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Subject: Pathology Topic: Cell Injury and Death I Lecturer: Dr. Luis Cruz Date of Lecture: 06/09/2011 Transcriptionist: Desiree Timtiman Pages: 12
PATHOLOGY y study of suffering or study of disease y study of the structural, biochemical, and f unctional consequences of injurious stimuli on cell s, tissues, and organs y structural changes: cell tissue organ and systems y Serve as bridge between basic sciences and clini cal medicine, and is the scientific foundation for all of me dicine. y MAJOR DIVISIONS: Anatomic o General y Acc to Doc, memorize understand st the 1 seven chapters of robbins! y Concerned with the reactions of cell s and tissues to abnormal stimuli and to inherited defects Systemic y Examines the alterations in specialize d organs and tissues that are responsible for disorders that involved these organs o Clinical Deals with laboratory side of pathology (hematology, microbiology, etc) Also used in correlation of anatomic changes with physiologic changes in the cells ASPECTS OF DISEASE PRO CESSES how it happened what what are What is the cause? affected as seen in the cells or tissues correlate examined correlate with the individuals sign and symptoms 1. Etiology or cause y Major classes: Genetic o Born with it (ex. Clef t pala te, polydactyly, etc) Inherited mutations Disease-associated gene variants polymorphism Acquired o Primarily environmental Infectious (microbiologic or biologic) Nutritional Chemical Physical
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2. Pathogenesis y sequence of events in the response of cells or tissues to the cause 3. Morphologic Changes y structural alterations 4. Functional Derangement y f unctional al terations y its clini cal signifi cance ex. etiology: infection pathogenesis: injury due to mosquito bite disruption of skin scratching the area with dirty nails infection Abscess f unctional derangement of limb due to abscess morphologic changes: abscess f unctional derangement: f unctionally deranged limb INTRACELLULAR SYSTEM VULNERABLE INJURY(Target INJURY(Target of Injurious Stimuli) 1. Integri ty of cell membrane 2. Aerobic Respiration 3. Synthesis of protein and enzyme 4. Cytoskeletal system 5. Intact genetic apparatus
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PRINCIPLES AND CONCEPTS Homeostasis y Present state of cell without any injurious stimuli y equilibrium y steady state Adaptation y stimulus(injurious or nonIntroduce injurious cell reacts depending on the stimulus(lethal lethality of the or sublethal)adaptive state or higher level of equilibrium y new but altered steady state achieved to preserve cell viabili ty y ultimate goal of adaptation: viability y structural reversible f unctional and responses to more severe physiologi c stresses and some pathologic stimuli y Types of adaptation: Atrophy o decrease in cell size Hypertrophy o increase in cell size entails an increase in building blocks(protein synthesis)
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Hyperplasia increase in the n umber of cells as a result of cell division also en tails an increase in protein synthesis Metap lasia replace adult cell by another type ex. Secretory columnar epithelium stimuliprotective injurious stratified squamous epitheli um
REACTIONS OF CELLS TO STIMULI y cell s can to adapt environment by hypof unctioning or hyperf unctioning y a persistent sublethat injury can lead to hyperplasia and hypertrophy y Hypof unctioning o If its not f unctioning i t becomes small Related to atrophy o y Hyperf unctioning Components o are added for it to hyperf unction Related to hyperplasia and hypertrophy o y Vulnerable systems are related to adaptability
increase in size of an organ due to in crease in number of cells CAUSE AUSES : 1. Physiologic a. Hormonal y estrogen stimulation of uterus; occurs with hypertrophy y glandural proliferation of breast during pregnancy b. Compensatory 2. Pathologic a. Excessive Hormonal stimulation y ex. Endometrial hyperplasia b. Viral induced y growth factors produced by virus y
MECHANISMS y
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OF CELL INJURY The cell ular response to injurious stimuli depends on the type of injury, its duration and its severity The consequences of cell inj ury depend on the type, state and adaptabi lity of the cell inj ury results from f unctional and Cell biochemical abnormali ties of several essential cell ular components
HYPERTROPHY y Result of increased of production of cellular proteins y Increase in size of an organ or tissue due to increase in size of the cell s y CAUSE AUSES: 1. Physiologic a. Hormonal estrogen stimulation of uterus in pregnancy average female has a uterus as big as her clenched fist and an average Filipino ne wborn baby is 3 kilos, hence there is a need for both hypertrophy and hyperpla sia to accommodate the fetus b. Compensatory 2. Pathologic Ex. Heart in CHF a. Excessive Hormonal stimulation b. Viral-induced
HYPERPLASIA
Normal cell in homeostasis has to adapt because of in crease demand or stresses. If it does not adapt due to some injurious stimulus, it will result into cell injury. Cell injury can lead to subcellular alterations which cant be seen under the light microscope or rever sible cell injury called light microscopic pattern of injury that is observable under the light microscope. If cell is unable to adapt due to severe, progre ssive and irreversible injury the cell may die or undergo apoptosis (programme d cell death) or necrosis.
