Cell Injury, Adaptations & Cell Death I hear, I forget I see, I remember I do, I understand Chinese Proverb
Homeostasis
♦Cells maintain normal homeostasis (=steady state), by maintaining their intracellular compartment within a narrow range of physiologic parameters LOSS OF HOMEOSTASIS = CELL INJURYCell injury and death
If the limits of adaptive capability are exceeded or if the external stress is severe, cell injury develops Within certain limit injury is reversible, and cells return to a stable baseline, however, severe or persistent stress result in irreversible injury and death of the affected cells.Causes of cell injury
1-Oxygen deprivation (hypoxia) Is decrease oxygen supply to the cell. It may resulted from : A- Loss of blood supply (Ischemia). B-Inadequate blood oxygenation due to e.g. cardiac failure and/or respiratory failure. C-Decrease in oxygen carrying capacity of the blood e.g. anemia and CO poisoning.2-Physical agents. 3-Chemical agents. 4-Infectious agents. 5-Immunological reactions. 6-Nutritional imbalance. 7-Genetic derangement. 8-Cell aging
Causes of cell injury
Mechanisms of cell injury
Cellular response to injurious stimuli is dependent on: 1- Type of injury, its duration and its severity. 2- Type of injured cell, its state and adaptability.Intracellular Mechanisms
The intracellular mechanisms of cell injury fall into one of five general pathways: ATP Depletion Defects in Membrane Permeability Influx of Intracellular Calcium Mitochondrial Damage Accumulation of Oxygen-Derived Free Radicals
ATP depletion: ATP is essential for ; 1- transport through cell membrane . 2-Protein synthesis. 3-Lipid synthesis. 4-Phospholipid turnover. ATP depletion produces the followings: 1-Reduction of the activity of plasma membrane energy dependent sodium pump. 2-Switch to anaerobic glycolysis, this leads to liberation of lactic acid, 3-Increase in the intracellular Ca+2 due to failure in the Ca++ pump 4-Structural disruption of protein synthetic apparatus,
Influx of Intracellular Calcium and Loss of Calcium Homeostasis
Increased cytosolic calcium activates phospholipases that degrade membrane phospholipids;proteases that breakdown membrane and cytoskeletal proteins;
ATPases that hasten ATP depletion; and endonucleases that cause chromatin fragmentation.Loss of Calcium Homeostasis
Mitochondrial DamageMitochondrial damage may occur directly due to hypoxia or toxins, or as a consequence of increased cytosolic Ca2+ , oxidative stress, or phospholipids breakdown. Damage results in formation of --a high-conductance channel (mitochondrial permeability transition, or MPT) that leaks protons --also leak cytochrome c, which can trigger apoptosis.
Mitochondrial Damage
DEFECTS IN MEMBRANE PERMEABILITY
Result from: Mitochondrial dysfunction. Loss of membrane phospholipids. Cytoskeletal abnormalities. Reactive oxygen species. Lipid breakdown products.Free Radical Cell Injury
Free radicals are compounds with a single unpaired electrons in the outer orbit. Free radical-induced injury is an important mechanism of cell damage in; -ischemic reperfusion injury. -chemical and radiation injury - toxicity from oxygen -cellular aging -microbial killing by phagocytic cells - inflammatory cell damage -tumor destruction by macrophageFree radicals may be generated within cells by:
A- O2-derived free radicals are produced as a byproduct of mitochondrial respiration. ♦ superoxides (O2.- ): neutralized by superoxide dismutase ♦ hydroxyl anions (OH. ): neutralized by glutathione peroxidase ♦ hydrogen peroxide (H2O2 ): neutralized by catalase and glutathione peroxidaseB- Drugs and chemical free radicals: e.g. Carbon tetrachloride (CCl4 ) is converted to CCl3., leading to liver cell necrosis with fatty changes.C- Nitric Oxide (NO), an important chemical mediator normally synthesized by a variety of cell types that can act as a free radical .D- The absorption of radiant energy (e.g., UV, X-rays). Ionizing radiation can hydrolyze water into hydroxyl ( OH. ) and hydrogen ( H. ) free radicals.Free Radical Cell Injury ……. Consequences of free radical injury: * Lipid peroxidation of membrane, leading to increased permeability of cells and organelles. * DNA fragmentation, implicated in both cell killing and the malignant transformation of cells. * Cross-linking of proteins, resulting in enhanced rates of degradation or loss of enzymatic activity.
