chronic inflammation, characteristic of
emphysema and that persists even after smoking cessation.
• Oxidative stress originating from constituents of cigarette smoke or
products of inflammatory cells can overcome the antioxidative capacity of
lung tissues and diminish antiprotease defenses
33. • A major consequence of oxidative stress is the activation of the
transcription factor nuclear factor-κB (NF-κB), which activates
transcription of proinflammatory cytokines
• Cigarette smoke also inhibits histone deacetylase, further promoting the
release of proinflammatory cytokines.
• Therefore, oxidant injury and lung inflammation act in concert to increase
alveolar destruction or compromise maintenance and repair of alveolar
structure.
• Antioxidant defenses are determinants of susceptibility to emphysema.
• A protective role for Nrf2, a transcription factor that regulates multiple
critical antioxidant enzymes, has been identified in pulmonary
emphysema.
34. • SOD mimetics abrogate alveolar cell apoptosis and emphysema in mouse
models.
• This blockade of apoptosis prevents oxidative stress and emphysema
further supporting the link between oxidative stress and apoptosis
35. 3. PULMONARY FIBROSIS
• IPF is characterized by exuberant ECM deposition, tissue contraction, and
apoptosis resistance of myofibroblasts, alongside apoptosisprone and
aberrantly differentiated alveolar type 2 cells.
• This loss of epithelial–mesenchymal homeostasis and communication is
central to the pathogenesis of IPF.
• Myofibroblasts are key effector cells in tissue remodeling and fibrosis,
typically contained in fibroblastic foci, which are a pathological hallmark of
IPF.
• Chronic inflammation, aberrant wound healing, and degenerative aging
processes have all been proposed as contributing to the pathogenesis of
IPF
36. • Oxidative stress is common to these processes and is implicated in IPF
pathogenesis.
• ROS/RNS released by phagocytes are involved in lung tissue damage in
interstitial lung diseases.
• IPF and pneumoconiosis may explain the high levels of hydroxyl radical
and superoxide anion concentrations in these diseases.
• Elevated oxidative and nitrosative stress in idiopathic pulmonary fibrosis
has also been demonstrated by increased levels of H2O2 in expired breath
condensate, increased eosinophilic mediators and myeloperoxidase
concentrations in BAL, enhanced levels of lipid peroxidation products
(such as 8-isoprostane) in BAL and condensate and elevated nitric oxide
concentrations in exhaled breath.
37. 4.PULMONARY ARTERIAL
HYPERTENSION
• Increased expression of ROS-generating enzymes, uncoupling of NOS
enzymes, and mitochondrial dysfunction all contribute to the oxidative
stress in PAH.
• Upstream dysregulation of ROS/NO• redox homeostasis impairs vascular
tone, which then triggers the activation of antiapoptotic and mitogenic
pathways, leading to cell proliferation and obliteration of the vasculature.
• Decreases in ROS inhibit a O2
- sensitive K+ channel leading to pulmonary
vascular constriction.
• ROS derived from the NOX2 and NOX4 isoforms are associated with
medial thickening, disordered proliferation and migration, impaired
angiogenesis, and disturbed fibrinolysis
38. • Xanthine oxidoreductases (XORs), including xanthine dehydrogenase (XD)
and xanthine oxidase (XO) are increased in idiopathic PAH patients.
• In hypoxia dependent PAH, hypoxia increases the expression of TGF-β1
and NOX4 expression.
• TGF-β–induced NOX4 expression and NOX4-mediated ROS production
have been implicated in PASMC (pulmonary artery smooth muscle cells)
proliferation.
• TGF-β1 also induces proangiogenic effects by upregulating VEGF.
• Nitrosative stress with increased nitrated eNOS is an early contributor to
the development of PAH. The vasodilatory effects of cGMP are mediated
through protein kinase G (PKG).
• This nitration-dependent reduction in PKG activity is observed in lungs of
patients with PAH. Nitration of carnitine acetyltransferase, an enzyme
that maintains normal mitochondrial function is another indicator of early
nitrosative stress in PAH
39. 5. ACUTE RESPIRATORY DISTRESS
SYNDROME
• ARDS is characterized by sudden onset, impaired gas exchange, and an
increase in pulmonary capillary permeability.
• Oxidative damage by ROS and RNS has been implicated in the pulmonary
vascular endothelial damage that characterizes ARD.
• The high inspiratory concentrations of oxygen required to achieve
adequate arterial oxygenation, infection, or extrapulmonary inflammation
lead to increased ROS production. This, combined with decreased
antioxidant capacity of tissues resulting from consumption of the natural
antioxidants leads to cellular damage and loss of vasomotor control.
• Measurements of antioxidant concentrations have revealed an oxidant–
antioxidant imbalance in ARDS patients
40. • The production of toxic levels of ROS and RNS not only leads to damage of
key molecules in cells but can signal changes in cellular responses such as
proliferation, apoptosis, and necrosis.
• H2O2 has been detected in the exhaled breath, while MPO and oxidized
α1-antitrypsin have been detected in BAL of ARDS patients.
• Nitration and oxidation of alveolar space proteins including the surfactants
have been identified ex vivo in patient samples with ARDS.
• Overabundance of ROS also induces adhesion molecules and cytokines
that contribute to endothelial injury.
41. CONCLUSION
• The lungs are exposed to exogenous oxidants from the environment, in
addition to endogenous generation of ROS/RNS from resident and
recruited inflammatory cells.
• Several measures of oxidative stress have been used to estimate oxidative
stress within the lungs; however, current approaches do not adequately
differentiate between different oxidative mechanisms and are used as
biomarkers of oxidative damage.
• Further investigations are needed to discover biomarkers that correlate
and differentiate between various types of oxidative injury
• A better understanding of factors that influence individual
susceptibilitywill also be useful in risk stratification of patients.
Investigations on how early life exposures to oxidants impact airway
morphology, immune function, and the airway epigenome may also aid in
determining susceptibility, disease expression, and progression