GGENERAL ENERAL ETIOPATHOGENESIS ETIOPATHOGENESIS

OF DISEASESOF DISEASES

Prof. J. HanProf. J. Hanaceacek, k, M.D.,M.D.,CSc.CSc.

EtiopathogenesisEtiopathogenesis• etiology – causes and conditions of diseases

onset

• genesis – development of disease

PathomechanismsPathomechanisms• Mechanisms which are involved in development of diseases

Monofactorial diseasesMonofactorial diseases

• One „big“ cause plus appropriate conditionsare necessary, e.g. tuberculosis (other infections)

Multifactorial diseasesMultifactorial diseases• More than one cause and appropriate conditions

are necessary, e.g. atherosclerosis

Homogenous diseases – diseases induced always by the same cause or complex of causes, e.g. whooping cough, small pox, poissoning by toadstool

He

Heterogenous diseases – diseases induced by different kinds of noxae or different complex of noxae, e.g. diabetes mellitus type 1 and 2; hypoxia-hypoxic, histotoxic, ischemic

Pathogenic factorsPathogenic factors

Different kinds of energy (inappropriate quantity and/or quality)

which lead to disturbances of homeostasis of iner

environement of human body.

Another name for pathogenetic factors are noxae

Main kinds of pathogenetic noxaeMain kinds of pathogenetic noxae

1.1. physicalphysical -- mechanical energy, enviromental temperature, mechanical energy, enviromental temperature, eleelecctrictric

current, atmospheric pressure and moisture, current, atmospheric pressure and moisture,

lasser beamlasser beam, ,

compression and decompresion, vibration, compression and decompresion, vibration,

acceleration,acceleration,

deceleration, microwaves, magnetic field and deceleration, microwaves, magnetic field and

others others

2.2. c chemicalhemical – – elements and compounds - elements and compounds - acids and lyes, plantacids and lyes, plant and and

animal toxins, toxic metals, cigarette smokeanimal toxins, toxic metals, cigarette smoke andand

otherother

kinds of smoke, sulphur dioxide, nitrogene oxides, kinds of smoke, sulphur dioxide, nitrogene oxides,

ozon, ozon,

pesticides,pesticides, herbicidesherbicides...... 3.3. b biologicaliological – – microorganismsmicroorganisms (microbes,viruses(microbes,viruses....), insect ), insect and and arthropods, organic dust andarthropods, organic dust and pollenpollen

4.4. psychologicalpsychological, social, social and ergonomic and ergonomic - - psychologic psychologic stress,stress, enormoenormous us strainstrain (physical or/and(physical or/and mental mental))

Physical noxae: Physical noxae: Crush syndromeCrush syndromeSSyndrome is characterized by tissue damage induced by yndrome is characterized by tissue damage induced by their their compressioncompression

-  cells are damaged by-  cells are damaged by pressure and ischemia pressure and ischemia

- anaerobic metabolianaerobic metabolissm going onm going on release of myoglobin from cells release of myoglobin from cells

precipitation of Mgl in kidney vessels precipitation of Mgl in kidney vessels damage of kidneydamage of kidney acute renal failureacute renal failure

After compressionAfter compression is is removed: removed:

-  recirculation -  recirculation inin the damaged tissue can occure the damaged tissue can occure after removing after removing

thethe compression compression

- -  washing out the toxic metabolites from thewashing out the toxic metabolites from the damageddamaged tissue to the wholetissue to the whole organism organism to toxic influencexic influence

-  accumulation of the blood in the damaged tissue-  accumulation of the blood in the damaged tissue (blood goes very easy through the leaky capillary wall(blood goes very easy through the leaky capillary wall))

-  hypovolemia and hypovolemic shock can occur-  hypovolemia and hypovolemic shock can occur

Blast syndromeBlast syndrome

SSyndrome is characterized byyndrome is characterized by tissue damage induced tissue damage induced

by strong pressure waveby strong pressure wave::

Consequences: Consequences: - bleeding to the tympanic membrane- bleeding to the tympanic membrane (ear (ear

drum)drum) and/or ruptureand/or rupture

- damage of the inner ear- damage of the inner ear

- damage of hollow organs- damage of hollow organs ((e.g. e.g. stomach, stomach,

intestineintestiness))

- rupture of alveoli and pulmonary- rupture of alveoli and pulmonary capilcapilllaryary

- commotio cerebri- commotio cerebri

Decompression sickness (caisson disease)

Who is in risk? – underwater construction workers

– deep sea divers

– unpressurised aircraf fly

Mechanisms: – return too quickly from deep level of sea to the surface causes a form of gas embolism

