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Tissue Injury
 

Tissue Injury

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Tissue Injury Tissue Injury Presentation Transcript

  • Chapter Two adaptation and injury
  • Adaptation & Cellular Injury :
    • Normal cell is in a steady state “Homeostasis”
    • Cells constantly adjust structure and function to accommodate changing demands and extracellular stress.
    • But within a relatively narrow range of physiologic parameter.
    • Change in Homeostasis due to stimuli - Injury
  • Irreversible Injury (cell death) Reversible Injury adaptation normal When cells encounter physiological stresses or pathological stimuli, they undergo adaptation, achieving a new a steady state and preserving viability. If the adaptive capacity is exceeded, cell injury develops. Within certain limits, injury is reversible. with severe and persistent stress, irreversible injury results.
  • adaptation
    • A state that between normal, unstressed cell and the injured, overstressed cell.
  • General principles
    • 1. The cellular response to injurious stimuli depends on the type of injury.
  • Incomplete occlusion of coronary artery Complete or prolonged occlusion hypertesion Prolonged starvation
  • General principles
    • 2.The consequences of an injurious stimulus depend on the type, status, adaptability, and genetic makeup of injured cell.
    • Skeletal muscle accommodates complete ischemia for 2 to 3 hours without irreversible injury.
    • cardiac muscle dies after 20 to 30 minutes.
    • Neuron dies after a few minutes.
  • General principles
    • 3.Cellular function is far before cell death occurs, and the morphologic changes of cell injury(or death) lag far behind both.
  •  
  • General principles
    • Cell membrane integrity, critical to cellular ionic and osmotic homeostasis;
    • ATP generation, largely via mitochondrial aerobic respiration;
    • Protein synthesis;
    • Intergrity of the genetic apparatus.
    4. four intracellular systems are particularly vulnerable.
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  • General biochemical mechanisms
    • Defects in plasma membrane permeability.
    • Oxygen deprivation or generation of reactive oxygen species(free radical).
    • Loss of calcium homeostasis.
    • Mitochondrial damage.
    • Chemical injury
    • Genetic variation
    • Cellular adaptation:
    • Atrophy
    • Hypertrophy
    • Hyperplasia
    • Metaplasia
    Section A
  • Types of adaptation
  • CELLULAR ADAPTATION
    • Excessive physiologic stresses.
    • Some pathologic stimuli.
    • A new, but altered state preserving
    • the viability of the cell.
    • ATROPHY
    • Decrease in mass of the cell
    • HYPERTROPHY
    • Increase in mass of the cell
  • ATROPHY
    • Inadequate nutrition.
    • Diminished blood supply.
    • Increased compression
    • Loss of innervation.
    • Decreased workload
    • Loss of endocrine stimulation.
    • Aging
    malnutrational Denervative endocrine Disuse compressive Aging
  • Morphology of atrophy
    • Brown atrophy
    • Reduction in the number of cell organelles.
    • Increase in the number of autophagic vacuoles.
    • Lipofuscin granules (Brown atrophy)
  • Fig 2-5
  • Cerebral atrophy - Alzheimers:
  • Atrophy of Brain
    • The left part of the brain diminishes in size.The gyrus is narrower and the gauge is widen.
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  • Hydropic change in ischemic - kidney Microvilli
  • Muscle ischemic atrophy:
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  • Hydronephrosis
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    • Hormonal hypertrophy : Specific hormonal stimulation
    • Compensatory hypertrophy : Increased functional demand
    HYPERTROPHY
  • Fig 2-6
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  • Heart hypertrophy in hypertension: Left Ventricle
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  • HYPERPLASIA
  • HYPERPLASIA
    • Physiologic hyperplasia:
    • Hormonal hyperplasia
    • Compensatory hyperplasia
    • Pathologic hyperplasia:
    • Excessive hormonal stimulation.