Hypertrophied heart (lt), normal heart (middle), heart with cell injury (upper rt), heart with necrosis (lower rt) Morphologi c change: hypertrophied heart Functional derangemen t: decreased in blood volume ejected by the heart and as a physiologic response leads to HPN
Signals that resu lt into cardiac hypertrophy:
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mechanical triggers (stretch) best explained by Starlings law y stretching the muscle has a corresponding amount of contraction y overstretching can cause dilation o trophic triggers (activation of a-adrenergic receptors) hormonal growth factors Signal transduction pathways can be turned on by the stimuli and lead to: o induction of genes that stimulate protein synthesis such as growth factors and structural proteins o
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Synthesis
of more proteins and myofilaments per cell which achieves improved performance and thus, a balance between demand and the cell f unctional capacity since its a reversible adaptive mechanism, removing the stresses will cause the heart to revert back to its normal f unctioning cell summary, stable tissue In abnormal stimulus(inc in f unctional[work]/metaboli c demand, inc endocrine stimulus or persistent tissue injury adaptive response(hypertrophy or hyperplasia or both)stable tissuereturn back to normal cell or per sistent altered state At a certain point, however, the adaptive response can bring about a dysf unctional state in the condition
End result of Hyperp lasia and Hypertrophy:
This
is a schematic diagram of hypertrophy and hyperplasia.
AGENESIS y failure of formation of embryonic cell mass APLASIA y failure of differentiation to organ specific tissue (ex. Kidney) y Failure of cell production y Fetal life o results in agenesis y later life cause of permanent loss of precursor cell s o in proliferative tissue such as bone marrow y Aplastic Anemia o aplasia in the bone marrow Remember that BM contains the precursor o cells for RBC, WBC, and platelets
HYPOPLASIA y decrease in cell production that is less extreme than that fou nd in aplasia; fail ure to grow to f ull size; y ex. Klinefel ter and Turner Syndrome o dysgonadal syndrome o partial lack of growth and maturation of gonadal structures
DYSGENESIS y failure to undergo structural organization of tissues into organs
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didnt go into so much details in this diagram but its self explanatory. Ill let your brains figure it out! Haha!
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ATROPHY y Decrease in the size of an organ or tissue resulting from decrease in the mass of preexisting cells y Decrease in the mass of cell i s the result of decrease in organelles; unnecessary organelles can be loss for it to be viable y Results from decreased protein synthesis and increased protein degradation because of reduced metabolic activity y Ubiquitin-proteasome Ubiquitin-proteasome pathway o main pathway in the degradation of proteins disuse and nutrient deficiency activates o ubiquitin ligases Ubiquitin ligases o Attaches ubiquitin to cell ular proteins target these and proteins for degradation in proteasomes o responsible for accelerated proteolysis y Accompanied by increased AUTOPHAGY and HETEROPHAGY Autophagy- eating up your cell s o Heterophagy- eaten up by another cell o y by presence of AUTOPHAGI C Marked GRANULES y Autophagic granules o Intracytoplasmic vacuoles containing debris from degraded organelles y Cancer cachexia is an example of a trophy y CAUSE AUSES : Physiologic: Tissues/ structures present in embr yo or in o childhood(e.g. thymus) may undergo
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atrophy as growth and developmen t progress Thymus disappears by the age of 2 y/o. o Pathologic: 1. Decreased workload or disused o Immobilized fractured bone in cast arm results in disused of m uscles within the cast which leads to atrophy 2. Loss of innervations/ dennervation atrophy o Damage to the nerves leads to atrophy of the muscle fibers supplied by those nerves o Due transaction of nerve or infe ction like polio 3. Ischemia o Diminished blood supply or oxygen deprivation 4. Inadequate nutrition (ex. Marasmus) 5. Loss of endocrine stimulation o Deprivation of hormonal stimulation o Ex. Loss of estrogen stimulation af ter menopause results in physiologic atrophy of the endometrium, vagina epi and breast 6. Senile atrophy Aging o supply due to o Decrease bld atherosclerosis Reduced activi ty leads to reduction in o size of the skeletal muscle 7. Pressure or Physical stress tissue compression for any length of o time can cause atrophy o ex. Benign tumor can cause atrophy in the surrounding uninvolved tissues o ex. bed ulcers Kinds of atrophy: General Atrophy o Starvation atrophy Senile a trophy o Local Atrophy Disuse Atrophy Pressure Atrophy Endocrine Atrophy Denervation Atrophy
Patient
with cancer cachexia
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The
figure above shows both atrophy and hypertrophy of sk. Muscle. Note the distinctive features of sk. Muscle: eccentrically multinucleated cell. The hypertrophied muscle is possibly compensating for the atrophied muscle.