– CO2 and N which are normally disolved in the

blood come out and forme tiny bubbles gas emboli

Consequences: – nitrogen bubbles may obturate microvessels in tissue and persist there – larger bubbles in larger vessels obstruct their lumenischemia in muscles, joints, tendons

pain, necrosis

Ionizing radiation (IR)

IR– any form of radiation capable of removing orbital electrons from atoms ions

Sorces of IR: – x-rays, γ rays, and particles, neutrons, protons, sunlight

The most abundant source of exposure to IR is:

– the environment – e.g. cosmic rays, buildings and soil radiation materials– diagnostic and treatment procedures e.g. CT scans may be responsible for

24% of the total „backround“ radiation to which the population is exposed in

the given year (Sin et al., 2011)

The mechanisms by which IR damages the cells

• Direct damage – influence of vulnerable molecules in the cell

• Indirect damage – radiolysis of water radicals

Consequences: – damage of DNA, genes, chromosoms

• damage of somatic cells necrosis, apoptosis, cancer

• damage of gamete genetic (inherited) diseases

• damage of fetus spontaneous abortus, increased perinatal mortality

Prolonged and strong vibrationMain sorces: - vibrating machinery, e.g. track and bus drivers, construction workers, farmers...

Whole-body vibration (resonance) - begins at 5Hz

Consequences: - oxygen consumption in tissues

- pulmonary ventilation

- development of bone deformities

- calcification of intervertebral discs

- incidence of bowel, blood, respiratory

and musculosceletal disordersSegmental vibration – often the fingers and hands are damaged

People in risk: - operators of chain saws, pneumatic hammer, rotary grinders

Cosequences: - Raynaud´s phenomenon

Characteristics: - numbness and white fingers

- some loss of fine movements due to

muscular control disorders

- decreased sensitivity to heat and cold

Noise – it is a sound that has potential for inflicting bodily harm (usually

more than 50dB)

Consequences: – hearing impairment

It can be due to: - acute loud noise

- cumulative effect of various intensities, frequences and durations of noise

• Acoustic trauma – rupture of eardrum,

– displace of ossicles of the middle ear,

– damage of organ of Corti in the inner ear

• Noise-induced hearing loss – is gradual due to prolonged exposure to intense sounds

Mechanism: – vasoconstriction of small vessels in cochlea

oxygen dilivery to hair cells hypoxic

damage

• Neurosis different kinds of psychosomatic disorders

Kinetosis (motion sickness) – your mind perceivinga movement that doesn't agree with what your sense of balance is telling you

– manifestation of vestibular system dysfunction

– dysfunction is manifested by „stormy“ reaction of

vegetative nerve system dysbalance sympathetic

and parasympathetic nerve systems

Main symptoms: - abdominal pain, nausea, dizziness

Main signs: - tachycardia, decrese of BP, vomiting

Acceleration–deceleration: sudden and quick changes in movement

directions of the body in the space

Consequences: - negative influence on CVS

- negative influence on vestibular system

Damages induced by electricityAlternate electric current is dangerous for living organisms,

only when its parameters are: - more than 50 V, more than

75 mA

Consequences: - thermic damage burns

- depolarisation of the cells nerv system and heart dysfunctions

- mechanical damage dysruption of skin and muscles

Mechanisms: - thermic damage – due to resistance heat creation

- depolarisation – due to depolarisation of the cell

membranes by high voltage current asystolia, ventricular fibrilation, muscle cramps

Chemical noxas

a/ Inorganic – elements: As, Hg, Pb.... compouds: SO2, NOx, organophosphates...b/ Organic – organic acids, amonium... – plant and animal toxins

1. Exogenous

2. Endogenous – NH3, uric acid, keton bodies...

The effect of chemical noxas on cells depends on: - dose exposed to - place of entry to the body - speed of entry - duration of exposition - properties of noxa - properties of tissue/cells - capacity of detoxification systems

Main mechanisms involved in injury by chemicals

1. Damage of cell structures

a/ cytoplasmatic – by heavy metals, alcohols, acids...

b/ membranes – by organic solvents, azbest...