    • Effects of locally produced GFs on target cells.
    female breast and uterus at puberty and pregnancy.
    • Fig 2-1
  • PARTIAL HEPATECTOMY Priming Proliferation Growth lnhibition GROWTH FACTORS AND CYTOKINES HGF TGF-  EGF TNF-  IL-6 Others ADJUVANTS Norepinephrine Insulin Glucagon Thyroid hormone GROWTH INHIBITORS TGF-  Others Growth factors Adjuvanis Matrix degradation
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  • Metaplasia
    • One adult cell type is replaced by another.
    • Genetic reprogramming of stem cells.
    • Epithelial and mesenchymal metaplasia.
  • Intestinal glandular epithelium
    • Squamous metaplasia
    • Glandular metaplasia
    • Intestinal metaplasia of gastric epithelia
    Bronchial epithelia Epithelia in bile duct Cervical epithelia Epithelial metaplasia Columnar epithelium Squamous epithelium Squamous epithelium Gastric glandular epithelium Barrett esophagitis
    • Connective tissue metaplasia
    • Bone metaplasia.
    • cartilige metaplasia.
    • Inmatured fibroblasts
    Osteocytes Chondrocytes mesenchymal metaplasia
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    • significance of metaplasia
    • A two-edged sword
    • An undesirable change
    • Survive but some important protective mechanism is lost.
    • The influences that predispose to such squamous metaplasia, if persistent, may promote cancer transformation in metaplastic epithelium.
    • Cell injury
    Section B
  • Causes of cell injury and disease
    • Oxygen deprivation ( hypoxia, ischemia)
    • Nutritional imbalances
    • Physical agents
    • Chemical agents and drugs
    • Infectious agents
    • Immunologic reactions
    • Genetic derangements
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  • HYPOXIA
    • Ischemia ( loss of blood supply ).
    • Inadequate oxygenation
    • ( cardiorespiratory failure ).
    • Loss of oxygen-carrying capacity of the blood ( anemia or CO poisoning ).
  • HYPOXIC INJURY
    • Loss of oxidative phosphorylation and ATP generation by mitochondria.
    • Decreased ATP (with increase in AMP): stimulating fructokinase and phosphorylation, resulting in aerobic glycolysis.
    • Depleted glycogen.
    • Reduced intracellular pH: Lactic acid and inorganic phosphate.
    • Clumping of nuclear chromatin.
  • Four biochemical themes
    • Oxygen-derived free radicals.
    • Loss of calcium homeostasis and increased intracellular calcium.
    • ATP depletion.
    • Defects in membrane permeability.
  • PHYSICAL AGENTS
    • Trauma
    • Heat
    • Cold
    • Radiation
    • Electric shock
  • CHEMICAL AGENTS AND DRUGS
    • Endogenous products: urea
    • Exogenous agents:
    • Therapeutic drugs: hormones
    • Nontherapeutic agents:
    • lead or alcohol
  • MECHANISMS OF CHEMICAL INJURY
    • Directly: Mercury of mercuric chloride binds to SH groups of cell membrane proteins, causing increased permeability and inhibition of ATPase-dependent transport.
    • By conversion to reactive toxic metabolites which in turn cause cell injury either by direct covalent binding to membrane protein and lipid, or more commonly by the formation of free radicals.
    MECHANISMS OF CHEMICAL INJURY
    • CCl 4 in SER of liver cell (P-450) – CCl 3 . – lipid peroxidation and autocatalytic reactions – swelling and breakdown of ER, dissociation of ribosome, and decreased hepatic protein synthesis ( loss of lipid acceptor protein – fatty change of liver cell) – progressive cellular swelling, plasma membrane damage, and cell death.
  • FREE RADICAL INITIATION
    • Absorption of energy (UV light and x-rays)
    • Oxidative metabolic reactions
    • Enzymatic conversion of exogenous chemicals or drugs (CCl 4 >CCl 3 . )
    • Oxygen-derived radicals
    • Superoxide
  • Cell injury caused by free radicals through
    • Peroxidation of lipids.
