Prepared by M.D., PhD, Marta R. Gerasymchuk Department of Pathophysiology Ivano-Frankivsk National Medical University

1. CELL DAMAGE

2. Classroom Etiquette:Classroom Etiquette:
 Turn off iPads and cell phones !Turn off iPads and cell phones !
 No tobacco use of any kindNo tobacco use of any kind
 Be considerate of others:Be considerate of others:
 Take out what you bring in.Take out what you bring in.
 Talk to me, NOT your neighbor!Talk to me, NOT your neighbor!
 Remember for personal hygiene - cleanliness above all!Remember for personal hygiene - cleanliness above all!
 Do not ask for release of classes, you are able go toDo not ask for release of classes, you are able go to
the dean’s office and student’s clinic!the dean’s office and student’s clinic!
 NO:NO:
 Be Late (in case You are late - look aboveBe Late (in case You are late - look above ↑↑))
 PlagiarismPlagiarism
 CheatingCheating
 Allowing others to copy from youAllowing others to copy from you
 Penalties can be severe !!!Penalties can be severe !!!
 REWORKS – every Tuesday at 4 p.m. (till last student)REWORKS – every Tuesday at 4 p.m. (till last student)

3. HOMEWORKHOMEWORK
Topic 2: Etiology. Pathogenic influence of electric current
1. Actuality of the theme. Due to continuous evolution organism has adapted to normal
atmosphere pressure. But in conditions of modern life man more often encounters with action of
changed atmosphere pressure. This is related to production activity (fliers, spacemen, divers),
sport (mountaineering). Action of changed atmosphere pressure on organism is used in medicine
for treatment (barotherapy). It is important to know rapid change of atmosphere pressure causes of
the symptoms, which is called barotrauma. In modern of contemporary war barotrauma can have
wide spread owing to influence of shock wave.
2.Length of the employment – 1,5 hours.
3.Aim:
To know external and internal causes of disease.
To be able:
1) analyze the role of environmental factors in disease occurrence;
2) persistence of the cause agent, which causes the disease, is delayed in organism (healthy
bacilli-carrier);
3) carry out independently the simplest experimental investigations on animals.
To perform practical work: Causes and consequences constantly change their places. The
cause (etiological factors) causes the pathologic reactions (process) and then these reactions return
to the first agent (etiological factor) and intensify it.
4. Basic level.
The name of the previous disciplines The receiving of the skills
1. histology
2. biochemistry
3. physiology
Gas composition of air and partial pressure
of oxygen. Functional units structure of
respiratory system, blood, blood circulation
system. Physical and chemical indexes of
gases interchange in organism.
Neurohumoral regulation of breathing and
blood circulation.
5. Control questions of the theme:
1. General doctrine of disease. The basic concepts of general nosology. Norm, health,
disease (definition of WHO). A pathological process. A pathological condition, pathological
reaction.
2. Disease as a biological, medical and social problem. The abstract and the concrete in
the concept “disease”. Unity of the destructive and protective in disease. Principles of disease
classification, classification of WHO. The main laws of a disease course.
3. Stages of disease development. Remission, relapse, complication. Variants of disease
outcome: complete and incomplete recovery.
4. Terminal conditions: pre-agony, agony, clinical death. Pathophysiological bases of
reanimation.
The main directions in the development of doctrine of disease: humoral (Hippocrates), cellular
(R. Virchow). Their development in the modern stage.
7. Practice Examination.
Practice examination type 1 (Examples of the tests):
Choose the correct answer:
Test 1. During action of increased atmospheric pressure supplementary amount of gases
dissolves in blood and organism tissues. This phenomenon is called:
A. Hyperoxia
B. Hypoxia
C. Hypercapnia
D. Saturation
Е. Desaturation
Test 2. Sudden death during dehermetizing of cockpit at height 19000 m is rose owing to:
A. Carbonic acid deficit
B. Organism desaturation
C. Gas embolism
D. Oxygen deficit
Е. Height meteorism
Practice examination type 2 (Examples of the real-life tasks):
Task. Alpinists slowly climb on south side of Everest. It was sixth hours of ascending. General
weakness was present. Breath became more difficult. There was palpitation. Pulse rate achieved to 100
beats for a minute. Dizziness, headache lowering of mood and appetite, and meteorism were observed.
1. What was the direct cause of these disorders in the alpinists?
2. How this symptomatic complex is called?
3. What height were alpinists on?
4. What significance in this situation had increased breathing and cardiac rhythm?
Answer for the task:____________________________________________
Practice examination type 3
1. Find the faulty answer to the following: Pathogenic effect of natural (lightning) electricity
depends on:
A. Permanency (constant, variable)
B. Strength
C. Tension
D. Direction
E. Duration of penetration through
the body
F. Reactivity of organism
G. Heredity
2. What direction of electricity through the human body is the most dangerous?
A. Head
B. Kidney
C. Heart
D. Liver
3. When the man is less sensitive to the electric current?
A. Under narcosis
B. Tiredness
C. Hypoxia
D. Alcohol intoxication
4. The most resistant to electric current are all the below mentioned except:
A. External epidermal layer
B.Tendons and bones
C.Nerves
D.Muscles
E. Blood
F. Cerebrospinal fluid
•IMPORTANT
•IMPORTANT
•IMPORTANT
•IMPORTANT

