Stages in the cellular response to stress & injurious stimuli

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1 Blok BBS 2 Departemen Patologi Anatomi Fakultas Kedokteran Universitas Sumatera Utara Medan Stages in the cellular response to stress & injurious stimuli 3/28/

2 Table 1-1.Cellular Responses to Injury Nature &Severity of Injurious Stimulus Altered physiologic stimuli: demand, trophic stimulation (e.g. growth factors, hormones) nutrients, stimulation Chronic irritation (chemical /physical) O2 supply; chemical injury; microbial infection Acute & self-limited Cellular adaptations: Cellular Response Hyperplasia, hypertrophy Atrophy Metaplasia Cell injury: Acute reversible injury Progessive & severe (including DNA damage) Irreversible injury cell death Mild chronic injury Metabolic alterations (genetic / acquired) Prolonged life span with cumulative sublethal injury Necrosis Apoptosis Subcellular alterations in various organelles Intracellular accumulations; calcifications Cellular aging 3/28/ Stresses/pathologic stimuli the cell Can undergo Adaptation Atrophy Hypertrophy Hyperplasia Metaplasia Irreversible injury & dies 3/28/

3 Perubahan sel & jaringan Agenesis Aplasia Hypoplasia Atrophy Hypertrophy Hyperplasia Metaplasia Dysplasia Anaplasia Granuloma 3/28/ Complete absent of organ e.g. : Agenesis Renal agenesis Ovarial agenesis Tubal agenesis, etc. Is present Aplasia But never develops e.g. : Lung aplasia with tissue containing rudimentary duct & connective tissue 3/28/

4 Hypoplasia Developved incompletly But the tissue histhologicaly normal e.g. : microcephaly 3/28/ Atrophy Decrease in the: Size Function of a cell But not dead 3/28/

$Causes of atrophy : 1. functional demand (immobilitationin fracture, prolonged bed rest) 2. Inadequate supply O 2 (ischemia) 3.$

5 Causes of atrophy : 1. functional demand (immobilitationin fracture, prolonged bed rest) 2. Inadequate supply O 2 (ischemia) 3. Insufficient nutrients (starvation, inadequate nutrition, chronic disease) 4. Interruption of trophicsignals transmitted by chemical mediators (endocrine system/neuromusculatortransmission) e.g. : thyroid, adrenal cortex, ovarium, testis. 5. Persistent cell injury by chronic inflamation e.g. : chronic gastritis, prolonged pressure 6. Aging : brain, heart (Senile Atrophy) 3/28/ Atrophy A section of heart muscle (myocardium). The spaces between muscle fibers are not present in normal myocardium. The muscle fibers are thinner DEPARTEMEN than normal PATOLOGI creating ANATOMI spaces FK- between them, a finding suggesting 3/28/2011 atrophy. 10 5

6 The mechanism of atrophy : Synthesis Catabolism Hormones e.g. : Insulin Tyroid stimulating hormon Glucocorticoids 3/28/ Hypertrophy size of cell accompanied by functional capacity Is a response to trophic signals Commonly a normal procesess 3/28/

7 hypertrophy Physiological (hormonal) hypertrophy in puberty production of sex hormon Hypertrophy breast tissue Abnormal hormon production in cancer Functional demands Exercise Pathological conditions (myocardial cell) Kidney hypertrophy on surgical removed 3/28/ Hypertrophy Myocardium in an area adjacent to a healed MCI ("heart attack"). Cardiac muscle cannot regenerate, fibrous connective tissue fills in the defect. Viable muscle cells, size to compensate for cells that died. Nuclei indicate the cells have undergone hypertrophy ( in volume of cells). Hypertrophy At higher magnification cardiac muscle cells & nuclei. Cardiac muscle cells cannot divide adapt by size (hypertropy). 3/28/

8 Hyperplasia the number of cells in an organ / tissue 3/28/ Hyperplasia can be : Physiologic hyperplasia Hormonal hyperplasia Compensatory hyperplasia Pathologic hyperplasia hormonal / growth factor stimulation e.g. : Endometrial hyperplasia 3/28/

Metaplasia 1 adult cell type another adult cell type (convertion of 1 differentiated cell type of another) Most common is the replacment of a glandular epithelium by a squamous cell.