Schematic
diagram of autophagy leading to atrophy
METAPLASIA y
This is an e xample of an atrophied brain. Compare the sulci of the normal brain(lt) and atrophied brain (rt) The sulci is wider due to the thinned gyri of the atrophied brain.
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reversible change in which one mature/adult cell type (epi thelial or mesenchymal) is replaced by another mature cell type A protective mechanism rather than a premalignant change According to older schools, dysplasia is a continuous spectrum of metaplasia CAUSE AUSES : Persistent Irri tation o o Infection o Malnutrition A
Examples: o
atrophied testes(rt)due to loss of hormonal stimulation. (lack of use daw sabi ni fi! Lol!)
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Bronchial
ciliated (pseudostratifie d, to stratified squamous
columnar) epithelium E.g., respiratory tract of smokers St. sq i s more protective than columnar but this will cause to the loss of secretory f unction that traps foreign material leading to compensatory mechanism: coughing Endocervi cal (columnar) to squamous epithelium E.g., chronic cervicitis Esophageal (squamous) to gastric or intestinal epithelium E.g., Barrett esophagus Mucous barrier is more protective than st. squamous ep.
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Arrow
is pointing at the Squamous metaplasia Transition area in the cervi x from endocervical epi to st. sq.
Transformation zone ( OBGYN GYN terminolog y)/ squamocolumnar zone/ squamocolumnar junction/ transition zone
*calculus- stone *chronic trauma leading to cartilage osseous due to calcification * vit a deficiency loss of translucency due to kerato-conjunctivitis or keratinization of cornea
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Same as the principles mentione d above. If the cell is able to adapt it will survive and leads to adaptive changes: hypertrophy, hyperpla sia, metaplasia and atrophy. And if the cell is unable to adapt it will not survive and lead to cell death
DYSPLASIA y Deranged development y Proliferation and atypical cytologi c alterations y change in size, shape and organization NOT an adaptive mechanism but a change for the ORSE WORSE Cell Adaptation Key Facts: y
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Adaptable
within physiological limi ts; beyond physiologic limits may cause cell death Heat shock proteins can respond to injury by producing cell stress proteins, which prote ct from damage and help in re covery Increased demands met by hypertrophy and hyperplasia Reduced demand met by atrophy Apoptosis- cell loss from tissues can be achieved by programmed cell death Tissues can adapt to demand by a change in differentiation known as metaplasia
Reaction of cells to injury on a biochemical level y Functional (biochemical)changes occur before gross morphologic changes appear y Changes occur as follows: Ultrastructurallight microscopic changes gross morphological change y Again, the light microscopic changes that can be appreciated are fatty change and cellular swelling Reactions of cell injury y Reversible injury(degeneration) o Cell f unctions impaired but cell can recover o Removing the stimuli will return the cell back to its original state y Irreversible inj ury o Cessation of all cell f unctions with cell ular death o Apoptosis Programmed cell death o Necrosis Sum degradative of and inflammatory reactions occurring af ter tissue death
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Note the influx of calcium, sodium and radicals that bring s about cellular changes. This will be f urther discussed in the succeeding lectures.
Fragmentation of the pyknotic nucleus Karyolysis y Fading of basophilia of chromatin y Dissolution y
REVERSIBLE INJURY : Morphologic changes y Light microscopic changes o Cell swelling (a/k/a hydropic change) Fatty change o Cell is replaced by a blank space which is actually fat that was removed by the alcohol (this is during the process of tissue slide preparation) with the nucleus at the periphery y Ultrastructural changes o Canno t be seen but implie d o Alterations of cell membrane o Swelling of and small amorphous deposits in mitochondria o Swelling of RER and detachment of ribosomes o Seen as cytoplasmic blebs IRREVERSIBLE INJURY: Morphologic changes y Light microscopic changes o Increased cytoplasmic eosinophilia (loss of RNA, which is more basophilic) o Cytoplasmic vacuolization o Nuclear chromatin clumping Very hard to distinguished y Ultrastructural changes Breaks cellular o in and organellar membranes o Larger amorphous densities in mitochondria o Nuclear changes: Pyknosis y Nuclear shrinkage and increased basophilia Karyorrhexis
Lung with pneumonia showing morphologic changes in the alveoli. Most cells in the picture are eosinophilic and lacking nucleus or having fragmented nucleus. CAUSES y y y y y y y y
OF INJURY: Hypoxia Chemicals and drugs Physical Agents Microbiologi c Agents Imm unologic reactions Genetic Defects Nutritional Imbalances Aging
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MECHANISMS y
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OF CELL INJURY Loss of calcium homeostasis o related to ATP depletion, because Calcium maintaining intracell ular necessitates ATP Defects in membrane permeabili ty o Due to defective Na-K channel which is also ATP depen dent Sodium is retained inside the cell due to o lack of Na-K ATPase pump. This will lead to swelling due to increase water content of the cell (water follows sodium). o Vulnerable in inj urious stimuli ATP depletion
Schematic
Loss of aerobic respiration (TCA and ETC) Oxygen and oxygen-derived free radicals Membrane damage and loss of calcium homeostasis are most crucial o
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LOSS OF CALCIUM HOMEOSTASIS y Some models of cell death suggest that a massive infl ux of calcium causes cell death y Too much cytoplasmic calcium: o Denatures proteins Poisons o mitochondria (oxidative phosphorylation and aerobic respiration) o Inhibits cellular enzymes (protein synthesis)
diagram of mechanism of cell injury.
