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Pathology lecture 1
Cell reaction to injury
Terms in this set (76)
Understanding how disease begins
What are the cardinal signs of inflammation?
-Functio laesa (loss of function)
Constant/ stable internal environment
When do we see subtle changes in homeostasis ?
-minor changes in steady state (bp, body temp)
When do we see noticeable changes in homeostasis?
-More severe physiologic stresses or noxious stimuli
-Cell injury (reversible or lethal)
Proteasomes are key participants in what?
-Response to stress
-Adaptation to altered extracellular environment
What is the function of proteasome?
-Selectively destroy certain proteins thru a process known as ubiquitin-proteasome pathway
-2 types: 20S and 26S
Ubiquitin- Proteasome pathways
What is the importance of ubiquitination?
-Fundamental to cellular adaptation to stress and injury
-Involved in disease processes
Adaptive response where a cell changes in its environment to stay viable
When can atrophy occur?
-Under both physiologic (loss of tropic signals) and pathologic situations (disease)
-Organ atrophy can be due to reversible cell atrophy (pressure atrophy) or irreversible loss of cell (Alzheimer's)
What are the mechanisms of atrophy?
--Best studied in skeletal muscle
Conditions associated with atrophy
-Reduced functional demand
-Inadequate supply of oxygen (ischemia)
-Interruption of trophic signals
-Chronic cell injury
-Aging (senile atrophy)- size decrease
What is hypertrophy
-Organs made of terminally differentiated cells respond to increase in trophic signals and/or functional demands solely by an increase in cell size
-In organs made of cells that can regenerate (thyroid, kidney, liver)
-Response can be both increase in cell size and cell number
What are the mechanisms of cellular hypertrophy?
-Signal for hypertrophy vary and depend on cell type and the situation
-Limited number of downstream pathways mediate effects
-Adaptive cellular remodeling (increase proteosomal degradation)
What are the mechanisms of cellular hyperplasia?
-Signals vary depending on tissue type
-Involves stimulating resting (G0) cells to enter the cell cycle (G1) and then multiply
What are causes for hyperplasia?
-Hormonal stimulation ( ex. gynecomastia)
-Increase functional demand (ex. Lymphoid hyperplasia)
-Chronic injury (ex. Foot calluses)
-Reversible change in which one adult cell type is replaced by another adult cell type that is better suited to tolerate a specific abnormal environment
-replacing one gene expression for another
-normal protective mechanisms may be lost
-noxious stimulus must be removed to go back to normal
-consistent signal may lead to dysphasia and neoplasia
-Reversible disordered growth and maturation of the cells in a tissue
-shares many cytology features with cancer (disturbance in growth regulation)
When does Dysplasia occur?
-most often in hyperplastic and/or metaplasia epithelium in response to a persistent injurious stimulus
-will regress with removal of noxious stimulus
How do we remove severe dysplasia?
-aggressive preventive therapy to cure cause
-eliminate the noxious agent
-surgically remove the dysplastic tissue
Reversible cellular injury
-Decrease oxidative phosphorylation
-depletion of energy stores (ATP)
-cellular swelling with stress on plasma membranes
Irreversible cellular injury
-Continuous or sever injury
-cell can't adapt or recover
-leads to death
What are the 2 types of death and how do they differ?
-differ in their morphology, mechanism and their physiologic and pathologic roles
What are some ultrastructural changes in reversible injury?
. Disaggregation of membrane-bound polyribosomes
.swelling due to affected energy gradient
.blebs that can detach from cell without loss cell viability
.mostly nucleoli changes
. Separation of fibrillation and granular component of nucleolus
. Diminished or absent granular component
What does the cellular response to injurious stimuli depend on?
-the nature of the injury
What does the consequences of cell injury depend on?