4. Chejou Logan
Chejou Logan
Kongne Nicole
Kongne Nicole
Amaish MohamedAmaish Mohamed
Khalid MohamedKhalid Mohamed
Uche EmmanuellaUche Emmanuella
ChichebemChichebem
Adamu NafiuAdamu Nafiu
AhmedAhmed
Czarnocka
Czarnocka
MilenaMilena
Ramos Torres
Ramos Torres
Kelly Tatiana
Kelly Tatiana
Yoganandham
Yoganandham
NavyasreeNavyasree
AbekahAbekah
DianaDiana
AmritAmrit
KaurKaur

5. AnamanAnaman
SimonSimon
uamduam
OgedegbeOgedegbe
ClementClement
Chigbu
Olivia
Ugochi
Neogi
Neogi
Reevu
Reevu
Hassan Ahmed
Hassan Abdel
Rahman
FernandesMeligen Rayner
Oyaide Mejebi
Oyaide Mejebi
CynthiaCynthia
Nwogu Geoffrey
Nwogu Geoffrey
Okechukwu Junior
Okechukwu Junior
AgboolaAgboola
AdesolaAdesola
AhmedAhmed

6. AlozieAlozie
SandraSandra
IbrahimIbrahim
MustaphaMustapha
OsinugaOsinuga
Oyindamola
Oyindamola
AlkheroAlkhero
Mohammed
Mohammed
DeyaaDeyaa
Kurdi MahmoodKurdi Mahmood
AhmedAhmed
AyedunSamuel Abiola
DawidDawid
GrybosGrybos
PratikshaPratiksha
PradhanPradhan
AsinAsin
Hamzei
Hamzei

7. Latawiec
Latawiec
Justyna
Justyna
HashimHashim
Fahad Ahmed
Fahad Ahmed
Adeyandju
AdeyandjuElizabeth Bolu
Elizabeth Bolu
Martyna
Wasik
Sobowale
Sobowale
Olainaka
Olainaka
Al-Zaatreh
Al-Zaatreh
Mohamad Musa
Mohamad Musa
MohammedMohammed
Amin IyaAmin Iya
Chipangura
Chipangura
YananaiYananai
AshianAshian
IrfanIrfan

8. •PrustyPrusty
•PrashantPrashant
•KumarKumar
•PrakashPrakash
•NarayanNarayan
•PrabhatPrabhat
•MadhogariaMadhogaria
•TusharTushar
•NayakNayak
•SulagnaSulagna
•MuruganMurugan
•VengdeshVengdesh
•MajumdarMajumdar
•RumpaRumpa
•Awukam
•Ifeabo
•Ojang

9. ContentContent
 Components and functions of normal cell.Components and functions of normal cell.
 Cellular injury. Characteristics of the concept of “injury”.Cellular injury. Characteristics of the concept of “injury”.
 Mechanisms and manifestations of damage of subcellularMechanisms and manifestations of damage of subcellular
structures: plasmatic membrane, mitochondria,structures: plasmatic membrane, mitochondria,
endoplasmatic reticulum, lysosomes, microtubules andendoplasmatic reticulum, lysosomes, microtubules and
microphilaments, nucleus and cytoplasm.microphilaments, nucleus and cytoplasm.
 Principles of classification of cell injuries.Principles of classification of cell injuries.
 Molecular mechanisms of cell injury.Molecular mechanisms of cell injury.
 Antioxidant mechanisms of cells.Antioxidant mechanisms of cells.
 Cell death.Cell death.
 Mechanisms of apoptosis.Mechanisms of apoptosis.
 Ageing.Ageing.

10. Cellular PathologyCellular Pathology
““All organ injuries start with structuralAll organ injuries start with structural
or molecular alterations in cells”or molecular alterations in cells”
concept began by Virchow in 1800's.concept began by Virchow in 1800's.

11. NORMAL CELLNORMAL CELL
• at the subcellular or molecular level.
• all cells share the basic organelles for the synthesis of:
• transport of ions and other substances.
• to understand pathology, review normal structure and
function of cells.
“you cannot appreciate the abnormal
before you understand the normal”
• Present day study of disease
attempts to understand how
cells react to injury.
proteinsproteins lipidslipids carbohydratescarbohydrates energyenergy
productionproduction

12. Plasma membranePlasma membrane
• phospholipid bilayerphospholipid bilayer with embedded
proteins / glycoproteins / glycolipids.
• semipermeable membrane with pumps
for ionic / osmotic homeostasis

13. 1.1. Lipid peroxidation (LPO), increased generation of free radicals
2. Activation of phospholipases and lysosomal hydrolytic enzymes
3. Membrane damage via amphiphilic, detergent substances
4. Cell swelling → membrane tension, rupture
5. Inhibition of repairof the damaged membrane compounds
(blockage of denovo synthesis)
6. Immune complex influence the membrane macromolecules
7.Conformation disorders of macromolecules
Damage to lipid bilayer → damage to phospholypase, lipase
activities of the membrane
Membrane damageMembrane damage
(main causes)(main causes)

14. NucleusNucleus
• nuclear envelope /nuclear envelope /
nuclear poresnuclear pores
• chromatinchromatin
(euchromatin vs(euchromatin vs
heterochromatin)heterochromatin)
• nucleolusnucleolus
(synthesis of(synthesis of
ribosomal RNA)ribosomal RNA)

15. MitochondriaMitochondria
• inner & outer membranes, cristaeinner & outer membranes, cristae
• intermembranous and inner matrixintermembranous and inner matrix
compartmentscompartments
• oxidative phosphorylation (main sourceoxidative phosphorylation (main source
of ATP)of ATP)