9 Metaplasia 1 adult cell type another adult cell type (convertion of 1 differentiated cell type of another) Most common is the replacment of a glandular epithelium by a squamous cell. Squamous metaplasia of the bronchial epithelium to tobacco Lower oesophagus by reflux acidic gastric Endocervical metaplasia Usually reversible if the stimulus is removed 3/28/ Metaplasia of normal columnar (left) to squamous epithelium (right) in a bronchus, (A) schematically and (B) histologically 3/28/

10 Dysplasia Cellular alteration in the size, shape & organization of the cellular component of a tissue 1. Size & shape of cells variation 2. Nuclei : >>, irregular & hyperchromatism 3. Disorderly arrangement of the cells within the epithelium The most common in the cervix & bronchus 3/28/ Dysplasia is a preneoplastic lession Necessary stage in the multistep cellular evolution to cancer. 3/28/

11 Anaplasia Normal cell primitive cell E.g. : Malignant cell Carcinoma Sarcoma Adenocarcinoma Lymphoma Etc. 3/28/ CELL INJURY 3/28/

12 2 principal pattern of cell death : NECROSIS Commonly : coagulative necrosis Cellular swelling Protein denaturation Organellar breakdown Cell rupture APOPTOSIS Regulated event Programmed death 3/28/ Term Necrosis Definition Antemortem pathologic cell death Apoptosis Antemortem programmed cell death Autolysis Postmortem cell death 3/28/

13 CAUSES OF CELL INJURY Hypoxia Physical Agent Chemical and drugs Microbiology Agents Immunologic Reaction Genetic Defects Nutritional Inbalance Aging 3/28/ CAUSES OF CELL INJURY Hypoxia Physical Agent Anemia Ischemia Intoxication CO 2 Aerobic oxidative respiration Mechanical trauma Extreme temprature : heat, cold Radiation: X-ray, sun light Electric shock Athmosphere pressure 3/28/

14 CAUSES OF CELL INJURY Chemical agent & drugs Sufficiently concentrated : Glucose, Salt, O 2 Air pollutants Insecticides Asbestosis Ethanol Cellular metabolism (i.e. waste products) Microbiology Agents Tape worms Rickettsia Virus Bacteria Fungi 3/28/ CAUSES OF CELL INJURY Immunologic Reaction Anaphylactic reaction Autoimmune diseases 3/28/

Genetic Defects Congenital malformation Sickle cell anemia G-6-PD Nutritional Imbalance

of Cell Injury Cellular response to injurious stimuli depends on : Injury type Duration

systems : Cell membrane integrity Aerobic respiration Protein synthesis Integrity

15 Genetic Defects Congenital malformation Sickle cell anemia G-6-PD Nutritional Imbalance Protein calori insufficiency Vitamins defficiency Diabetes Aging 3/28/ Mechanism of Cell Injury Cellular response to injurious stimuli depends on : Injury type Duration Severity Current Status : Nutritional Hormonal Adaptibility of the cell Intercellular systems : Cell membrane integrity Aerobic respiration Protein synthesis Integrity genetic apparatus O 2 & oxygen derived free radicals : Ischemic Hypoxic injury 3/28/

16 Normal cell & changes in reversible & irreversible cell injury (necrosis) The ultrastructural features of these stages of cell injury. 3/28/ /28/

Reversible injury Reduced of : Oxidative phosphorylation in mitochondria Activity Na Pump Cellular swelling Loss of microvilli Glycogen depleted protein synthesis Formation of cell surface blebs

17 Reversible injury Reduced of : Oxidative phosphorylation in mitochondria Activity Na Pump Cellular swelling Loss of microvilli Glycogen depleted protein synthesis Formation of cell surface blebs Irreversible injury Severe vacuolization of mitochondria Damage of : Mitochondrial matrix Plasma membrane Swelling of lysosomes Accumulation of amorphous calcium Rich dentities in mitochondrial matrix 3/28/ /28/

18 3/28/ Figure 1-6. Cellular features of necrosis (left) & apoptosis (right) 3/28/

Feature Necrosis Apoptosis Cell size Enlarged (swelling) Reduced (shrinkage) Nucleus Pyknosis karyorrhexis

especially orientation of lipids Cellular contents Enzymatic digestion; may leak out of cell Adjacent inflammation

may be released in apoptotic bodies Often physiologic, means of eliminating unwanted cells; may be pathologic after

Reversible acute cell injury 2. Necrosis (cell death after irreversible injury) 3.