O2 is converted to superoxide by oxidative enzymes then converted to H2O2 by dismutation and thence to OH• by Fenton reaction. Resultant free-radical damage to lipid (by peroxidation), proteins, and deoxyribonucleic acid (DNA) leads to various forms of cell injury. The major antioxidant enzymes are superoxide dismutase (SOD), catalase, and glutathione peroxidase.
Ischemia/ reperfusion injury
Reperfusion into ischemic tissues may cause further damage by the following means: Restoration of blood flow bathes compromised cells in high concentrations of calcium when they are not able to fully regulate their ionic environment; Reperfusion of injured cells result in a locally augmented recruitment of inflammatory cells; Damaged mitochondria in compromised but still viable cells yield incomplete oxygen reduction and therefore increased of free radical species; ischemically injured cells have compromised antioxidant defense mechanisms.Cellular response to injurious stimuli
1-Cellular adaptive processes: e.g. hypertrophy, hyperplasia, atrophy, metaplasia 2-Acute cell injury: -Non-lethal (reversible cell injury): e.g. hydropic swelling and fatty changes. -Lethal (irreversible cell injury/cell death) : necrosis and apoptosis. 3-Subcelluar alterations. 4-Intracellular storage (accumulations) :e.g. lipid, glycogen, protein, pigment. 5-Cell aging.Cellular Responses (Stress and Noxious Stimuli )
Stages in cell response
steady state to normal physiologic demands
Hyperplasia Hypertrophy Atrophy metaplasia
Apoptosis Necrosis
Hypertrophy
Increase in cell size and functional capacity without cellular proliferation. Etiology: It can be physiologic or pathologic -physiologic: e.g. -- increase in muscle cell size with exercise -- massive enlargement of the uterus and mammary glands during pregnancy/lactation. -Pathologic: e.g., -- enlargement of myocardial fibers in case of heart failure or hypertension. .Physiologic hypertrophy (uterus during pregnancy)
normalgravid
normal
gravid
Microscopy
Hyperplasia
Increase in organ size or tissue mass caused by increased number of constituent cells; occurs in tissues whose cells are capable of replication. Hyperplasia can be physiologic or pathologic. a- Physiologic hyperplasia; 1) hormonal hyperplasia e.g., proliferation of glandular epithelium of female breast at puberty and during pregnancy. 2) compensatory hyperplasia, e.g., hyperplasia that occurs when portion of tissue is removed or diseased; e.g. when a liver is partially resected.Hyperplasia…… b- Pathologic hyperplasia: 1- endometrial hyperplasia due to hormonal imbalance. 2- wound healing, in which proliferating fibroblasts and blood vessels aid in repair. 3- viral infections; e.g., papilloma viruses cause skin warts and mucosal lesions composed of masses of hyperplastic epithelium.
Atrophy
Shrinkage of cell size by the loss of cell substances; i.e. catabolic processes exceed anabolic processes. When a sufficient number cells is involved, the entire tissue or organ diminishes in size, becoming atrophic. Although atrophic cells may have diminished functional capacity, they are not dead.Causes of Atrophy
Decreased work load (=disuse atrophy) Loss of innervation (denervation atrophy) Diminished blood supply/hypoxia (e.g., partial ischemia) Inadequate nutrition (e.g., starvation associated with chronic disease) Loss of endocrine stimulation (e.g., endometrium atrophy after menopause) Aging (senile atrophy)ATROPHY
82-year36-year
Gyri
Sulci
A-Physiologic atrophy of the brain in an 82-year-old male. The meninges have been stripped B-Normal brain of a 36-year-old male.
Metaplasia
A reversible change in which one differentiated cell type is replace by another differentiated cell type. Example squamous metaplasia in smokersMETAPLASIA
Columnar to Squamous
Squamous to columnar type
Reversible cell injury:
indicates that the cellular changes will regress and disappear when the injurious agent is removed; 1- Cloudy swelling (Hydropic changes) light microscope : increase in the size of the cell with pallor of the cytoplasm (cloudy swelling), with further water accumulation, clear vacuoles are created within the cytoplasm (vacular degeneration). 2- fatty changesFatty changes
abnormal accumulation of fat within parenchymal cells, not the stroma. (Fatty degeneration, fatty infiltration) occurs in the liver, myocardium, and the kidney. causes of fatty liver: alcohol, anoxia, obesity, diabetes mellitus, protein malnutrition, and hepatotoxins.Mechanisms of Fatty Change
1. Excessive entry of lipids into the liver (DM, Starvation) 2. Enhanced fatty acid synthesis by hepatocytes 3. Decreased oxidation of fatty acids by mitochondria (Alcohol, Anoxia) 4. Increased esterification of fatty acids to triglycerides 5. Decreased apoprotein synthesis(CCl4 and malnutrition ) 6. Impaired lipoprotein excretionGross features : In mild case, no gross changes. but with severe case , the liver enlarges & become increasingly yellow, soft & greasy . Microscopically : In the early stages there are small fat vacuoles around the nucleus. As the process progresses, the vacuoles coalesce, creating cleared spaces that displace the nucleus to the periphery of the cell.