16. Endoplasmic reticulum (ER),Endoplasmic reticulum (ER),
Ribosomes & Golgi ApparatusRibosomes & Golgi Apparatus
• Rough (RER) vs smooth (SER)
endoplasmic reticulum
• Ribosomes (free in cytosol or
attached to RER)
• Polysomes (threaded by
mRNA).
• Condensing vacuoles/
secretory vesicles

17. LysosomeLysosome• Enzymatic (acid
hydrolases) digestion
of materials in the
cell
• Endocytosis
• Phagocytosis /
phagosome;
• Pinocytosis /
pinocytotic vesicle;
• Receptor-mediated
endocytosis

18. PeroxisomePeroxisome• Enzymes
(ex.
catalase,catalase,
oxidasesoxidases) !
metabolism
of hydrogen
peroxide &
fatty acid

19. Cellular functionsCellular functions
1.1. MovementMovement – muscle cells can generate forces that produce motion.– muscle cells can generate forces that produce motion.
2.2. ConductivityConductivity – is the main function of nervous cells. Conduction as a– is the main function of nervous cells. Conduction as a
response to a stimulus is manifested by a wave of excitation, an electricalresponse to a stimulus is manifested by a wave of excitation, an electrical
potential.potential.
3.3. Metabolic absorptionMetabolic absorption – all cells take in and use nutrients and other– all cells take in and use nutrients and other
substances from their environment.substances from their environment.
4.4. SecretionSecretion – certain cells are able to synthesize new substances and– certain cells are able to synthesize new substances and
secrete them.secrete them.
5.5. ExcretionExcretion – all cells are able to rid themselves of waste products– all cells are able to rid themselves of waste products
resulting from the metabolic breakdown of nutrients.resulting from the metabolic breakdown of nutrients.
6.6. Respiration (oxidation)Respiration (oxidation) – cells absorb oxygen which is used to– cells absorb oxygen which is used to
transform nutrients into energy in the form of ATP (in mitochondria)transform nutrients into energy in the form of ATP (in mitochondria)
7.7. ReproductionReproduction – tissue growth occurs as cells enlarge and reproduce– tissue growth occurs as cells enlarge and reproduce
themselves.themselves.
8.8. CommunicationCommunication – is critical for all the other functions listed above– is critical for all the other functions listed above
enabling the survival of the society of cells. Constant communicationenabling the survival of the society of cells. Constant communication
allows the maintenance of a dynamic steady state.allows the maintenance of a dynamic steady state.

20. Cell InjuryCell Injury
1. Cause1. Cause •• intrinsic,intrinsic, •• extrinsicextrinsic
•• infectious,infectious, •• non infectiousnon infectious
2. The type of influence.2. The type of influence.
•• directdirect •• mediatedmediated
•• acuteacute •• chronicchronic →→ by the courseby the course
•• reversiblereversible •• irreversibleirreversible
3. Manifestations of injury.3. Manifestations of injury.
a. specifica. specific b. stereotypical (non specific)b. stereotypical (non specific)
4. In dependence on the4. In dependence on the pathogenically mechanismspathogenically mechanisms of cellsof cells
damage divide on: a) violent (forced); b)damage divide on: a) violent (forced); b) cytopath(ogen)iccytopath(ogen)ic
Cell injuryCell injury is defined as such a change in cell structure, metabolism,is defined as such a change in cell structure, metabolism,
physico-chemical properties and function which leads to impairment of itsphysico-chemical properties and function which leads to impairment of its
vital activityvital activity

21. REVERSIBLE CELL INJURYREVERSIBLE CELL INJURY
 It occurs whenIt occurs when
environmentalenvironmental
changes exceed thechanges exceed the
capacity of the cell tocapacity of the cell to
maintain normalmaintain normal
homeostasis.homeostasis.
 If the stress isIf the stress is
removed in tissue orremoved in tissue or
if the cell withstandif the cell withstand
the assault the injurythe assault the injury
is reversibleis reversible

22. IRREVERSIBLE CELL INJURYIRREVERSIBLE CELL INJURY
 If the stress remains the severe, the cellIf the stress remains the severe, the cell
injury becomes irreversible and lead toinjury becomes irreversible and lead to
cell deathcell death

23. Comparative analysis of reversible and irreversible cell injuryComparative analysis of reversible and irreversible cell injury
1. Mitochondrial oxygenation ↓
2. ATP ↓
3. Na+
K+
pump ↓
4. Intracellular Na +
, Ca2+
↑,
extracellular K+
↑
glycolysis ↑
lactate ↑, pH ↓
5. H20 ↑
6. Acute cell swelling
a. nuclear chromatin
shrinking
b. lysosomal swelling
Enlargement of
endoplasmic reticulum
Ribosome order ↓
Protein synthesis ↓
Impaired lipid deposition
Reversible injury Inreversible injury
1. Membrane damage
a. Loss of phospholipids
b. Cytoskeleton injury
c. Free radical ↑
d. Lysis of lipids
2. Ca2+
influx ↑
Increased Ca2+
load of mitochondria
Uncoupling of oxidative phosphorilation
3. Release of cytoplasmic enzymes (LDG)
4. Release of lysosomal enzymes
5. Autophagy