2. Disturbancies in synthesis of macromolecules e.g. ribonukleotides by alfa-amanitin (from toadstool-green)

3. Damage of transport membrane mechanisms e.g. by bees and snaky venoms

4. Damage of energetic metabolism of the cells e.g. glycolytic process damaged by fluorids or oxidative phosphorylation by cyanide

5. Cell division – e.g. by cytostatics

6. DNA – e.g. mutagens

Main consequences of chemical injury

A/ Inactivation or/and denaturation of cell enzymes

B/ Creation of inactive complexes by interaction of noxa with

important cell molecules: e.g. cyanide +Fe3+ inactive complex impairment of oxidative phosphorylation, ihibition of cytochrome oxydase a3 ihibition of tissue “breathing“ e.g. arsenic +pyruvatedehydrogenase inactive complex:

- if it is in the heart there is alternative way for

energy creation no heart damage - if it is in nerves there is not alternative way for energy production blockade of energy creation damage of

the nerve system

C/ Damage of conjugation process- toxic chemicals can't be conjugated and excrete from the body

D/ Lethal synthesis – due to „mistake“ of detoxication proces creation of very toxic product

E/ Binding of chemicals on important molecules e.g. CO on Hb

Stages of cell injury by chemicals

cytopathic effect – the functions of the cell is changed/inhibited but it is able to live and can proliferate

cytostatic effect – cell is still alive but it lost the ability to proliferate

cytotoxic effect – cell death

Intoxication by organophoshates

Organophosphates: - chemical compounds used as insecticides and herbicides (e.g. Fosdrin, Intrathion)

Entry to the body: - skin, conjunctives, mucose membranes of respiratory and GIT systems

Detoxified in: - liver, kidney

Main effects of organophoshates: – inhibition of ACH-

esterases

Consequences: -concentration of ACH in synaptic cleft

stimulation of

postganglionic cholinergic nerve fibres

Manifestations: - muscarinic effect: nausea, vomiting,

abdominal pain, diarhoe, sweating, miosis, overproduction of mucus in the airway

- nicotinic effect: tremor, muscle twitches,

cramps

- stimulation of sympathetic NS: BP, HR

- stimulation of CNS: cramps, coma

Entry of noxaEntry of noxaee to the organism to the organism

NoxaNoxaee can entry to the organism through: can entry to the organism through:

-  skin-  skin

-  mucous membranes-  mucous membranes of : of : respiratory tractrespiratory tract

gastrointestinal tractgastrointestinal tract

-- CNSCNS (psychogenic predominantly)(psychogenic predominantly)

Predilection placesPredilection places - - places in the organism throughplaces in the organism through which the noxawhich the noxaee can enter the organism more easy then through can enter the organism more easy then through other onesother ones

Spreading of noxaSpreading of noxaee in the organism in the organism

1.1. hematogenous wayhematogenous way

2.  lymphatic way2.  lymphatic way

3.  3.  alongalong nerv nerveess

4.  canalicular way4.  canalicular way

5.  per continuitatem5.  per continuitatem

Types of interaction between causes of disease Types of interaction between causes of disease and disease itselfand disease itself

Disturbances autoregulation of body functions Disturbances autoregulation of body functions - their importance for pathogenesis- their importance for pathogenesis

• AutoregulationAutoregulation - - Autoregulation is a process within many biological Autoregulation is a process within many biological systems, resulting from some internal adaptive systems, resulting from some internal adaptive mechanism that works to adjust (or mitigate) mechanism that works to adjust (or mitigate) the systems response to stimulithe systems response to stimuli

- processes which are responsible for maintaining processes which are responsible for maintaining homeostasishomeostasis

• Mechanisms of autoregulationMechanisms of autoregulation - - they are present and active at different they are present and active at different level of the bodylevel of the body structuresstructures::

a)a) autoregulation at the level of subcellular structuresautoregulation at the level of subcellular structures - - gen regulation (cell „tels“ to DNA what the cell needs, the DNA to gen regulation (cell „tels“ to DNA what the cell needs, the DNA to

produce)produce) -- enzymatic reactionsenzymatic reactions, cell division, cell death, e.g. by apoptosis, cell division, cell death, e.g. by apoptosis

b) b) supracellular control mechanismssupracellular control mechanisms - - by releasingby releasing different kind of different kind of

cytokinescytokines,, hormons by which thormons by which the communication cell to cell is he communication cell to cell is

performedperformed – – e.g. control number of cells in tissuese.g. control number of cells in tissues

•• Homeostatic curveHomeostatic curve - - it shows autoregulative capacity of it shows autoregulative capacity of tthe body he body

organs,organs, systemssystems and whole organism and whole organism (see scheme)(see scheme)

•• Dysregulative pathophysiologyDysregulative pathophysiology - - deals with the pathomechanisms deals with the pathomechanisms

in which thein which the disturbance of disturbance of autoregulation autoregulation mechanisms mechanisms areare primary primary

causecause of disease of disease, e, e.g. endocrine.g. endocrine glands dysfunction, malignant glands dysfunction, malignant

processesprocesses

c) c) autoregulation at autoregulation at the the level level of of organs organs and and systemssystems of the bodyof the body

