Cellular response to stress

Transcription

1 Cellular pathology - cell injury, death and adaptations Pathology Göran Andersson Cellular response to stress Cells differ in their capacity to tolerate changes in their microenvironment Acute, severe stress often results in reversible or irreversible cell damage Chronic, mild stress often leads to cell adaptation 1

2 Cell stress/injury death or adaptation Tissues sections have been stained with triphenyltetrazolium chloride (an enzyme substrate that colors viable myocardium magenta) Cell death or adaptation 2

3 Factors determining stress response Concentration/intensity of the harmful factor Duration of exposition Mechanisms of cell injury Acute cell injury when environmental changes exceed the cell s capacity to maintain normal homeostasis If stress factor is removed on time changes are reversible If stress factor is not removed on time irreversible injury/cell death 3

4 Examples of etiological factors Infectious e.g microorganisms (bacteria, virus, parasites) Chemical (Drugs, toxins) Physical (temperature changes, trauma) Nutritional Immunological Endocrine (Hormones) Impaired tissue perfusion of oxygen Pathways of cell injury and death 4

5 Ultrastructural features of reversible cell injury Reversible cell injury = degeneration Cells have normal nucleus but altered cytoplasm. Accumulation of cytoplasmic vacuoles or increase in cytoplasmic volume Hydropic degeneration increased water content in the cytoplasm due to increased ion retention (lack of ATP, toxins, temperature) Fatty degeneration Accumulation of fat vacuoles liver, kidney, skeletal and heart muscle 5

6 Hydropic swelling Reversible increase in cell volume Number of organelles is unchanged Dilated endoplasmic reticulum Increased intracellular Na + concentrations maintenance of osmotic conditions Hydropic swelling liver of patient with toxic hep 6

7 Normal and fatty liver Fat vacuoles in hepatocytes 7

8 Fatty degeneration Hepatocyte Diabetes Starvation Ethanol Hypoxia Toxins Malnutrition increased supply of FFA increased esterification of FFA to triglycerides decreased oxidation of FFA decreased apoprotein availability impaired export of triglycerides via lipoproteins Necrosis Death of cells or tissues as a result of external trauma such as physical damage or lack of oxygen Cell and organelle swelling, ATP depletion, plasma membrane permeability, release of macromolecules from the cell In response: acute inflammation 8

9 Necrosis - features Nuclear changes Irreversible cell swelling, disintegration Irreversible cell injury = cell death =necrosis Detected by changes in the cell nuclei Pyknosis nuclear condensation Karyorrhexis nuclear fragmentation Karyolysis nucleolysis Necrosis often induce an inflammatory response due to release of nuclear and cytoplasmic danger proteins serves to remove dead cells 9

10 Necrosis normal pyknosis karyorrhexis Other cellular changes: Dilated ER Disaggregated ribosomes Swollen and calcified mitochondria Aggregated cytoskeletal elements karyolysis PYKNOSIS 10

11 Karyorrhexis Hypoxia Reduced blood flow (ischemia) Low oxygen partial pressure (hypoxemia) Low oxygen-binding capacity (anemia) 11

12 Infarct tissue necrosis due to hypoxia Coagulative necrosis after cardiac ischemia - histology hr hr 12

13 Arteriosclerosis cause of ischemia Arteriosclerosis from fatty change to calcification 13

14 Coagulative necrosis of the kidney cortex Coagulative (koagulations-) necrosis Preservation of basic structures, blocked proteolysis -myocardial infarction, other hypoxic cell deaths Normal kidney Coagulative necrosis 14

15 Coagulative necrosis and inflammation Inflammatory cell infiltration Liquefactive necrosis of brain 15

16 Liquefactive necrosis in stroke Enzymatic fat necrosis - pancreas 16

17 Enzymatic fat necrosis - histology Caseous necrosis in tuberculosis 17

18 Gangrenous necrosis Mechanisms of lethal cell injury Hypoxia Oxidative stress by increased formation of reactive oxygen Membrane damage due to lipid peroxidation loss of permeability barriers Calcium induced nuclear changes 18

19 low oxygen, mitochondrial dysfunction Ischaemia Anoxia Mitochondria Heart infarct, Stroke, etc. Ceased ion gradient (inflow of Ca 2+, Na + ) No electron transport Decrease of ATP amount No energy Activation of phospholipases Lost membrane stability Coagulative necrosis O 2 H 2 O ADP ATP Cytochrome c oxidase Ceased membrane potential Damaged phospholipids 19

20 Loss of calcium homeostasis Oxidative stress/injury 20

21 Factors causing oxidative stress PMNs, macrophages Inflammation Xanthine oxidase Reperfusion Redox reactions and metabolic activation Chemical toxicity ROS Injury Cell death Radiation Ionization ROS Reactive Oxygen Species Superoxide anion Hydrogen peroxide Hydroxyl radical e - e - + 2H + e - + H + e - + H + O 2 O 2 -. H 2 O 2 HO. H 2 O H 2 O 21