24. The main causes ofThe main causes of cellcell injuryinjury
Internal stresses
• metabolic imbalances, nutritional deficiencies ormetabolic imbalances, nutritional deficiencies or
excessesexcesses
• genetic abnormalitiesgenetic abnormalities
• acquired derangementsacquired derangements →→ hypoxiahypoxia →→ impairment inimpairment in
aerobic tissue respirationaerobic tissue respiration, ischemia, ischemia →→ decrease in blooddecrease in blood
supplysupply
External
•• physical agents (physical agents ( mechanical injury, high and lowmechanical injury, high and low
temperature, radiation, electrical shock, sudden fluctuations oftemperature, radiation, electrical shock, sudden fluctuations of
the barometric pressure, acceleration, etcthe barometric pressure, acceleration, etc…)…)
•• natural toxins, venomsnatural toxins, venoms
•• drugs, "chemicals" (Paracelsus)drugs, "chemicals" (Paracelsus) →→ abundantabundant
oxygen, increase in glucose, high doses of dietary salt, poisons,oxygen, increase in glucose, high doses of dietary salt, poisons,
insecticides, carbon monoxide, asbestos, drugs, socialinsecticides, carbon monoxide, asbestos, drugs, social
stimulators, e.g. alcohol, narcotics.stimulators, e.g. alcohol, narcotics.

25. Cell injury signsCell injury signs
a. Swelling
b. Dystrophy
c. Thesaurismosis
d. Dysplasia
e. Necrosis
f. Autolysis
a. Decrease in function
b. Cellular
1. Increase in permeability
2. Cytoplasmic enzymes
leakage to the blood
c. Metabolic derangements
d. Injury mediators
e. Synthesis impairments
f. Electrolyte balance disorders
Morphological Functional

26. 1. Lipid:
1) free oxidation of lipids (FOL), Increased free radical
generation and lipid peroxydation → oxidative stress
2) activating of phospholipase and
3) detergent action of free fat acids.
2. Impairment in calcium homeostasis (calcium stress)
3. Electrolyte-osmotic balance disorders
4. Acidosis (intracellular, extracellular)
5. Protein disorders – enzymatic derangements
6. Nucleic acid disorders (transcription, translation, DNA
repair disorders) → nucleic acid stress
7. Violation of power providing of cell.
Molecular mechanisms of cell injuryMolecular mechanisms of cell injury

27. FREE RADICALSFREE RADICALS A commonA common "final"final
pathway"pathway" in a variety ofin a variety of
forms of cell injury,forms of cell injury,
including injury broughtincluding injury brought
about by inflammatoryabout by inflammatory
cells, is generation ofcells, is generation of
free radicals, i.e.,free radicals, i.e.,
molecular species with amolecular species with a
single unpaired electronsingle unpaired electron
available in an outeravailable in an outer
orbital.orbital.
 Single free radicalsSingle free radicals
initiate chain reactionsinitiate chain reactions
which destroy largewhich destroy large
numbers of organicnumbers of organic
moleculesmolecules

28. Formation, Function, Types of Free RadicalsFormation, Function, Types of Free Radicals
Ionizing
Radiation
Produces Hydroxyl
FRs
Prod. Superoxide FRs
Damaged
Mitochondria
High
Concentration of
O2Prod. Superoxide &Prod. Superoxide &
Hydroxyl FRsHydroxyl FRs
Prod. HydrogenProd. Hydrogen
Peroxide (H2O2)Peroxide (H2O2)
Oxidase
Reactions
1. NADPH1. NADPH oxidase inoxidase in
the PMN & monocytethe PMN & monocyte
cell membranecell membrane
MyeloperoxidaseMyeloperoxidase
Hypochlorouse acidHypochlorouse acid
2. Xanthine oxidase2. Xanthine oxidase isis
a ROS – generate FRsa ROS – generate FRs
Prod. Superoxide FRsProd. Superoxide FRsDrugsDrugs
(e.g.(e.g.
acetaminophen)acetaminophen)Conv. toConv. to
acetaminophen FRsacetaminophen FRs
in the liverin the liver
CarbonCarbon
tetrachloridetetrachloride
Conv. to CCl3 FRsConv. to CCl3 FRs
in the liverin the liver
MetalsMetals
(e.g. iron, copper)(e.g. iron, copper)
Prod. Hydroxyl FRsProd. Hydroxyl FRs
(Fenton reaction)(Fenton reaction)
Nitric OxideNitric Oxide
FRs prod. by macrophagesFRs prod. by macrophages
& endothelial cells& endothelial cells
Intima of elastic &Intima of elastic &
muscular arteriesmuscular arteries
LDL are oxidized by FRs,LDL are oxidized by FRs,
lead to atherosclerotic pl.lead to atherosclerotic pl.
FRs attack aFRs attack a
molecule &molecule &
“steal” its“steal” its
electronelectronFRs : damageFRs : damage
membranes &membranes &
DNADNA

29. FREE-RADICALFREE-RADICAL
GENERATIONGENERATION
 1.1. Oxidation ofOxidation of
unsaturated fatty acidsunsaturated fatty acids
in membranesin membranes ("lipid("lipid
peroxidation", etc.)peroxidation", etc.)
* Basic biologists:* Basic biologists:
These are the sameThese are the same
reactions that makereactions that make
unsaturated fats turnunsaturated fats turn
rancid.rancid.
 2. Cross-linking of2. Cross-linking of
sulfhydryl groups ofsulfhydryl groups of
proteins.proteins.
 3. Genetic mutations3. Genetic mutations Ionizing radiation: homolytic break of covalent
bonds in water, DNA and other biomolecules
H 2 O O H + H
io n iz in g
r a d ia t io n
h ν