– – neuralneural and endocrineand endocrine (humoral) (humoral) mechanisms (feed-backmechanisms (feed-back loops loops))

– – result is co-ordinating function of organs and systemsresult is co-ordinating function of organs and systems

HOMEOSTATIC CURVEHOMEOSTATIC CURVE

yy = the level of living processes = the level of living processes

xx = external (internal) damaging factors = external (internal) damaging factors

yy

xx

AA

BB

CC

Decreasing activity of EASe.g. enzymatic defect or decreased activity of cell enzymes due to changed cell environment (acidosis) cell function

Increased activity of EAS

e.g. increased activity of cell enzymes cell activity (body temperature)

•• Disturbance of EASDisturbance of EAS

a)  activity of EAS a)  activity of EAS is is decreadecreasedsed

b)  activity of EAS b)  activity of EAS is is increasincreaseded

• • Endogenous amplifying system of cell (EAS)Endogenous amplifying system of cell (EAS) -- t the system which amplify the signal coming tohe system which amplify the signal coming to the cell the cell many times (10many times (1077 - 10 - 1088))

•• Dysregulation of calcium level in Dysregulation of calcium level in a a cellcell

[ Ca[ Ca++++] in cell ] in cell activation of cell proteases,activation of cell proteases, lipases lipases cell cell proteinsproteins

and and membranemembrane proteins proteins damage damage cell deathcell death• Dysregulation of apoptosis

apoptosis number of cells

apoptosis number of cells

● Dysregulation of feed-back mechanisms

Norm: blood glucose levelinsulin production blood glucose

level insulin production

Pathol: blood glucose levelinsulin production insulin resistance

another insulin production development glucose tolerance

Examples:

•• Dysregulative diseasesDysregulative diseases

- Disturbances of breathing controlDisturbances of breathing control (e.g. (e.g. central central sleep apnoea sy., Pikwick sy.)sleep apnoea sy., Pikwick sy.)

- Disturbances of blood pressure controlDisturbances of blood pressure control (essential hypertension)(essential hypertension)

- Diabetes mellitus type 2Diabetes mellitus type 2

- - HHypo- or hyperthyreosis, alergy, immunodeficiency, ypo- or hyperthyreosis, alergy, immunodeficiency, hyporeactivity,hyporeactivity, hyperreactivityhyperreactivity of airway,... of airway,...

Examples

•• Antagonistic regulation of body functionsAntagonistic regulation of body functions

-- re repolarization of cellpolarization of cell depolarisationdepolarisation

- - stimulationstimulation inhibitioninhibition - - proteasesproteases antiproteasesantiproteases - - oxidantsoxidants antioxidants antioxidants

- - stressstress antistressantistress

- sympathetic nervsympathetic nerve e parasympathetic nervparasympathetic nervee system activitysystem activity system activitysystem activity

Under normal condition there is Under normal condition there is dynamic dynamic balance between balance between antagonistic functions in the human body antagonistic functions in the human body homeostasishomeostasis

Antagonistic regulation of body functions

Example: it is the existence of two opposing systems (A and neg – A) activated by a common signal and controling a single target system

System A System -A

Common signal

Single target system-final reaction

Stressor

Catecholamins

Skin vessels Muscle vessels

Vasoconstriction-Vasodilation

Apoptosis in the pathogenesis of diseaseApoptosis in the pathogenesis of disease

•• In multicellular organisms, homeostasis is maintained through In multicellular organisms, homeostasis is maintained through

a a balance between cellbalance between cell proliferation and cell deathproliferation and cell death

•• Different cell types vary widely in the mechanisms by which Different cell types vary widely in the mechanisms by which they they maintainmaintain themselves over the life of the organism:themselves over the life of the organism:

•   •   blood cellsblood cells - constant renewal - constant renewal

•   •   cell of reproductive systemcell of reproductive system - cyclical expansion and- cyclical expansion and contractioncontraction• neural cellsneural cells - limited capacity for self - limited capacity for self - renewal- renewal

Control of cell number is determined by balance betweenControl of cell number is determined by balance betweencell proliferation and cell deathcell proliferation and cell death

The effect of different rates of cell death on homeostasisThe effect of different rates of cell death on homeostasis

In mature organisms, cell number In mature organisms, cell number iis controlled as a result of the net effects s controlled as a result of the net effects

of cell proliferation and cell death. Here, the rates of cell proliferation and cell of cell proliferation and cell death. Here, the rates of cell proliferation and cell

death are indicated by the size of the arrows. In the absence of compensatorydeath are indicated by the size of the arrows. In the absence of compensatory

changes in the rate of cell proliferation, changes in the rate of cell death changes in the rate of cell proliferation, changes in the rate of cell death

can result in either cell accumulation or cell losscan result in either cell accumulation or cell loss

Fig. Fig. 22

• Regulation of cell death is just as complex as theRegulation of cell death is just as complex as the regulation of cell proliferation:regulation of cell proliferation:

- The cells appear to share the ability to curry out The cells appear to share the ability to curry out their own death their own death throughthrough activation of an internally encoded activation of an internally encoded ""suicide programsuicide program"". .