INTEGRITY OF CELL MEMBRANES y Injured membranes are leaky y Enzymes and other proteins that escape through the leaky membranes make their way to the bloodstream, where they can be measured in the serum Some enzymes that leak out are dangerous to the cell and cause lysis or metabolic derangement
increase cytosolic calcium can increase your ATPase, Phospholipase, Protease and endonuclease causing the decreased in ATP, decreased in phospholipids(component of cell membrane), disruptions of membrane an d cytoskeletal proteins and damage the nuclear chromatin, respectively
HYPOXIC CELL INJURY y Hypoxia o any state of reduction of O2 supplied to cells and tissues and results in decreased ATP production. y Hypoxia can result from: cardiorespiratory failure o o loss of blood supply o reduced transport of O2 in blood (anemia or CO toxicosis) anemia because of less O2 carrier CO toxicosis: CO has a greater affini ty to Hgb than Oxygen, replacing it and decreasing the oxygen tension leading to a de crease in relea se of oxygen in the tissue. o blockage of cell enzymes (e.g. cyanide) affects the CYP450 blocks the last electron acceptor in ETC no ATP production o Ischemia is decreased blood supply or usion of tissues usually due to perf us constriction or obstruction of blood vessels. Spastic phenomenon y Vasospasm or vasoconstriction for a long time leads to hypoxic episodes, however, when bld vessels dilates, too much blood passes through leading to ischemia reperfussion injury (increase in bld supply hyperoxygenation inc free radicals)
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Ischemia tends to injure tissue faster because substrates for glycolysis are not delivere d, anaerobic generation of ATP stops faster, glycolytic f unction is inhibited by metabolite accumulation.
Schematic
diagram of hypoxia and its effe cts on the cellular components of the cell.
ISCHEMIA -- REPERFUSIO RE PERFUSION N INJURY Reoxygenation by increased generation of free radicals y Compromised cellular antioxidant defenses Promotion of the mitochondrial permeabili ty transition precludes mitochondrial energization and ATP recovery y Inflammation resulting from cytokines and increased adhesion molecules from parenchymal and endothelial cells. Leukocyte influxes adds to damage. y Activation of complement pathway
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Mitochondrial
oxidative phosphorylation is disrupted first Decreased ATP o Decreased Na/K ATPase gain of intracell ular Na cell swelling o Decreased ATP-dependent Ca pumps increased cytoplasmic Ca concentration Altered metabolism depletion of glycogen o o Lactic acid accumulation decreased pH o Detachment of ribosomes from RER decreased protein synthesis End result is cytoskeletal disruption with loss of microvilli, bleb forma tion, etc
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Oxygen and y
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swelling with formation of large amorphous densities in matrix Lysosomal membrane damage leakage of proteolytic enzymes into cytoplasm Mechanisms include: o Irreversible mitochondrial dysf unction markedly decreased ATP Severe impairmen t of cell ular and o organellar membranes
oxygen derive d free radicals causing cell injury
Mitochondrial
EXAMPLES OF FREE RADI CALS y Chemical (e.g., CCl4, acetaminophen) y Inflammation / Microbial killing y Irradiation (e.g., UV rays skin cancer) y Oxygen (e.g., exposure to very high oxygen tension on ven tilator) y Physiological age-related changes MECHANISMS OF FREE RADICAL
FREE RADICAL y Free radicals have an unpaired electron in their outer orbit y Free radicals cause chain reactions y Generated by: Absorption of radiant energy o Oxidation of endogenous constituents o Oxidation of exogenous compounds o
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INJURY Lipid peroxidation damage to cell ular and organellar membranes Protein cross-linking and fragmentation due to oxidative modification of amino acids and proteins DNA damage due to reactions of free radicals with thymine
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Free radicals and its pathologi c effects.
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of transcription
Whew! I didnt thought Ill be making a twelvepaged tranx for an hour lecture!! Hahaha! Anyways, good luck and study hard batch 2014! Heres to a great year for all of us!
In all these things we have complete victory through him who loved us. Romans 8:37-39
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