    • Cross linking proteins by the formation of disulfide bonds.
    • Induction of DNA damage that has been implicated both in cell killing and malignant transformation.
  • INFECTIOUS AGENTS
    • Viruses
    • Rickettsiae
    • Bacteria
    • Fungi
    • Parasites
    • Marfan syndrome
    • Fibrillin, a scaffolding on which tropoelastin is deposited to form elastic fibers.
    • FBN1, 15q21, mutations in Marfan syndrome.
    • FBN2, 5q3, mutations in congenital contractual arachnodactyly.
          • Genetic derangements
    • Adenomatous polyposis coli
    • APC loci, 5q21
    • Adenomatous polyposis in colons (in teens).
    • 100% malignant transformation (  40ys ).
    • APC protein in the cytoplasm.
    • Several partners, including  -catenin.
    •  -catenin  entering the nucleus  activating transcription of growth-promoting genes.
    • Causing degradation of  -catenin  maintaining
    • low level of  -catenin in the cytoplasm.
  • CELLS REACT TO ADVERSE INFLUENCES
    • ADAPTING
    • SUSTAINING REVERSIBLE INJURY
    • SUFFERING IRREVERSIBLE INJURY AND DYING
  • CELL INJURY AND NECROSIS
    • General mechanisms:
    • Maintenance of the integrity of cell membranes.
    • Aerobic respiration and production of ATP.
    • Synthesis of enzymes and structure proteins.
    • Preservation of the integrity of the genetic apparatus.
  •  
  • Irreversible Injury Reversible Injury adaptation normal
  • Types of cell injury
    • reversible
    • irreversible
    necrosis apoptosis
  • Reversible injury
    • Cellular swelling
    • Fatty change
    • Hyaline change
  • Cellular swelling
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    • Excessive entry of free fatty acids into the liver
    • (starvation, corticosteroid therapy).
    • Enhanced fatty acid synthesis.
    • Decreased fatty acid oxidation.
    • Increased esterification of fatty acid to
    • triglycerides (alcohol).
    • Decreased apoprotein synthesis (CCl 4 ).
    • Impaired lipoprotein secretion from the liver
    • (alcohol).
    FATTY CHANGE
    • Morphology of fatty change
    • Sudan III, Oil red O, Osmic acid
    • Liver
    • Heart
    • Kidney
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    • Intracellular hyaline changes
    • Hyaline degeneration of arterioles
    • Hyaline degeneration of connective tissue
    Hyaline changes (degeneration)
    • Absorption of protein causing hyaline
    • droplets in proximal epithelial cells in
    • the kidney.
    • Russel bodies in plasma cells.
    • Viral inclusions in the cytoplasm or
    • the nucleus.
    • Masses of altered intermediate filaments
    • (Mallory bodies).
    Intracellular hyaline changes
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  • Hyaline change of the central artery of the spleen (spleen of hypertension disease)
    • The narrowing of the lumina with thickened vessel wall. Homogeneous pink hyaline material deposits under the intima.
    • Mucoid Degeneration
    • mucopolysaccharide deposition in the stroma of connective tissue.
  • mucoid degeneration
    • A heterogeneous group of pathogenic
    • fibrillar proteins accumulating in tissues
    • and organs.
    • Excess synthesis
    • Resistance to catabolism
    AMYLOIDOSIS
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  • Chemical nature of amyloid fibrils Two major forms: AL (amyloid light chain protein) AA (amyloid-associated protein): Derived from serum AA (12kd) synthesized in liver and elevated in inflammatory states.
  • Minor forms of amyloid fibrils: Transthyretin (TTR): A mutant form of a serum protein in familial amyloid polyneuropathy. A variant of TTR in aging. Beta-2-microglobulin (the component of class I MHC molecules) in long-term hemidialysis.