30. Reactive oxygen and nitrogen species
ROS/RNS
Free radical – each molecule or its fragment, which can
exists independently and contains one or two unpaired
electrons
Reactive oxygen species - species, which contain one or
more oxygen atoms and are much more reactive than
molecular oxygen
ROS/RNS
Free radicals
superoxide radical
hydroperoxyl radical
hydroxyl radical
nitric oxide
hydrogen peroxide

31. Cellular 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

32. Oxidative Stress and Oxygen Free RadicalsOxidative Stress and Oxygen Free Radicals
• Superoxide anionSuperoxide anion (O(O22
--
) –) –
may be formed via themay be formed via the
cytochrome Pcytochrome P450450 systemsystem,,
found in hepatocytes,found in hepatocytes,
which metabolizes manywhich metabolizes many
drugs and toxins – itdrugs and toxins – it cancan
be removedbe removed byby superoxidesuperoxide
dismutasedismutase
• Hydrogen peroxideHydrogen peroxide (H(H22OO22))
–– removedremoved byby catalasecatalase oror
glutathione peroxidaseglutathione peroxidase
• Hydroxyl radicalHydroxyl radical ((..
OH) –OH) –
initiates lipid per-oxidationinitiates lipid per-oxidation
and DNA damageand DNA damage

33. Mechanisms of cell injury mediated by ROS and RNSMechanisms of cell injury mediated by ROS and RNS
ROS a RNS
Modification of aa,
fragmentation and
aggregation of proteins
Lipid peroxidation DNA damage
Membrane damage
Loss of membrane
integrity
Damage to Ca2+
and other
ion transport systems
Inability to maintain
normal ion gradients
Activation/deactivation of
various enzymes
Altered gene
expression
Depletion of ATP
Lipids Proteins DNA
Cell injury/
Cell death
aa – amino
acids

34. Antioxidants andAntioxidants and
secondary defensesecondary defense
systemssystems
 Prevent ROS formation
 Eliminate radicals by formation of
nonradicals or less reactive radicals
 Repair dameged molecules and cell
structures
 Expression of genes coding for
antioxidant enzymes
Antioxidants and secondary
defense systems
Enzyme
antioxidants
Nonenzymatic
antioxidants
Chelating agents
Enzymes of
repair and de
novo synthesis
of damaged
molecules
Water-soluble
Lipid-soluble
Endogenous
Present in diet

35. Increased production of ROS + decreased activity of antioxidantIncreased production of ROS + decreased activity of antioxidant
system = oxidative stresssystem = oxidative stress
Antioxidant systemAntioxidant system
I. Enzymatic
a. Superoxide dismutase
(SOD)
b. Catalase
c. Glutathione peroxidase (
glutathione, GSH)
d. ubiquinone
II. Non enzymatic
a. α-tocopherol
b. Ascorbic acid
c. Cysteine, mannitol,
serotonin, selenium,
riboflavin, retinol,
carotinoids,
d. Reduced glutathioneGlutathione system
Vitamins
Microelements (Selenium)
Amino acids with SH group

36. Nonenzymatic antioxidantsNonenzymatic antioxidants
Endogenous antioxidants - Synthesized in the bodyEndogenous antioxidants - Synthesized in the body
bilirubínbilirubín
glutathione and other thiocompounds (thioredoxin)glutathione and other thiocompounds (thioredoxin)
uric aciduric acid
coenzyme Q (Ubichinon-10/Ubichinol-10)coenzyme Q (Ubichinon-10/Ubichinol-10)
lipooic acidlipooic acid
melatoninmelatonin
sex hormonessex hormones
2-oxoacids (pyruvate, 2-oxoglutarate)2-oxoacids (pyruvate, 2-oxoglutarate)
dipeptides containig His (carnosine, anserine)dipeptides containig His (carnosine, anserine)
albumin (-SH groups)albumin (-SH groups)
Dietary antioxidantsDietary antioxidants
ascorbic acidascorbic acid
vitamine Evitamine E
carotenoidscarotenoids
flavonoids – plant phenols (catechin, quercetin etc)flavonoids – plant phenols (catechin, quercetin etc)
Synthetic antioxidantsSynthetic antioxidants
N-acetylcystein (scavenger of ROS), deferoxamine (chelator),N-acetylcystein (scavenger of ROS), deferoxamine (chelator),
alopurinol (inhibitor of XO), acetyl salicylic acid (feritine synthesis)alopurinol (inhibitor of XO), acetyl salicylic acid (feritine synthesis)

37. • Vitamin EVitamin E
(fat-soluble)(fat-soluble)
1) Prevents lipid1) Prevents lipid
peroxidation in cellperoxidation in cell
membranes;membranes;
2) Neutralizes2) Neutralizes
oxidized LDLoxidized LDL
• Vitamin CVitamin C (water-(water-
soluble)soluble)
1) Neutralizes FRs1) Neutralizes FRs
produced byproduced by
pollutants andpollutants and
cigarette smokecigarette smoke
• Smokers haveSmokers have 
levels of Vit.Clevels of Vit.C
because they arebecause they are
used up inused up in
neutralizing FRsneutralizing FRs
derived from cigarettederived from cigarette
smoke.smoke.
2) Best neutralizer of2) Best neutralizer of
hydroxyl FRs.hydroxyl FRs.