-depends on the, state, and adaptability of the injured cell
-cell's nutritional and hormonal status and metabolic needs are also important
-cell injury can trigger multiple mechanisms that can cause damage
Ischemic cell injury
-blood flow impairment leads to oxygen deprivation
-anaerobic metabolism leads to chemical and pH imbalances
-generation of injurious free radical species
-O2 good and bad (can produce partially reduced species that can react to other molecules in body)
-short periods of ischemia may be reversible
What are some consequences of decreased ATP during cell injury?
-reversible changes seen with transient ischemia
-Persistent ischemia can lead to cell death
What are the consequences of mitochondrial dysfunction?
-necrosis or apoptosis
What are some injuries that increased cytosolic calcium may inflict on a cell?
Mechanisms of membrane damage in cell injury
-decrease in O2 and increase in cytosolic Calcium are typically seen in ischemia but may accompany other forms of cell injury
-ROS are often produced on reperfusion of ischemic tissues
What are the Reactive Oxygen Species (ROS)?
-Lipid peroxide radicals
Role of activated oxygen species in human diseases
Cell death diagram
What are some characteristics of necrotic cells?
-Spectrum of morphological changes that follow cell death in living organism
-largely due to progressive destructive action of enzymes on the injured cells
-Necrotic cells are unable to maintain membrane integrity and their contents often leak out
-causes inflammation in the surrounding tissue
-require hours to develop in tissue (4-12 hrs in myocardial necrosis)
What is autolysis
The digestion of tissue by intracellular enzymes that leaks after death of the organism
Morphology of necrotic cells under light microscopy
-increase of eosinophilia
-loss of the normal basophils a imparted by the RNA in the cytoplasm
-Increased binding of eosin to denatured intracytoplasmic proteins
-Glassy appearance due to loss of glycogen particles
-Vacuolated cytoplams due to enzymatic digestion
-Dead cells may be replaced by myelin figures
What are myelin figures?
Large, whirled phospholipid masses
Morphology of Necrotic cells under electron microscopy
-overt discontinuities in plasma membranes
-marked dilation of mitochondria
-intracytoplasmic myelin figures
-amorphous osmiophilic debris
-aggregates of fluffy material representing denatured protein
What are the 3 patterns of nuclear change during necrosis?
-they are all due to nonspecific breakdown of DNA
Fading the basophils of the chromatin due to DNase activity
Nuclear shrinkage and increased basophilia
-seen in adoptive cell death
-Fragmentation of the nucleus
-With time the nucleus disappears
What are the 6 types of necrosis?
-preservation of basic cell outline at least for a few days
-gross- pallor area with firm texture
-micro: acidophilus, coagulated, anucleated cells may persist for weeks
-ultimately removed by fragmentation and phagocytosis of the cellular debris by scavenger leukocytes
-Most often seen in the central nervous system
-disappearance of recognizable cells following hypoxic death and/or bacterial infection
-Bacterial or fungal infections stimulate the accumulation of inflammatory cells
-complete digestion of the dead cells by the inflammatory cells turns tissue into a liquid viscous mass
-Shares features of both coagulation and liquefaction necrosis
-Gross: architecture not preserved but tissue not liquefied; soft and cheese-like white material
. amorphous granular debris of fragmented cells with affinity for acidophilus dyes
-Dry and wet gangrene depending on the site
-interruption of blood supply to a limb or to a segment of bowel
-with superimposed bacterial infection, Liquefactive action of bacteria and leukocytes leads to wet gangrene
-morphological appearance depend on tissue involved bacterial actions
-Release of pancreatic enzymes with auto-digestion of pancreatic parenchyma
-trauma to fat cells
-Gross: visible chalky white areas (fat saponification)
-Micro: shadowy outlines of necrotic fat cells, with basophillic calcium deposits and acute inflammation
-often associated with immune-mediated vasculitis
-deposition of fibrin-like proteinaceous material in walls of arteries
.insudaion and accumulation of plasma protein
. Homogeneously eosinophilic zone may represent necrosis or accumulated plasma protein
-program cell death
-cellular suicide mechanism
-prearranged pathway triggered by a number of extracellular and intracellular signals to determine cell death when
. It i no longer useful
. It may be harmful to the larger organism
What is the role of p53 in apoptosis?
