general etiopathogenesis of diseases prof. j. hanacek, m.d.,csc
TRANSCRIPT
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