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MAJOR CREDIT SEMINAR ON
MOLECULAR MECHANISM OF PARENCHYMAL CELL INJURY AND THEIR ULTRASTRUCTURE
PRESENTED BY- SWATI CHAUDHARY M VSc SCHOLAR IVRI
M 5429
Introduction
Rudolph Virchow , “father of cellular pathology” , put forward the concept that disease begins at the cellular level.
METHODS OF STUDYING PATHOLOGY
• Gross examination• Light microscopy• Immunochemistry• Electron microscopy• Molecular biology
Organ Parenchymal cells
Brain Neurons and glial cells
Heart Myocyte
Kidney Nephron
Liver Hepatocyte
Lungs
Alveolar tissue with respiratory
bronchioles, alveolar ducts and terminal
bronchioles
Ovary Follicles with egg cells
PancreasIslets of
Langerhans and Pancreatic acini
Spleen White pulp and red pulp
Ultrastructure of a typical animal cell
Plasma membrane
Ultrastructure of different organelles of the cell
Cell injury
Cell injury is a sequence of events that occur if the limits of adaptive capability are exceeded or no adaptive response is possible.
The capacity for adaptation and the sensitivity to different types of injury varies according to cell type.
+ Stress
Injury+Stress
Apoptosis
Necrosis
- Stress
- Stress
Overview of cell injury
AdaptedCell
Normal cell
Reversiblyinjured cell
Irreversibly Injured cell
AdaptedCell
Dead cell
CausesCauses of cell injury of cell injury
Hypoxia Ischemia Physical agents Chemical agents Infective agents Immunologic reaction Genetic injury Nutrition imbalance
Common bio molecular mechanism of cell injury1. ATP depletion
2. Loss of calcium homeostasis
3. Oxidative stress
4. Damage to mitochondria
5. Defect in membrane permeability
Cell injury caused by ATP depletion /hypoxia
Neurons and cardiac myocytes are rapidly injured by ATP decrease
The Na+/K+ ATPase Pump Almost one-third of all the energy generated by the
mitochondria in animal cells is used to run this pump.
Formation of lactic acid during Formation of lactic acid during ATP depletionATP depletion
lactate and H+, causes cytosolic acidosislactate and H+, causes cytosolic acidosis Interferes with the functions of the intracellular Interferes with the functions of the intracellular
enzymes, thus resulting in the inhibition of the enzymes, thus resulting in the inhibition of the glycolysis so that this last source of ATP dries upglycolysis so that this last source of ATP dries up
Change in conformation of protein moleculesChange in conformation of protein molecules Increase of Permeability of cellular membranesIncrease of Permeability of cellular membranes Activating enzymes of lysosomes.Activating enzymes of lysosomes.
Ca2+ Mg ATPase pump
It uses the energy provided by one molecule of ATP to pump one Ca2+ ion out of the cell.
Increased ICF Ca+2 in cell due to reduced ATP production
Sustained rise in Ca level is initial step of irreversible injury.
Increased Cytosolic Calcium in Cell Injury
Uncoupling of gap junction
Mitochondrial damage
• Phospholipase damage to membrane
• Formation of high conductance channels c/d as MPT
• Loss of the H+ gradient , preventing ATP generation.
• Swelling due to ionic shifts• Deposition of amorphous substance• Finally, rupture of membrane
followed by progressing increased calcification.
Swollen mitochondria and endoplasmic reticulum
Loss of cristae
Rupture of mitochondria
MEMBRANE DAMAGE
SOME PORE-FORMING BACTERIAL TOXINS
Toxins Bacterial source
Hemolysin Escherichia coli
Listeriolysin Listeria monocytogenes
Anthrax EF Bacillus anthracis
Alpha toxin Staphylococcus aureus
Pneumolysin Streptococcus pneumoniae
Streptolysin O Streptococcus pyogenes
Leukocidin Staphylococcus aureus
Perfringiolysin O Clostridium perfringens
Ultra structural changes in plasma membrane
Cellular swelling Formation of cytoplasmic blebs Blunting and distortion of microvilli Creation of myelin figures Deterioration and loosening of intercellular
attachments
Ultra structural changes in Endoplasmic reticulum
Free Radicals in Injury
Radiation-Induced Cellular Injury
Direct DNA damageDNA directly absorbs the UV radiationCauses thymine dimer formation.