When activated,When activated, characteristic form of cell death is initiated.characteristic form of cell death is initiated.

-- This form of cell death is called apoptosisThis form of cell death is called apoptosis

•• Apoptosis can be triggered by a variety of extrinsic and Apoptosis can be triggered by a variety of extrinsic and intrinsic signalsintrinsic signals TheThe result is: result is: - elimination of cells:- elimination of cells:

•   •   produced in excessproduced in excess

•   •   developed improperlydeveloped improperly - have sustained genetic damage- have sustained genetic damage•• damaged cellsdamaged cells

Inducers of ApoptosInducers of Apoptosiiss

Physiologic activatorsPhysiologic activators

1.TNF family1.TNF family

2. Transforming2. Transforming growth factor growth factor

3. Neurotransmitters 3. Neurotransmitters -Glutamate-Glutamate -Dopamine-Dopamine -N- methyl-D-aspartate-N- methyl-D-aspartate

4. Growth factor withdrawal4. Growth factor withdrawal

5. Loss of matrix attachment5. Loss of matrix attachment

6. Calcium6. Calcium

7. Glucocorticoids7. Glucocorticoids

Damage-relatedDamage-related Inducers Inducers

1.1.Heat shockHeat shock

2. Viral infection2. Viral infection

3. Bacterial toxins3. Bacterial toxins

4. Oncogenes4. Oncogenes myc, rel, E1Amyc, rel, E1A

5. Tumor suppressors p535. Tumor suppressors p53

6. Cytolytic T cells6. Cytolytic T cells

7. Oxidants7. Oxidants

8. Free radicals8. Free radicals

9. Nutrient deprivation-9. Nutrient deprivation- antimetabolitesantimetabolites

Inducers of ApoptosInducers of Apoptosiiss

Therapy-associatedTherapy-associated

1.1.ChemotherapeuticChemotherapeutic drugsdrugs - c- cisplatinisplatinaa, doxorubicin, doxorubicin bleomycin, cytosinebleomycin, cytosine arabinoside, nitrogenarabinoside, nitrogen mustard, metho-mustard, metho- trexate, vincristinetrexate, vincristine

2. Gamma radiation2. Gamma radiation

3. UV radiation3. UV radiation

ToxinsToxins

1. Ethanol1. Ethanol

2. 2. -amyloid-amyloid

peptidepeptide

Diseases Associated with Increased ApoptosisDiseases Associated with Increased Apoptosis

11.. AIDSAIDS

2.2. Neurodegenerative disordersNeurodegenerative disorders Alzheimer's disease Alzheimer's disease Parkinson's disease Parkinson's disease Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis Retinitis pigmentosa Retinitis pigmentosa Cerebellar degenerationCerebellar degeneration

3.3. Myelodysplastic syndromesMyelodysplastic syndromes Aplastic anemiaAplastic anemia

4.4. Ischemic injuryIschemic injury Myocardial infarction Myocardial infarction Stroke Stroke Reperfusion injuryReperfusion injury

5.5. Toxin-induced liver diseaseToxin-induced liver disease AlcoholAlcohol

Neurodegenerative disease

- Due to genetic disorders: mutated gene repeat CAG nucleotid triplet (encodes glutamín) a) polyglutamine tract creation of glutamine residues toxic

properties of them polyglutamine disease

b) alpha – synuclein (amyloid precursor protein – in Alzheimer

disease)

Autoregulative pathways in removing of pathologic proteins:

Proteosome enzymes +ubiquitin cleaving of irregular protein

Autophagy-lysosome pathway = a form of programmed cell

death

- macroautophagy – involved within nutrient recycling of

macromolecules

under condition of starvation

- chaperon-mediated autophagy

If these processes are ineffective accumulation of toxic protein in

cells

•• Although diverse signals can induce apoptosis in Although diverse signals can induce apoptosis in

a wide variety of cell types, a number of evolutionary a wide variety of cell types, a number of evolutionary

conserved genes regulate a final common cell death conserved genes regulate a final common cell death

pathway that ispathway that is conserved from worms to humansconserved from worms to humans

•• Apoptotic cell death can be distinguished from Apoptotic cell death can be distinguished from necrotic cell deathnecrotic cell death