22 Defense against ROS Enzymes e.g. Superoxide dismutase, catalase, Gluthathione peroxidase Free radical scavengers e.g. vit. E, vit. C, retinoids Ischemia-Reperfusion injury Ischaemia Calcium Reperfusion Oxygen ATP ADP Ca-activation of cytosolic proteases AMP Proteolytic conversion of Adenosine xanthine dehydrogenas Hypoxanthine Xanthine oxidase Substrate Enzyme Hypoxanthine+xanthine oxidase +O 2 -. Uric acid + H 2 O 2 + O 2 Cellular Fe 3+ (catalyst) O 2 + OH - + HO. Cell injury Secondary cell injury Inflammation 22

23 Ionizing radiation H 2 O HOṚadiolysis Hydroxyl radical Proliferating cells DNA-damage Impaired replication capacity Non-proliferating cells Lipid peroxidation of phospholipids in membranes Lost membrane stability Ceased protein synthesis Cell death Apoptosis Important in development and physiological processes Eliminates obsolete cells Eliminates defective cells Defense against dissemination and infection 23

24 Apoptosis triggered by a variety of extra- and intracellular stimuli organized cellular signaling cascades Liver with viral hepatitis Skin in erythema multiforme Morphology of apoptosis Nuclear condensation and fragmentation Segragation of cytoplasmic organelles into distinct regions Blebs of plasma membrane Membrane-bound cellular fragments, which often lack nuclei Leukemic 24

25 Apoptosis Adaptive responses Atrophy Hypertrophy Hyperplasia Metaplasia Dysplasia Intracellular storage 25

26 Cellular adaptive changes Atrophy - reduction in cell size Involution/ Hypoplasi - reduced cell numbers Hypertrophy - increased cell size Hyperplasia - increased cell numbers 26

27 The etiology of atrophy Decreased functional demand Inadequate supply of oxygen Decreased hormonal stimulation Denervation Insufficient nutrients Aging Decreased functional demand Disuse atrophy due to immobilization - skeletal muscle, bone 27

28 Hormone-dependent atrophy of endometrium Uterus from a woman in reproductive age Uterus from a 75 yrs old woman Ageing atrophy of brain Brain of young adult Brain of an 82-yr-old man 28

29 Inadequate oxygen supply (ischemia) Partial ischemia due to incomplete arterial occlusion - muscle, brain, kidneys Decreased hormonal stimulation Hormone deficiency due to removal of/injury to primary endocrine organs 29

30 Denervation Loss of neuromuscular transmission - selective muscular atrophy Involution Physiological mechanism to reduce organ size by apoptosis Thymus involution during puberty Uterus involution after pregnancy 30

31 Uterus involution Thymic involution 31

32 Mechanisms of cell shrinkage Cytoplasmic proteins ubiquitinmediated proteasomal degradation Cell organelles induction of autophagy Autophagy=cellular self-eating 32

33 Hypertrophy Increase in the size and functional capacity of an organ (pathologic or physiologic circumstances) Cell size versus cell number Cellular remodelling Skeletal muscle hypertrophy 33

34 Cardiac hypertrophy Hyperplasia Increase in the number of cells in an organ or tissue Cell type and tissue-type specific Stimulation of resting cells to enter the cell cycle and to multiply: hormonal stimulation, increased funtional demand, chronic injury 34

35 Endometrial hyperplasia Hyperplasia Normal epidermis Epidermal hyperplasia in psoriasis 35

36 Benign Prostate Hyperplasia Thyroid hyperplasia 36

37 Adrenal hyperplasia Often due to ACTHproducing pituitary tumours Increased number of cortison-producing cells in the adrenal cortex Hypercortisolism- Mb. Cushing Adipocyte development 37

38 Obesity Usually a combination of hyperplasia and hypertrophy of adipocytes Hypertrophy is associated with lowgrade (subacute) inflammation and insulin resistance (metabolic syndrome) Life-span of adipocytes are similar (10 years) in lean and obese Metaplasia Conversion of differentiated cell type to another (replacing the expression of one set of differentiation genes with another) Adaptive response to chronic, persistent injury Usually fully reversible 38

39 Metaplasia Replacement of one differentiated epithelial cell type with another. Squamous cell metaplasia - from respiratory epithelia in smokers - from papilloma-virus infected glandular epithelia in cervix uteri Intestinal metaplasia from squamous epithelia of esophagus in patients with acid reflux (Barret s esophagus) Barrett s esophagus 39

40 Gastric metaplasia in the duodenum Dysplasia Disordered growth and maturation of the cellular components of a tissue Variation in cell size and shape Nuclear enlargement, irregularity and hyperchromatism Disarray in the arrangement of cells within the epithelium Preneoplastic lesion Morphologic disturbance in growth regulation 40

41 Dysplasia Epithelium of the uterine cervix 41

42 Dysplasia cancer in situ invasive cancer Normal Dysplasia Ca in situ Invasive Observation Operation Op/Kemoter./Stråln. 42