19 Feature Necrosis Apoptosis Cell size Enlarged (swelling) Reduced (shrinkage) Nucleus Pyknosis karyorrhexis karyolysis Fragmentation into nucleosome-size fragments Plasma membrane Disrupted Intact; altered structure, especially orientation of lipids Cellular contents Enzymatic digestion; may leak out of cell Adjacent inflammation Frequent No Physiologic or pathologic role Invariably pathologic (culmination of irreversible cell injury) Intact; may be released in apoptotic bodies Often physiologic, means of eliminating unwanted cells; may be pathologic after some forms of cell injury, especially DNA damage 3/28/ Forms & Morphology of Cell Injury 1. Reversible acute cell injury 2. Necrosis (cell death after irreversible injury) 3. Apoptosis (cell death by suicide) 4. Subcellularalteration as a respond to chronic or persistent injury stimuli 5. Intracellular accumulations of a number of substance 3/28/

20 Necrosis Morphologic changes that follow cell death in living tissue 1. Intense eosinophiliaof the dead cell is due to loss of RNA & coagulation of protein 2. Nuclei undergo: 1. Pyknosis 2. Karyorhexis 3. Karyolysis Leaving a shrunken cell devoid of nucleus 3. Protein may be liberated from the dead cell 3/28/ The morphologic appearance of necrosis is the result of 2 essentially processes : 1. Enzymatic digestion of the cell 2. Denaturation of protein Autolysis : is a cell death by hydrolitic enzymes Heterolysis : cell death by the lysosomesof invading inflammatory cells. 3/28/

3/28/2011 41 Nuclear Changes: Pyknosis While cytoplasmic changes associated with cell death are not specific, nuclear changes are.

21 Nuclear Changes: This nucleus is faded -- karyolysis. Karyolytic nuclei suggest that DEPARTEMEN cells have PATOLOGI died ANATOMI (undergone FK- necrosis). 3/28/ Nuclear Changes: Pyknosis While cytoplasmic changes associated with cell death are not specific, nuclear changes are. The large arrow indicates a normal-appearing nucleus while the smaller arrow indicates a nucleus that is small and dark -- features of "pyknosis." Pyknotic nuclei suggest 3/28/2011 DEPARTEMEN PATOLOGI ANATOMI FKthat cells have died (are undergoing necrosis)

Fragmented nuclei suggest that cells have died.

The nucleus indicated by the large arrow may be undergoing

The smaller arrow indicates a fragmented nucleus: it could

22 Fragmented nuclei suggest that cells have died. Karyorrhexis is the term used for this circumstance. The nucleus indicated by the large arrow may be undergoing karyorrhexis. The smaller arrow indicates a fragmented nucleus: it could be karyorrhexis or a mitotic figure (a cell 3/28/2011 DEPARTEMEN PATOLOGI ANATOMI FKundergoing mitosis). 43 3/28/

23 Morphologic changes in reversible and irreversible cell injury (necrosis). A, Normal kidney tubules with viable epithelial cells B, Early (reversible) ischemic injury C, Necrotic (irreversible) injury of epithelial cells 3/28/ Types of Necrosis Depends on : 1. Cells compotitions 2. Speed of necrosis 3. Type of injuries 3/28/

24 Coagulative Necrosis The structural protein & enzymatic protein thus blocking cellular proteolysis Cahareteristic of hypoxic death of cells in all tissue except the brain e.g. : Myocardial Infarction (occlusion of arterial supply) 3/28/ Liquefactive/Colliquativa Necrosis Dead tissue Appears semi liquid Result of dissolution of tissue by the action of hydrolytic enzymes e.g.: cerebral infarction, necrosis caused by bacterial inf. Caseous Necrosis Dead cell Form amorphous proteinaceaus mass No original architecture can be seen (histologic) Soft & white resembling cream cheese Most often in TBC infection with central necrosis 3/28/