Left: Normal liver Right: Fatty change in liver. Liver from an alcoholic shows large vacuoles (V) in the hepatocytes (H) with displacement of nucleus (N).
Hepatic steatosis in an uncontrolled diabetic
Objectives
Define necrosis and apoptosis List the different types of necrosis, examples of each and its features List the different conditions associated with apoptosis and its mechanism Know the difference between apoptosis and necrosisIRREVERSIBLE CELL INJURY
NECROSIS:���� is a pathological process in which cells and tissues die in a living organism ���� Affect both nucleus and cytoplasmApoptosis: death of single cells during lifeNECROSIS
Cytoplasmic changes :Eosinophilia (pink) Glassy, homogenous appearanceCell membranes are fragmented Nuclear changes: Pyknosis – small and dense nucleiKaryolysis – complete lysis of the nucleiKaryorrhexis – fragmented nuclei (generally seen in apoptosis)Renal cortex .
Spleen with parvovirus infection has fragmentation of lymphocyte nuclei (karyorrhexis) because of the infection. Many of these nuclear changes may be due to apoptosis.Centrilobular hepatocytes are pale and necrotic. Note that in the necrotic areas many of the nuclei are lost. This is karyolysis. Some of the dark nuclei that are remaining are actually endothelial cell nuclei lining the sinusoids. Note the "pre-necrotic" cells that are only at the stage of cell swelling?
NECROSIS…. TYPES Coagulative:����In: infarcts of heart, kidney, spleen����Gross: pale , yellow, opaque, firm����Mic.: All cellular details are lost but general architecture of the tissue is preserved����Surrounding tissue----acute inflammation
Coagulative necrosis. A, A wedge-shaped kidney infarct (yellow). B, Microscopic view of the edge of the infarct, with normal kidney (N) and necrotic cells in the infarct (I). The necrotic cells show preserved outlines with loss of nuclei, and an inflammatory infiltrate is present
Liver with centrilobular necrosis. In this case the necrotic cells retain their cell outlines and usually have a pyknotic nucleus. This is coagulation necrosis.
NECROSIS……… TYPES Liquefactive:���� infarcts of C.N.S.����In: centers of pyogenic abscess���� Necrotic tissue---completely liquified---turbid fluid----absorbed----space
Stroke- Liquefactive necrosis
The liver shows a small abscess here filled with many neutrophils. This abscess is an example of localized liquefactive necrosisNECROSIS…… TYPES Fat necrosis:����Traumatic: in female breast����Enzymatic: in acute pancreatitis• Gross: opaque& white
Fat necrosis in acute pancreatitis. The areas of white chalky deposits represent foci of fat necrosis with calcium soap formation (saponification) at sites of lipid breakdown in the mesentery.
Fat necrosis
Mic:• fat cells appearcloudy, surroundedby chronicinflammatory cells,histiocytes, foreignbody giant cellsNECROSIS…… TYPES Caseous necrosis:Coagulative + Liquifactive necrosis����In: Tuberculosis, Fungal infections,���� Necrotic tissue is partially liquefied---cheesy material (caseation)���� Mic: Both cellular details & generalarchitecture of dead tissue are lost---structure less eosinophilic material
Caseous necrosis, with confluent cheesy tan granulomas in the upper portion of this lung in a patient with tuberculosis.
Caseous necrosis
Gangreneis necrosis with the putrefaction of the tissues. The affected tissues appear black due to the deposition of iron sulphide from degraded hemoglobin. 'dry' gangrene sterile; 'wet' gangrene - with bacterial putrefaction.
Gangrene Intestine -
Fibrinoid necrosisIntense eosinophilic staining of involved (necrotic) tissue. (like fibrin) E.g., Fibrinoid necrosis of blood vessels in malignant hypertension & vasculitis
Fibrinoid necrosis in an artery in a patient with polyarteritis nodosa. The wall of the artery shows a circumferential bright pink area of necrosis with protein deposition and inflammation (dark nuclei of neutrophils).