●● Necrotic cell deathNecrotic cell death = = pathologic fpathologic fororm of cell death m of cell death resulting resulting from acute cellular injury,from acute cellular injury, which is typified bywhich is typified by rapid rapid cellcell swelling and lyswelling and lyssis,is, accompaniedaccompanied byby inflammatory inflammatory reactionreaction

A hypothetical model for the regulation of A hypothetical model for the regulation of apoptotic cell deathapoptotic cell death

Growth factorGrowth factorwithdrawalwithdrawal

Activation of Activation of death death

receptorsreceptors

CytotoxicCytotoxic T cellsT cells

EndonucleasEndonucleasee activation activation

Central cell Central cell death signaldeath signal

Protease Protease

activationactivation

Cell Cell surfacesurface

alterationalterationss

PhagocytosiPhagocytosiss

DNA DNA damagedamage

Metabolic or cell Metabolic or cell cycle cycle

perturbationsperturbations

CytoskeletalCytoskeletalreorganireorganissatiati

onon

BCL 2BCL 2P 53

•• Apoptotic cell death = physiologic fApoptotic cell death = physiologic fororm of cell death characterized bym of cell death characterized by

controlledcontrolled autodigestionautodigestion of the cellof the cell. .

No inflammatory reaction is presentNo inflammatory reaction is present

- Cells appears to initiate their own apoptotic death through the Cells appears to initiate their own apoptotic death through the

activation ofactivation of endogenous proteasesendogenous proteases cytoskeletal disruption, cytoskeletal disruption,

cell shrinkage, membranecell shrinkage, membrane blebbingblebbing

- The nucleus undergoes condensationThe nucleus undergoes condensation asas endonucleases endonucleases are are

activated activated degradation of nuclear degradation of nuclear DNADNA

-  -  Loss of mitochondrial functionLoss of mitochondrial function  

- PhagocytosisPhagocytosis

- Cells not immediately phagocytosed break down into smaller Cells not immediately phagocytosed break down into smaller

membrane – boundmembrane – bound fragments called fragments called apoptotic bodiesapoptotic bodies

•  •  ReReccent evidence suggests that the ent evidence suggests that the failure of cells to undergo apoptotic failure of cells to undergo apoptotic cell death might becell death might be involved in the pathogenesis of a variety of human involved in the pathogenesis of a variety of human diseasesdiseases

•  •  Wide number of diseases characterized by cell loss, may Wide number of diseases characterized by cell loss, may

result from accelerated rates ofresult from accelerated rates of physiologic cell deathphysiologic cell death

•• So, talking about pathogenesis of different kind of diseases So, talking about pathogenesis of different kind of diseases we have we have

to take intoto take into a account the changed apoptosis for explanation ccount the changed apoptosis for explanation

of some pathological processesof some pathological processes

Inhibitors of ApoptosisInhibitors of Apoptosis

Fig. Fig. 66

Physiologic InhibitorsPhysiologic Inhibitors1. 1. Growth factorsGrowth factors

2. Extracellular matrix2. Extracellular matrix

3. CD40 ligand3. CD40 ligand

4. Neutral amino acids4. Neutral amino acids

5. Zinc5. Zinc

6. Estrogen6. Estrogen

7. Androgens7. Androgens

Viral genesViral genes1.1. Adenovirus Adenovirus E1BE1B 2. 2. Baculovirus Baculovirus p35p35 3. 3. Baculovirus Baculovirus IAPIAP 4. 4. Cowpox virus Cowpox virus crmAcrmA 5. 5. Epstein-Barr virus Epstein-Barr virus BHRF1, LMP-1BHRF1, LMP-1 6. 6. African swine fever virus African swine fever virus LMW5-HL LMW5-HL

7. 7. Herpesvirus Herpesvirus 34.534.5

Pharmacological agentsPharmacological agents1.1. Calpain inhibitorsCalpain inhibitors 2.2. Cysteine protease inhibitorsCysteine protease inhibitors3. 3. Tumor promotersTumor promoters

- PMA - PMA PhenobarbitaPhenobarbitall - - HexachlorocydohexaneHexachlorocydohexane

Diseases Associated with the Inhibition ofDiseases Associated with the Inhibition of aapoptospoptosiiss

1.1. CancerCancer

Follicular lymphomas Follicular lymphomas Carcinomas with Carcinomas with p53 p53 mutations mutations - - Hormone-dependent tumorsHormone-dependent tumors - - Breast cancerBreast cancer - - Prostate cancerProstate cancer - - Ovarian cancerOvarian cancer

2.2. Autoimmune disordersAutoimmune disorders

Systemic lupus erythematosus Systemic lupus erythematosus Immune-mediated glomerulonephritisImmune-mediated glomerulonephritis