  • Minor forms of amyloid fibrils: Beta-2-amyloid protein forms the core of cerebral plaques and deposits within cerebral vessel walls in Alzheimer disease, deriving from a transmembrane glycoprotein precursor.
  • Minor forms of amyloid fibrils: Transthyretin (TTR): A mutant form of a serum protein in familial amyloid polyneuropathy. A variant of TTR in aging. Beta-2-microglobulin (the component of class I MHC molecules) in long-term hemidialysis.
  • Minor forms of amyloid fibrils: Beta-2-amyloid protein forms the core of cerebral plaques and deposits within cerebral vessel walls in Alzheimer disease, deriving from a transmembrane glycoprotein precursor.
    • primary (B-cell dyscrasia, AL)
    • Secondary or reactive (AA):
    • Collagen diseases, bronchiectasis, chronic
    • osteomyelitis.
    • Hemodialysis-related: Beta-2-microglobulin
    • deposition.
    • Hereditary (AA)
    Clinical forms of amyloidosis Systemic amyloidosis:
    • Nodular (tumor-forming deposits,
    • B-cell dyscrasia, AL)
    • Endocrine amyloidosis (procalcitonin)
    • Amyloidosis of aging: Heart, lung,
    • pancreas, spleen, brain.
    Localized amyloidosis
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    • Exogenous:
    • Carbon
    • Tattooing
    • Endogenous:
    • Lipofuscin
    • Melanin
    • Hemosiderin
    • Bilirubin
    Pigmentation
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    • Dystrophic calcification
    • Metastatic calcification
    Pathologic calcification
    • Necrotic tissues
    • Atheroma
    • Damaged heart valves
    Dystrophic calcification
    • Fig 2-13
  •  
    • Increased secretion of parathyroid
    • hormone
    • Destruction of bone tissue
    • Vitamin D-related disorders:
    • Sarcoidosis
    • Renal failure
    Metastatic calcification Hypercalcimia
  • Metastatic calcification Affecting Interstitial tissue of gastric mucosa Kidneys Lungs Pulmonary veins Systemic arteries
  • Section C CELL DEATH
  • TYPES OF CELL DEATH
    • necrosis
    • Coagulation necrosis
    • Caseous necrosis
    • Gangrene
    • Liquefaction necrosis( fat necrosis)
    • Fibrinoid necrosis
    • Apoptosis
    • Swelling, denaturation and coagulation
    • of proteins
    • Breakdown of cellular organelles
    • Cell rupture
    Common type of necrosis after exogenous stimuli.
  • NECROSIS The sum of the morphologic changes that follow cell death in living tissue and organ:
    • Denaturation of proteins.
    • Enzymatic digestion of organelles
    • and cytosol.
    • Enzymatic digestion by lysosomal enzymes of the dead cells themselves.
    AUTOLYSIS HETEROLYSIS
    • Digestion by lysosomal enzymes of immigrant leukocytes.
    • Nucleus changes :
    • The hallmarks of cell death in three patterns:
    • Basic Pathologic Change of Necrosis
    Normal cell Chromatin margination karyorrhexis pyknosis karyolysis Nuclear Alteration of Necrosis
  • 1)Three pattern of nuclear changes Karyolysis (DNase activity) Pyknosis (DNA condensation) Karyorrhexis (fragmentation of pyknotic nucleus)
    • Pyknosis : nuclear shrinkage and increased basophilia, and the DNA apparently condenses into a solid, shrunken basophilic mass. 
    • Karyorrhexis: nucleus undergoes fragmentation, scattered about the cytoplasm.
    • Karyolysis: the basophilia of the chromatin may fade and the nucleus disappears.
  •  
    • Cytoplasm change:
    • increased eosinophilium and a more glassy homogeneous appearance and even vacuolated cytoplasm.