Indirect damage Absorption of radiant energy (ultraviolet light & x-rays): H2O OH* & H*
Chemical injury
A very large number of chemicals can produce reversible and irreversible injury. Hepatic cells is the most common target for toxic chemical injury
(REYNOLD.E.S., 1963)
Liver injury by CCl4
Dilatation of golgi
Dilatation of mitochondria
Dilatation of ER
(Jeffrey H. Teckman) 2002
Effects of viruses• Inhibition of Host Macromolecular Biosynthesis• Changes in the Regulation of Gene Expression• Appearance of New Antigenic Determinants on the Cell Surface. • Cell Fusion
Infectious agentsInfectious agents
virus infection, Liver
H&E EM
Reversible Injury
Caused by mild injury of short duration characterized by
• Cell Swelling• Hydropic or Vacular
Degeneration• Intracellular
accumulation
REVERSIBLE CELL INJURY
Mitochondrial swelling in acute ischemic cell injury
Renal tubular epithelium –reversible ischemic injury
• Loss of microvilli • Surface blebbing • Slight swelling of
mitochondria• Clumping of
nuclearchromatin
(http://www.studyblue.com)
PCT cell
Irreversible injury
The transition to irreversible injury depends on the extent of ATP depletion and membrane dysfunction especially of mitochondria
Enzymatic digestion of dead cellular elements
Denaturation of proteins Cytoplasm - increased eosinophilia
Epithelial cell proximal kidney tubule A. NormalB. Reversible ischemic changesC. Irreversible ischemic changesc changes
http://www.studyblue.com
Autophagic vacuoles (a) containing
damaged mitochondria after induced hypoxia of
15 mins
(Decker R.S. and Wildenthal (1979)
Myocyte after 1h of hypoxia. Display many
feature of irreversible cell injury ,severely condensed
chromatin (N), relaxed myofibril (S) , rupture of
sarcolemma is also observed(SL)
Decker et al., 1980
Death of cells occurs in three ways
Necrosis
Apoptosis
pyro ptosis
Necrosis
Necrosis is accidental, uncontrolled, un-programmed cell death
Pyknosis
Karyorrhexis
Karyolysis
Normal Pyknosis Karyorrhexis Karyolysis
Histological changes in necrosis
(Jerome niquet 2003)
Necrosis in neuronal cell due to hypoxia
Apoptosis
An internally programmed series of events effected by dedicate gene products
In necrotic neurons, the mitochondrial structure is irreversibly damaged, but appears functional in apoptotic cells. because apoptosis needs energy for it’s own cellular destruction.
Pyroptosis
Is a form of programmed cell death associated with antimicrobial responses during inflammation
Immune cells that recognize certain danger signals within themselves , produce cytokines, swell, burst and die.
Releases the cytokines, attracts other immune cells , contributes to inflammation.
Pyroptosis occurs for example in salmonella infected macrophages and in HIV-infected T helper cells.
Characteristics Apoptosis Pyroptosis necrosis
Morphology
Cell lysis NO YES YES
Cell swelling NO YES YES
Pore formation NO YES YES
Membrane blebbing
YES NO NO
DNA fragmentation
YES YES YES
Mechanism
Caspase-1 NO YES NO
Caspase-3 YES NO NO
Cytochome-c release
YES NO NO
OutcomeInflammation NO(anti) YES YES
Programmed cell death
YES YES NO
CONCLUSION Cell is the structural and functional unit of tissue
or organ Normal cell has to remain live with in narrow
range of structure and function Cell try to escape from injury by adaptive
responses like hypertrophy, hyperplasia If adaptive capability exceeded cell suffer from
injury it may be reversible or irreversible . Necrosis and apoptosis are main mechanisms of
cell death. Apoptosis can be a physiological and pathological process
Knowledge about injury at the sub cellular organelle and molecular levels is essential for development of new therapeutic strategies.
References McGavin.D.M.,and Zachary.J.F.,(2012) Pathologic Basis of
Veterinary Disease,, 4th ed. chapter 1. Mosby Elsevier
Cheville. N.F., (2007) Introduction to veterinary pathology , ,third ed
Decker .R.S.Wildenthal K.(1979) Lysosomal alterations in hypoxic and reoxygenated heart vol98.no.2 1980 American journal of pathology
Tamara Hirsch, Philippe Marchetti, Santos A Susin, Bruno Dallaporta, Naoufal Zamzami, Isabel Marzo, Maurice Geuskens
and Guido Kroemer The apoptosis-necrosis paradox. Apoptogenic proteases activated after mitochondrial permeability transition determine the mode of cell death
Reynold Edward S (1963) vol.19 1963 liver parenchymal cell injury with ccl4 The journal of cell biology
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