Free radical induced injury

pathology

1. Free radical-Free radical-
induced injuryinduced injury
By: Pulak Agrawal
Roll. No.: 01

2.  Chemical species with single unpaired electron in outer
most orbit.(highly unstable)
Reactive oxygen and nitrogen species (RONS)
Attack & degrade membranes,protiens& nuclic acid to gain
stability.
Initiate autocatalytic reactions.
Free radical - what is it?Free radical - what is it?

3. Important free radicalImportant free radical
ROS/RNS
Free radicals
superoxide radical
hydroperoxyl radical
hydroxyl radical
nitric oxide
hydrogen peroxide

4. Generation of free radicals:-Generation of free radicals:-
1.Redox reaction
eg:- oxidative phosphorylation in mitochondria
2.Enzymatic metabolism of exogenous/endogenous chemicals or drug.
eg:- CCl4 can generate CCl3•
3.Absorption of radiant energy (UV,X- ray)
eg:-
4. Transition metals ( Cu&Fe) accept or donate free electrons during
intracellular process.
eg:- Fenton reaction

5.During inflamation –ROS are produced by activated leucocytes.
6.Nitric oxide(potent vasodialator)- produced by endothelial
cell,macrophages,neurons.

H
2
O O H + H
i o n i z i n g
r a d i a t i o n
hn
F e
2 +
+ H
2
O
2


F e
3 +
+ H O + O H
-

5. Sources of ROS, RNS and other oxidantsSources of ROS, RNS and other oxidants

6. Cellular sources of ROSCellular sources of ROS
xanthine oxidase
hemoglobin
riboflavin
catecholamines
Cytochrome P450
electron
transport chain
lipid peroxidation
NADPH oxidase (oxidative burst: phagocytes)
oxidases
flavoproteins
myeloperoxidase
(oxidative burst: phagocytes)
transient metals

7. Formation of ROS during ischemia and reperfusionFormation of ROS during ischemia and reperfusion
ATP
ADP
AMP
adenosine
inosine
hypoxanthine
Xanthine
dehydrogenase
Xanthine oxidase
Xanthine + •O
2
-
+ H
2O
2
I

S

C

H

E

M

I

A
R E P E R F USION
Ca
2+
proteolysis

8. Mechanism of damage/pathological Mechanism of damage/pathological
effects of free radicalseffects of free radicals
1.Damage of Membranes(Lipid peroxidation in membranes)
-Autocatalytic chain reaction
2.Damage of protiens(Oxidative modification of protiens)
-Protein fragmentation and protein-protein
cross-linkage
2.Damage to DNA (lesion in DNA)
-Single strand breaks (genomic and mitochondrial)

9. Oxidative modification of proteinsOxidative modification of proteins::
OH OH
R R
dityrosine
OH
NO
2
R
3-nitrotyrosine
dityrosine and 3-nitrotyrosine –
markers of protein damage by
ROS and RNS

10. Oxidative damage to DNA:
Formation of thymine dimers
Modification of purines – 8-hydroxy-deoxyguanosine
Marker of the oxidative damage to DNA

11. Protective/scavanging mechanism of Protective/scavanging mechanism of
Free radical removalFree radical removal
◦Spontaneous decay
◦Anti-oxidants
E.g. Vitamin E, vitamin A, vitamin C, glutathione
◦Storage proteins
E.g. transferrin, ferritin, ceruloplasmin
◦Enzymes
Catalase,
 Superoxide dismutase(SOD),
 glutathione peroxidase

12. Examples of free radical injury:Examples of free radical injury:
Chemical injury
Radiation injury
Microbial killing
Cellular aging
Inflamatory damage
Ischemic reperfussion
injury
Hypoxic/ischemic injury

13. Major diseases/disorders linked to ROS/RNSMajor diseases/disorders linked to ROS/RNS
•Respiratory system
•Inhalation of oxidants (SO
2
, NO
2
, O
3
)
•Smoking
•Brain
•Alzheimer`s disease
•Parkinson`s disease
•Amyotrophic lateral sclerosis
•Down syndrome
•Traumatic injury
•Cardiovascular system
•Atherosclerosis
•Ischemia-reperfusion injury
•Myocardial infarction and heart failure
•Selenium deficiency (Keshan disease)
Skin
Ionizing radiation
Thermal injury
Porphyrias
Photosenzitizers and other reagents
Muscle
Exercise
Muscular dystrophy
Others
Aging
Cancer
Cataracts
Diabetes mellitus
Inflamatory and autoimmune diseases
Liver damage by endotoxins
or halogen derivatives of hydrocarbons
Kidney diseases/disorders
AIDS

14. Thank YouThank You