    The Necrosis of heptocytes
    • Types of Necrosis
    Coagulative Necrosis Liquefactive Necrosis Fibrinoid Necrosis Necrosis Gangrenous Necrosis
  • Morphologic appearance of necrosis
    • Increased eosinophilia:
    • Loss of RNA in the cytoplasm
    • Increased binding of eosin to denatured
    • cytoplasmic protein
    • More glassy homogeneous appearance
    • Loss of glycogen particles
    • Vacuolated and moth-eaten cytoplasm
    • Calcification of necrotic cells
  • Coagulation necrosis Denatures of both structural and enzymatic proteins by injury or the subsequent increasing intracellular acidosis.
  • Renal Infarction - Coagulative
  • Splenic Infarction - Coagulative necrosis
  • Infarction - Adrenal gland:
  •  
  • Caseous necrosis A subtype of coagulation necrosis White and cheesy Tuberculosis Completely obliterated tissue architecture
  • Caseous necrosis of kidney
    • The necrosis area is soft, white-yellow cheesy appearance.
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  • Extensive Caseous necrosis Tuberculosis
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    • Liquefactive necrosis
    • Bacterial or fungal infections
    • Central nervous system
    • Amebiasis
  • Liver abscess: Liquifactive necrosis
  • Stroke- Liquifactive necrosis
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    • Fat necrosis
    • Traumatic
    • Activated pancreatic lipases
  • Fat necrosis(Steatonecrosis)
    • Only shadowy outlines of necrotic fat cells may be seen, with basophilic calcium deposits and a surrounding inflammatory reaction.
    • Fibrinoid degeneration Deeply eosinophilic
    • Collagen diseases
    • Necrotic vasculitis
    • Malignant hypertension
  • Fibrinoid Necrosis
    • homogeneous, deeply eosinophilic in necrosis.
    • Gangrene
    • A subtype of coagulation necrosis
    • Dry gangrene
    • Wet gangrene
    • Gas gangrene
  • Caseous necrosis - Tuberculosis
  • Gangrene - Amputated Diabetic foot
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  • Gangrene Intestine - Thrombosis.
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    • Absorption
    • Discharge: Erosion Ulcer
    • Sinus Fistula Cavitation
    • Organization
    • Encapsulation
    • Calcification
    Fates of necrosis
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  • Section D APOPTOSIS
  • APOPTOSIS (Programmed cell death)
    • Programmed destruction of cells during
    • embryogenesis.
    • Hormone dependent involution of tissues
    • in the adult.
    • Cell deletion in proliferating cell popula-
    • tions (intestinal crypt epithelium),
    • tumors, and lymphoid organs.
    • Pathologic atrophy in parenchymal
    • organs after duct obstruction.
    • Cell death by cytotoxic T cells.
    • Cell injury in certain viral diseases.
    • Cell death produced by a variety of
    • injurious stimuli given in low doses
    • (e.g. mild thermal injury).
  • MORPHOLOGICAL FEATURES OF APOPTOSIS
    • Cell shrinkage
    • Chromatin condensation and fragmentation.
    • Formation of cytoplasmic blebs and apoptotic
    • bodies.
    • Phagocytosis of apoptotic bodies by adjacent
    • healthy cells or macrophages.
    • Lack of inflammation.
  • Necrosis Apoptosis Stimuli Hypoxia Physical Toxins Pathological Histology Cell swelling Single cell Coagulation N Chromatin Disruption of condensation organelles Apoptotic bodies DNA Random Internucleosomal breakdown Diffuse
  • Necrosis Apoptosis Mechanism ATP depletion Gene activation Membrane Endonuclease injury Free radicals Tissue Inflammation No inflammation reaction Phagocytosis of apoptotic bodies
    • Fig 1-18
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  • Biochemical features of apoptosis 1.PROTEIN CLEAVAGE: Caspases (cysteine protease) Nuclear scaffold Cytoskeletal protein 2.PROTEIN CROSS-LINKING: Transglutaminase Cytoplasmic protein  shrunken shalls  apoptotic bodies Biochemical features of apoptosis
  • 3. DNA breakdown: 50-300 kb pieces Ca2+, Mg2+ dependent endonucleases DNA oligonucleosomes DNA ladders (also seen in necrosis) 4. PHAGOCYTIC RECOGNITION Receptors on macrophages for the surface components (phosphatidylserine, thrombospondin) on apoptotic bodies.