38. Reperfusion Injury andReperfusion Injury and
Activated OxygenActivated Oxygen
• Toxic oxygen species are
generated, not during the
ischemia itself, but during
reperfusion, hence the term
reperfusion injuryreperfusion injury
• This has clinical relevance,
since reperfusion of heart
muscle is commonly achieved
with per-cutaneous angioplasty.
Patients more than 20
minutes post-infarction
are at risk for reperfusion
injury.

39. Mechanisms of membrane damage in
ischemia and reperfusion

40. Summary:Summary:
• ReperfusionReperfusion generates free radicals fromgenerates free radicals from
parenchymal, endothelial, andparenchymal, endothelial, and
inflammatory cells in the injured tissue,inflammatory cells in the injured tissue,
often producing more cellular injury thanoften producing more cellular injury than
the initial ischemia, largely due tothe initial ischemia, largely due to
membrane damagemembrane damage
• Be able to identify grossly andBe able to identify grossly and
microscopically: Myocardial infarction,microscopically: Myocardial infarction,
renal infarction (pale infarct), gangrenerenal infarction (pale infarct), gangrene

41. Activating of membraneActivating of membrane
phospholipasephospholipase
• The surplus activating of
phospholipase A2 has an important
value in pathogenesis of cell damage.
This enzyme carries out breaking up of
phospholipids of cell diaphragms to
a) unsaturated fatty acids and
b) lysophospholipids.
• Unsaturated fatty acids, in particular
arachidonic acid, under act of certain
enzymes transform to biologically
active matters - eicosanoids.
• Lysophospholipids have ability to
create a micelle and they are very
strong detergents. High concentration
of ions of Ca2+ in a cytoplasm is the
basic reason of activation of
phospholipase A2.

42. Detergents action of surplus of free fatty acidsDetergents action of surplus of free fatty acids
• Free fatty acids in large concentrations similarly as lysophospholipids
damage bimolecular lipid layer of cellular membranes.
• It is possible to select 4 basic mechanisms of increase of maintenance
of free fatty acids in a cell:
• 1) Entering of free fatty acids is increased cell in the presence of high
level of lipids in blood, that is observed during activating of processes of
lipolysis in fatty tissues (stress, diabetes).
• 2) Formation of free fatty acids is increased in lysosomes (at
atherosclerosis).
• 3) Liberation of free fatty acids is increased from phospholipids of
cellular membranes under act of phospholipases.
• 4) The use of free fatty acids is broken by a cell as energy sources
(diminishing of enzymes is a beta-oxidization and to the Krebs cycle
during hypoxia).

43. CaCa2+2+
- homeostasis disorders- homeostasis disorders
1. Increased entrance1. Increased entrance
a.a. HypercalciaHypercalcia
b.b. Impaired barrier function of the membranesImpaired barrier function of the membranes
(increase in peroxidation processes)(increase in peroxidation processes)
22.. Impaired effluxImpaired efflux →→ Ca-accumulationCa-accumulation
a.a. Ca-pump disorder, Ca-channels impairmentsCa-pump disorder, Ca-channels impairments →→
disorders in synaptic plasticitydisorders in synaptic plasticity
b.b. CaCa2+2+
- Na- Na++
exchange mechanism disorderexchange mechanism disorder

44. Cytosolic free calcium is a potent destructive agent.
•The increase ofThe increase of
concentration ofconcentration of
CaCa22+ ions causes in+ ions causes in
a cytoplasm:a cytoplasm:
a)a) contraction ofcontraction of
fibrillar structuresfibrillar structures
of cellof cell
(myofibrillar);(myofibrillar);
b)b) activating ofactivating of
phospholipase Aphospholipase A22
c)c) violationviolation ofof
connection betweenconnection between
the processes ofthe processes of
oxidization andoxidization and
phosphorylationphosphorylation..

45. Mitochondria Ca2+ Endoplasmic
reticulum Ca2+
Increase of cytosolicIncrease of cytosolic CaCa2+2+
ATP-ase Phospholipase Proteinase Endonuclease
Reduction of
phospholipids
Decrease
ATP
Destruction of
membrane and
cytoskeleton
proteins
Segmentation of
nuclear chromatin
CaCa2+2+
Pathological stimuli
Pathogenetic effects of Ca stress

47. •Disorders of function of Na-K-
pump can be conditioned the
deficit of АТP in a cell, multiplying
maintenance of cholesterol in lipids
bilayer of membrane (for example,
at atherosclerosis), by the action of
a number of specific inhibitors Na-
K-ATP-elements (for example,
strophanthine (ouabaine)).
•A change in maintenance ofA change in maintenance of
ions of Na+ and K+ is causedions of Na+ and K+ is caused:
•a) loss of electric potential of
cellular diaphragm;
•b) it was swollen cells (edema);
•c) osmotic injury of cellular
membranes, which is accompanied
the increase of their permeability.
Electrolyte-osmoticElectrolyte-osmotic
mechanismmechanism of cellof cell
damagedamage.