25 Coagulative & liquefactive necrosis A. Kidney infarct (coagulative necrosis) B. Liquefactive necrosis (kidney caused by fungal infection). 3/28/ Gumatous Necrosis Dead tissue, it is firm & rubbery like caseous necrosis in the spirochetal infection syphilis. Hemorrhagic Necrosis Dead tissue suffused with extravasated red cell, when cell death is due to blockage Fat Necrosis Not really necrosis. Focal areas of fat destruction tipically occuring following pancreatic injury /after trauma to fat for (ex. in the breast) Describes foci of hard yellow material seen in dead adipose tissue 3/28/

Fibrinoid Necrosis Fibrin deposited in damage necrotic vessel walls in hypertension and vasculitis Gangrene Extensive tissue necrosis ; is

26 Fibrinoid Necrosis Fibrin deposited in damage necrotic vessel walls in hypertension and vasculitis Gangrene Extensive tissue necrosis ; is complicated to a variable degree by secondary bacterial infection 3/28/ Fibrinoid necrosis in an artery (polyarteritis nodosa) 3/28/

APOPTOSIS Responsible for the programmed cell death in several important physiology processes Including : During embryogenesis (in implantation, organogenesis, & developmental involution)

27 APOPTOSIS Responsible for the programmed cell death in several important physiology processes Including : During embryogenesis (in implantation, organogenesis, & developmental involution) Hormondependent physiologic involution (endometrium, lactating, prostate after castration) Cell deletion in proliferating population (intestinal crypt epithelium / cell dead in tumor) Deletion of autoreactivet cell in the thymus, cell death of cytokine starved lymphocytes 3/28/ Apoptosis of epidermal cells in an immunemediated reaction A. Apoptotic cells are visible in the epidermis with eosinophilic cytoplasm and small, dense nuclei. B. High power of apoptotic cell in liver in immune-mediated hepatic cell injury. 3/28/2011 (Courtesy of Dr. Scott Granter, Brigham and Women's DEPARTEMEN Hospital, Boston, PATOLOGI AM.) (Courtesy ANATOMI of Dr. Dhanpat FK- Jain, Yale University, New Haven, CT.) 54 27

28 Granuloma Special type of chronic inflamation in tissue reaction. Cause : infection : TBC fungal syphilis, etc noninfection : sarcoidosis Crohn s disease 3/28/ NECROBIOSIS Necrobiosis is physiological death of a cell, and can be caused by certain conditions Such as : Basophilia Erythema or Presence of a tumor It can be identified both with/without necrosis 3/28/

29 Necrobiosis Gradual cell damage Progressive Singly / small group cells Reversible (+/-) Example : Hepar cell deg. Cell death healing fibrosis. 3/28/ Cellular Aging Alterations in structure & function that may lead to cell death, or at least diminished capacity of the cell to respond an injury Reduced cell in : Pleomorphic vacuolated mitochondria Repair of chromosomal damage 3/28/

30 Cellular Aging Morphologic alteration in : Pleomorphic vacuolated mitochondria endoplasmic reticulum Disorted Golgi Apparatus Accumutaion of lipofuscin pigment 3/28/ Cellular senescence is multifactorial : The cumulative effects of: 1. Extrinsic influences: free radical damage 2. Intrinsic molecular program of cellular aging cellhaveafinitelifespan 3/28/

31 DEGENERATION Cloudy swelling Fatty change Hydropic Atropy Hyaline Mucoid Amyloid Calcification 3/28/ Ballooning degeneration 3/28/

32 Hydropic change of gestational mole 3/28/2011 DEPARTEMEN PATOLOGI ANATOMI FK 63 Fatty Change At higher magnification the intracytoplasmic fat droplets are clearly evident. 3/28/2011 DEPARTEMEN PATOLOGI ANATOMI FK 64 32

These DEPARTEMEN droplets PATOLOGI appear ANATOMI homogeneous, FK-

33 Hyaline Droplet Degeneration Sometimes protein droplets appear within the cy_toplasm of sick cells. These DEPARTEMEN droplets PATOLOGI appear ANATOMI homogeneous, FK- glassy, bead-like structures -- an apearance known as "hyaline. 3/28/ THANK YOU SELAMAT BELAJAR 3/28/

CELL INJURY, DEATH, AND ADAPTATION

CELL INJURY, DEATH, AND ADAPTATION Definitons Pathology is a dicipline bridging clinical practice and basic sience To render diagnosis and guide therapy - Identity changes in gross - Morphology ( microscopy