3.3. Viral infectionsViral infections HerpesvirusesHerpesviruses,, Poxviruses Poxviruses,, Adenoviruses Adenoviruses

Fig. Fig. 55

Regulation of cell volume in health and diseaseRegulation of cell volume in health and disease

• •   Maintenance of a constant volumeMaintenance of a constant volume in the face of extracellular in the face of extracellular

and intracelullar osmoticand intracelullar osmotic perturbations perturbations is critically important is critically important

for for cells cells existence and functionexistence and function

• •     There is a lot of physiological and pathological situations in the body, There is a lot of physiological and pathological situations in the body, which arewhich are characterized by characterized by changes of osmolality in intra- and/or changes of osmolality in intra- and/or

extracellular spaceextracellular space

● ● Most cells respond to swelling or shrinkMost cells respond to swelling or shrinkinging by by activating specific activating specific

metabolic ormetabolic or membrane – transport processes that return cell membrane – transport processes that return cell

volume to volume to its normal resting stateits normal resting state

RememberRemember eessential biophysical law: ssential biophysical law: Water will flow from Water will flow from hypoosmotic space to hyperosmotic onehypoosmotic space to hyperosmotic one!!

Activation of mechanisms regulating cell volume Activation of mechanisms regulating cell volume in response to volume perturbationsin response to volume perturbations

TimeTime TimeTime

RReellaattíívvee

CCeellll

VVoolllluummee

Extracellular hypotonicityExtracellular hypotonicity

Regulatory volumeRegulatory volumedecreasedecrease

Regulatory volumeRegulatory volumeincreaseincrease

Extracellular hypertonicityExtracellular hypertonicity

Fig. 8Fig. 8

•  •  Volume of the cell can be Volume of the cell can be controled controled by by decreasing ordecreasing or increasingincreasing

concentration ofconcentration of osmoticalosmoticallly active solutes in the cells.y active solutes in the cells.

Volume-regulatory accumulation and loss of electrolytesVolume-regulatory accumulation and loss of electrolytes are are

mediatedmediated

byby changes in the activity of membrane carriers and channels changes in the activity of membrane carriers and channels

(K(K++; Cl; Cl--; ; NaNa++KK++2Cl2Cl--; ; HH++// NaNa++;; HCOHCO33- - //CCll--))

• Key role in cell-volume homeostasis belongs to Key role in cell-volume homeostasis belongs to organic osmolytesorganic osmolytes

(polyols(polyols - - sorbitol, myo-inositol; aminoacidssorbitol, myo-inositol; aminoacids taurine, alanine and proline; taurine, alanine and proline;

methylamines - betain,methylamines - betain, glycerylphosphorylcholine). glycerylphosphorylcholine).

These are "compatible", "nonperturbing" solutesThese are "compatible", "nonperturbing" solutes

Mechanisms involved in cell-volume Mechanisms involved in cell-volume regulationregulation

When a When a shrinkage of a cellshrinkage of a cell is present the cell reacts to the situation is present the cell reacts to the situation

immediately byimmediately by activation of membrane transport systemactivation of membrane transport system

(inside of seconds - Fig. 9A - left side). It will(inside of seconds - Fig. 9A - left side). It will lead to lead to accumulation of accumulation of

anorganic osmolytesanorganic osmolytes (Na(Na++, K, K++, Cl, Cl--) inside the cell, and secondary,) inside the cell, and secondary,

accumulation of water.accumulation of water.

•  •  When When extracellular hyperosmolalityextracellular hyperosmolality will last longerwill last longer (48h and longer) (48h and longer)

than than anorganicanorganic osmolytes in the cell are substituted by organic osmolytes in the cell are substituted by organic

one's one's (Fig. 9B - left side)(Fig. 9B - left side)

•• Swelling of a cellSwelling of a cell will activate immediately the regulatory volume will activate immediately the regulatory volume

decrease mechanismsdecrease mechanisms (Fig. 9 A - right side). If a swelling (Fig. 9 A - right side). If a swelling lasts for lasts for

a short time,a short time, only, the regulatory volumeonly, the regulatory volume decrease is done decrease is done by loss by loss

of KCof KCll, , very quickly.very quickly.

•• Cell swelled for a longer time are unable to loss accumulated Cell swelled for a longer time are unable to loss accumulated

organic organic

osmolytes veryosmolytes very quickly when exposed to normotoquickly when exposed to normotonnic extracellular ic extracellular

spacespace – –

this is the reason this is the reason why why they willthey will accumulate water and extreme cell accumulate water and extreme cell swelling will occurswelling will occur..