48. Water-ion balance impairmentWater-ion balance impairment
NaNa++
- K- K++
pump disorder leads to:pump disorder leads to:
1. Rest potential impairment → changes
in threshold, action potential, impulse
transduction
2. Swelling of the cell
3. Osmotic tension of the membrane
4. Impairment of membrane barrier
function
5. Impaired electrogenesis (ECG, EEG)

51. MechanismMechanism
of acidosisof acidosis
Reasons of cell acidosis:Reasons of cell acidosis:
• 1) there is the surplus entering of1) there is the surplus entering of
H+ ions in cell from a extracellularH+ ions in cell from a extracellular
environment;environment;
• 2) formation of sour products in a2) formation of sour products in a
cell during glycolysis activatingcell during glycolysis activating
(lactic acid – lactate), violations of(lactic acid – lactate), violations of
Krebs cycle (carbons acids),Krebs cycle (carbons acids),
hydrolitic breaking uphydrolitic breaking up
(disintegration) phospholipids of(disintegration) phospholipids of
cellular membranes (free fat acids,cellular membranes (free fat acids,
phosphoric acid) and others;phosphoric acid) and others;
• 3) violation of fastening of free H+3) violation of fastening of free H+
ions is as a result of insufficiencyions is as a result of insufficiency
of the buffer systems of cell;of the buffer systems of cell;
• 4) violation of move out H+ ions4) violation of move out H+ ions
from a cell. Reason of this isfrom a cell. Reason of this is
disorders of Na-H-exchangedisorders of Na-H-exchange
mechanism, and also in themechanism, and also in the
conditions of the broken localconditions of the broken local
circulation of blood in tissue.circulation of blood in tissue.

52. Conclusions of acidosis of cell:Conclusions of acidosis of cell:
a)a) change conformation ofchange conformation of
protein molecules withprotein molecules with
violation of them function andviolation of them function and
properties;properties;
b)b) increase of permeability ofincrease of permeability of
cellular membranes;cellular membranes;
c)c) activating enzymes ofactivating enzymes of
lysosomes.lysosomes.
• If there is a lack of OIf there is a lack of O22, energy, energy
metabolism switches tometabolism switches to
anaerobic glycolysis.anaerobic glycolysis.
• The formation of lactic acid,The formation of lactic acid,
which dissociates into lactatewhich dissociates into lactate
and H+, causes cytosolicand H+, causes cytosolic
acidosis that interferes withacidosis that interferes with
the functions of thethe functions of the
intracellular enzymes, thusintracellular enzymes, thus
resulting in the inhibition ofresulting in the inhibition of
the glycolysis so that this lastthe glycolysis so that this last
source of ATP dries up.source of ATP dries up.
MechanismMechanism
of acidosis.of acidosis.

54. Proteins MechanismsProteins Mechanisms
• The proteins mechanisms of cell damage
contain:
• 1) inhibition enzymes (reverse and irreversible);
• 2) denaturation, that violation of native structure of
albumins molecules as a result of conditioned the
break connections of changes of the second or
tertiary structures of proteins;
• 3) proteolisis, that is carried out under the action of
lysosomal enzymes.

55. Proteins used in diagnosis of tissue damage
by blood testing

56. The nucleic mechanismsThe nucleic mechanisms
► It’s conditioned with violationsIt’s conditioned with violations
of nucleic acids (DNA, RNA).of nucleic acids (DNA, RNA).
Its disturbance of replication,Its disturbance of replication,
transcription and translationtranscription and translation
processes.processes.
► Thus, universal mechanismsThus, universal mechanisms
of increase of permeability ofof increase of permeability of
cellular membranes are:cellular membranes are:
1) activating of FOL;1) activating of FOL;
2) activating of phospholipases;2) activating of phospholipases;
3) osmotic breaking up3) osmotic breaking up
membranes;membranes;
4) adsorption of albumens is on4) adsorption of albumens is on
a membrane.a membrane.

57. The damage of
mitochondrias is
accompanied:
1) oppressing the
processes of the
cellular breathing,
2) violation of
connection between
the processes of
oxidization and
phosphorilation.

58. Mechanisms of cell death.Mechanisms of cell death.
Terminology:Terminology:
 Necrosis:Necrosis: Morphologic changes seen inMorphologic changes seen in
dead cells within living tissue.dead cells within living tissue.
 Autolysis:Autolysis: Dissolution of dead cells by theDissolution of dead cells by the
cells own digestive enzymes. (not seen)cells own digestive enzymes. (not seen)
 Apoptosis:Apoptosis: Programmed cell death.Programmed cell death.
Physiological, for cell regulation.Physiological, for cell regulation.

59. Mechanisms of cell deathMechanisms of cell death
 ““ApoptosisApoptosis is a pathway of cell death that isis a pathway of cell death that is
induced by a tightly-regulated suicide program ininduced by a tightly-regulated suicide program in
which cells destined to die activate enzymes thatwhich cells destined to die activate enzymes that
degrade the cell’s own nuclear DNA and nucleardegrade the cell’s own nuclear DNA and nuclear
and cytoplasmic proteins”and cytoplasmic proteins”
– Developmental morphogenesisDevelopmental morphogenesis
– RadiationRadiation
– Immune system regulationImmune system regulation
– Viral infectionsViral infections
– CancersCancers
– ToxinsToxins
The process was recognized in 1972 by the distinctive morphologicThe process was recognized in 1972 by the distinctive morphologic
appearance of membrane-bound fragments derived from cells, andappearance of membrane-bound fragments derived from cells, and
named after the Greek designation for “falling off.”named after the Greek designation for “falling off.”