    • Fig 1-19
    • Apoptosis-associated genes
    • bcl-2, c-myc, p53
    • Fig 1-20
    • Occuring conditions
    • during embryogenesis and development;
    • as a homeostatic mechanism to maintain normal cell populations of tissue in the face of cell turnover;
    • as a defense mechanism such as in immune reactions;
    • when cells are damaged by diseases or noxious agents, such as injury, tumors and inflammation;
    • reduction cell during atrophy;
    • in aging.
    • Morphologic features
    • Cell shrinkage.
    • Chromatin condensation
    • Apoptotic bodies formation
    • Phagocytosis of apoptotic bodies by adjacent cells or macrophages.
    • Intacted membrane.
    • Morphology Biochemistry of Apoptosis
    • A specific biochemical feature
    • breakdown of DNA into large 180 to 200-kilobase pieces, by Ca 2+ /Mg 2+ dependent endogenous nucleases.
  • normalcell Cellular swelling, chromatin cluping Membrane damage Nuclear chromatin condensation and fragmentation Cytoplasmic budding and apoptosisi body Phagocytosisi of apoptosis body The sequential ultrastructual changes in necrosis and apoptosis
  • Apotosis of hepatocytes
  • Comparison of cell death by apoptosis and necrosis
  • Terminology:
    • Necrosis: Morphologic changes seen in dead cells within living tissue.
    • Autolysis: Dissolution of dead cells by the cells own digestive enzymes. (not seen)
    • Apoptosis: Programmed cell death. Physiological, for cell regulation.
  • Types of Necrosis:
    • Coagulative – Eg. Infarction
    • Liquifactive - Brain, abscess
    • Fibrinous - colleagen
    • Caseous - Bacterial / Tuberculosis
    • Gangrene - With infection
  • Ageing:
    • “ Progressive time related loss of structural and functional capacity of cells leading to death”
    • Senescence, Senility, Senile changes.
    • Ageing of a person is intimately related to cellular ageing.
  • Factors affecting Ageing:
    • Genetic – Clock genes, (fibroblasts)
    • Diet – malnutrition, obesity etc.
    • Social conditions -
    • Diseases – Atherosclerosis, diabetes etc.
    • Werner’s syndrome.
  • Cellular mechanisms of ageing
    • Cross linking proteins & DNA.
    • Accumulation of toxic by-products.
    • Ageing genes.
    • Loss of repair mechanism.
    • Free radicle injury
    • Telomerase shortening.
  • Telomerase in ageing: Germ Cells Somatic Cells
  • Ageing –changes:
    • Gradual atrophy of tissues and organs.
    • Dementia
    • Loss of skin elasticity
    • Greying and Loss of hair
    • BV damage – atherosclerosis/bruising.
    • Loss of Lens elasticity  opacity  vision
    • Lipofuscin pigment deposition – Brown atrophy in vital organs.
  • Pathology of elderly
  • Factors affecting ageing:
    • Stress
    • Infections
    • Diseases
    • Malnutrition
    • Accidents
    • Diminished stress response.
    • Diminished immune response.
    • Good health.
  • Conclusions:
    • Cellular Injury - Various causes
    • Reversible Injury  Adaptations
      • Hypertrophy, Hyperplasia, Atrophy
      • Accumulations - Hydropic, hyaline, fat..
    • Irreversible Injury - Necrosis
      • Coagulative, Liquifactive, Caseous
    • Ageing - Causes, Changes, Factors