•• This is the situation when patient suffering from long-lastingThis is the situation when patient suffering from long-lasting hyperosmolarity of hyperosmolarity of extracellular fluid (e.g. decompensated extracellular fluid (e.g. decompensated diabetesdiabetes

mellitus - DM) is rehydrated quickly with resulting mellitus - DM) is rehydrated quickly with resulting

normoosmolality of normoosmolality of extracellular fluid. Such a situation extracellular fluid. Such a situation will lead to cell edema –will lead to cell edema – eesspeciallypecially edema of brain cellsedema of brain cells

Measurements of cell-volume changes in rat C6 glioma cells Measurements of cell-volume changes in rat C6 glioma cells acclimated to brief periods of hypertonicityacclimated to brief periods of hypertonicity

LLIIGGHHTT

SSCCAATTTTEERRIINNGG

(V)(V) 77

55

33

11

-1-1

- 3- 3

- 5- 5

00 400400 800800 15001500

S e c o n d sS e c o n d s

0.70.7

1.01.0

1.41.4 RREELLAATTIIVVEE

VVOOLLUUMMEE

HYPERTONICITYHYPERTONICITY

Fig. Fig. 10 A10 A

NORMOTONICITY

11

00

-1-1

-2-2

-3-3

- 4- 4

- 5- 5

00 400400 800800 12001200S e c o n d sS e c o n d s

1.01.0

1.21.2

1.41.4HYPERTONHYPERTON

Measurements of cell-volume changes in rat C6 Measurements of cell-volume changes in rat C6 glioma cells acclimated to prolonged periods of glioma cells acclimated to prolonged periods of

hypertonicityhypertonicity

Fig. Fig. 10 B10 B

RREELLAATTIIVVEE

VVOOLLUUMMEE

LLIIGGHHTT

SSCCAATTTTEERRIINNGG

(V)(V)

NORMOTONICITY

• Disturbances of cell volume regulation is one important Disturbances of cell volume regulation is one important patomechanismpatomechanism

involved ininvolved in development of diabetic complications (peripheral development of diabetic complications (peripheral neuropathy, neuropathy,

retinopathy, cataractretinopathy, cataract formation).formation).

•• Unproper function of cell volume regulatory Unproper function of cell volume regulatory

mechanisms are involved in sickle cell crisismechanisms are involved in sickle cell crisis (Fig. 11).(Fig. 11).

Model of Shrinkage- Induced Sickling of Model of Shrinkage- Induced Sickling of Red Cell in Patients Homozygous for HbSRed Cell in Patients Homozygous for HbS

Essential forms of pathological answers of the Essential forms of pathological answers of the organism to noxaorganism to noxaee

1.1. pathological reactionpathological reaction

- it is usually short and quantitatively and/orit is usually short and quantitatively and/or qualitativelyqualitatively different from physiological reactiondifferent from physiological reaction

Examples:Examples: • • pathological reflexespathological reflexes

•   •   allergic reactionallergic reaction (some types, only)(some types, only)

•   •   decreasing of systemic blood pressure for a short timedecreasing of systemic blood pressure for a short time (syncopa)(syncopa)

- essential, the most simple reaction of the essential, the most simple reaction of the organism to organism to tthehe influence of noxainfluence of noxaee

2.2. pathological processpathological process - complex of pathological - complex of pathological reactions, adaptive and defensivereactions, adaptive and defensive reactions induced reactions induced by influence of noxas by influence of noxas

Examples:Examples: • • malignant neoplasmmalignant neoplasm•   inflammation and fever•   inflammation and fever•   •   edemaedema

3. 3. pathological statepathological state - the result of pathological- the result of pathological process or accident lasted for years orprocess or accident lasted for years or during the during the whole life whole life

Examples: Examples: • • congenital diseasescongenital diseases •  •  deaf and dumbdeaf and dumb

• • leg amputationleg amputation

Exacerbation of a diseaseExacerbation of a disease - - occurence of repeated occurence of repeated eepisodespisodes of acute attacs of disease in the course of chronic of acute attacs of disease in the course of chronic diseasedisease

Recidivation of a diseaseRecidivation of a disease - if a disease is interrupted by - if a disease is interrupted by full or partial recovery for a certain timefull or partial recovery for a certain time and than and than it flares it flares up againup again

Remision of a diseaseRemision of a disease - some symptoms and signs may - some symptoms and signs may disappear in the course of chronic disease or they loss their disappear in the course of chronic disease or they loss their intensity for a certain time. This period is called intensity for a certain time. This period is called remisionremision

Two types of disease courseTwo types of disease course•   •   benign coursebenign course•   •   malignant coursemalignant course