-pivotal molecule in the cell's life-death sequence
- preserves the viability of an injured cells when DNA alteration can be repaired
-Sends cell toward apoptosis if the damage is irreparable
Morphology of apoptosis
-formation of cytoplasmic blebs and apoptosis bodies
-phagocytosis of apoptotic cells by macrophages
Signaling for apoptosis
- two pathways
1. Receptor-ligand interactions (TNF-alpha and FAS) at the cell membrane
2. Mitochondrial proteins (regulated by Bcl-2)
-Signals are transferred down via caspases (family of cysteine proteases)
What causes apoptosis in physiologic situations?
-the programmed destruction of cells during embryogenesis
-hormone-dependent involution in the adult
-cell deletion in proliferating cell populations
-elimination of potentially harmful self-reactive lymphocytes
-cell death induced by cytotoxic T cells
What causes apoptosis in pathologic conditions?
-Cell death produced by a variety of injurious stimuli
-Cell injury in certain viral diseases
-pathologic atrophy in parenchymal organs after duct obstruction
-cell death in tumors
What are the two apoptosis pathways?
1. Mitochoiondrial (intrinsic) pathway
2. Death receptor (extrinsic) pathway
What are the signaling molecules for the two apoptosis pathways?
-Death Receptor (extrinsic) pathway
.receptor-ligand interactions on cell membrane
.TNF-alpha and FAS
-Mitochondrial (intrinsic) pathway
.regulated by Bcl-2
What happens when apoptosis is defective and there is an increase cell survival?
-p53 mutation leads to cell with damaged DNA that fail to die and can become cancerous
-postulated to be the basis of autoimmune diseases
-can cause failure to eliminate harmful lymphocytes that can react against self-antigens
What happens if apoptosis is defective and there is excessive cell death?
- can be caused by mutations, or misfiled proteins
-ischemic injury (myocardial infarction, stroke) may occur
Necrosis vs. apoptosis chart
What does metabolic derangements lead to?
-Intracellular accumulation of abnormal amount of various material
Intracellular storage/ accumulations
.normal or abnormal
.endogenous or exogenous
.harmful or innocuous
-nutrients are stored for later use
Can overload of normal body constituents cause cell injury?
-abnormal proteins may be toxic if retained in the cell (ex. Lewy bodies in Parkinson's disease)
What happens to substances that can't be metabolized?
-accumulate in cells
-endogenous substrates that cant be processed
-aggregates of normal or abnormal proteins
-insoluble endogenous pigments (lipofuscin, melanin)
-exogenous particles (inhaled carbon, injected tattoo pigments)
What are the 4 types of abnormalities that lead to intracellular accumulations?
1. Abnormal metabolism
2. Defect in protein folding transport
3. Lack of enzyme
4. Ingestion of indigestible materials
What are the two types of pathologic calcification?
-calcium in previously damaged tissue
-serum calcium concentration usually normal
. Necrotic tissue (TB)
.Scared ❤️ valves
. Atherosclerotic lesion
.Psammoma bodies (single necrotic cell)
-usually due to hypercalcemia
.Osteolytic lesion (tumor)
. Excess calcium intake
-Alkaline condition in tissue favor metastatic calcification
-The result of a progressive decline in cellular function and viability
-It is a regulated process under genetic influence
What causes aging?
-accumulation of cellular and molecule damage due to effects to exposure to exogenous influences
-random errors occurring during mitosis
-latent viruses or increase autoimmune reactions
-free radicals formed during cell metabolism
- genetic syndrome that causes premature aging
-1/10th of disorder associated with mutations in the LMNA gene
-The mutant gene codes for a defective precursor of lamin A (progerin)
Diagram describing inputs to cellular aging
Different biochemical pathways of cell injury
THIS SET IS OFTEN IN FOLDERS WITH...
Pathology: Cell Rxn to Injury
Pathology Lecture 2
Pathology Lecture 3
Pathology lecture 4
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