60. General biochemical mechanismsGeneral biochemical mechanisms
 Defects in plasma membrane permeability.Defects in plasma membrane permeability.
 Oxygen deprivation or generation of reactiveOxygen deprivation or generation of reactive
oxygen species (free radical).oxygen species (free radical).
 Loss of calcium homeostasis.Loss of calcium homeostasis.
 MitochondrialMitochondrial
damage.damage.
 Chemical injuryChemical injury
 Genetic variationGenetic variation

61. 1. Cell shrinkage.
2. Nuclear chromatin condensation
and fragmentation
3. Apoptotic bodies formation
4. Phagocytosis of apoptotic bodies
by adjacent cells or macrophages.
5. Intacted membrane.
Morphologic features of ApoptosisMorphologic features of Apoptosis

63. Role of apoptosis in physiology and pathologyRole of apoptosis in physiology and pathology
1. During embryogenesis ( implantation, organogenesis, growth,1. During embryogenesis ( implantation, organogenesis, growth,
metamorphosis)metamorphosis)
2. In adults hormone dependent involution (2. In adults hormone dependent involution (during menstrual cycle,during menstrual cycle,
menopausemenopause, atrophy of, atrophy of prostate and breastsprostate and breasts))
3. Destruction of cells in the3. Destruction of cells in the reproducingreproducing cellular populations (epithelialcellular populations (epithelial
cells of intestine )cells of intestine )
4. Cell death in tumor (regression)4. Cell death in tumor (regression)
5. Death of neutrophils in the active inflammatory process5. Death of neutrophils in the active inflammatory process
6. Death of immune cells (B,T- lymphocytes)6. Death of immune cells (B,T- lymphocytes)
7. Death of cytotoxic T- lymphocytes7. Death of cytotoxic T- lymphocytes
8. Pathological atrophy in the8. Pathological atrophy in the parenchimatous organsparenchimatous organs
9. During the some viral infections (hepatitis)9. During the some viral infections (hepatitis)
10. Temperate action of various noxious factors10. Temperate action of various noxious factors

64. Confocal 3d images of nuclei from nonapoptotic (A) and
apoptotic (B) cells stained with PI
A B

65. Morphogenesis of cell injuryMorphogenesis of cell injury
Atrophy - physiological, pathological
Types - local, general, dysfunctional, due to
compression, blood circulation, neurogenous
Necrosis, necrobiosis (protein dystrophy)
Autolysis, caryorhexis, caryolysis, plasmorrhexis,
plasmolysis, demarcation zone, inflammation
around the necrosis

66. Morphology of necrotic cellsMorphology of necrotic cells
• Cell and nuclear swelling
• Vacuolization of cytoplasm
• Patchy chromatin condensation
• Mitochondrial swelling
• Plasma membrane rupture
• Dissolution of chromatin
• Attraction of inflammatory cells

68. Comparison of cell death by apoptosis and necrosisComparison of cell death by apoptosis and necrosis

70. PathologyPathology
of elderlyof elderly

71. Ageing:Ageing:
““Progressive time related loss ofProgressive time related loss of
structural and functionalstructural and functional
capacity of cells leading tocapacity of cells leading to
death”death”
►Senescence, Senility, SenileSenescence, Senility, Senile
changes.changes.
►Ageing of a person is intimatelyAgeing of a person is intimately
related to cellular ageing.related to cellular ageing.

72. Factors affecting ageing:Factors affecting ageing:
• Stress
• Infections
• Diseases
• Malnutrition
• Accidents
• Diminished stress
response.
• Diminished immune
response.
• Good health.

73. Cellular mechanismsCellular mechanisms
of ageingof ageing
 Cross linking proteins &Cross linking proteins &
DNA.DNA.
 Accumulation of toxic by-Accumulation of toxic by-
products.products.
 Ageing genes.Ageing genes.
 Loss of repairLoss of repair
mechanism.mechanism.
 Free radicale injuryFree radicale injury
 Telomerase shortening.Telomerase shortening.

74.  General and clinical pathophysiology / Edited by Anatoliy V. Kubyshkin – Vinnytsia: Nova
Knuha Publishers – 2011. – P. 134–165.
 Gozhenko A.I. General and clinical pathophysiology / A.I. Gozhenko, I.P. Gurcalova // Study
guide for medical students and practitioners. Edited by prof.Zaporozan, OSMU. – Odessa. –
2005.– P. 30–41.
 Robbins and Cotran Pathologic Basis of Disease 8th
edition./ Kumar, Abbas, Fauto. – 2007. –
Chapter 1. – P. 1–30
 Essentials of Pathophysiology: Concepts of Altered Health States (Lippincott Williams &
Wilkins), Trade paperback (2003) / Carol Mattson Porth, Kathryn J. Gaspard. – Сhapters 1-2.
– P. 1–14, 28–35.
 Copstead Lee-Ellen C. Pathophysiology / Lee-Ellen C. Copstead, Jacquelyn L. Banasik //
Elsevier Inc, 4th edition. – 2010. – P. 30–84.
 Corwin Elizabeth J. Handbook of Pathophysiology / Corwin Elizabeth J. – 3th
edition.
Copyright В. – Lippincott Williams & Wilkins – 2008. – Chapter 1. – P. 3–35.
 Silbernagl S. Color Atlas of Pathophysiology / S. Silbernagl, F. Lang // Thieme. Stuttgart. New
York. – 2000. – P. 2–13.
 Pathological physiology / Yu.I. Bondarenko, M.R. Khara, V.V. Faifura, N. Ya. Potikha. –
Ternopil: Ukrmedkniga. – 2006. – 312 p.
 Pathophysiology, Concepts of Altered Health States, Carol Mattson Porth, Glenn Matfin.–
New York, Milwaukee. – 2009. – P. 99–109.

75. Thank you for attention!