4. Irreversible Injury Flashcards
Irreversible injury = ____
Cell death in pathology, we’re talking about ____ (apoptosis plays a role, but it is predominantly a physiologic event, but it can be a pathologic event)
Necrosis > cell death, and changes to cells post-death > necrotic changes gives us a clue to the ____ and how the cell died
cell death
necrosis
etiologic triggers
Irreversible cell injury
- Primary targets of damaging stimuli: ____, mitochondria, ____ and DNA
- Due to ____, damage to one target leads to secondary damage to others
- Cell death (irreversible injury) occurs when threshold of ____ is surpassed; not defined by specific morphologic or biochemical events.
- Typically, cells lose ability to restore ____, loss of of structure and function of ____ and loss of ____
membranes
cytoskeleton
interpendence
accumulated damage
mitochondrial function
membrane proteins
DNA integrity
Necrosis (accidental death)
Necrosis = ____ death; no physiologic example (apoptosis is physiologic but it can be pathologic)
Changes result from hydrolytic enzymes break down the cell (intra: enzymes released by lysosomes called ____; extra: enzymes derived from adj cells or inflam cells called ____, but same effect as autolysis)
Unable to maintain membrane integrity > material leaks out > ____ > most common cause of inflammation is dead tissue; it will also cause more dead tissue; certain proteins/enzymes end up in blood (i.e. during a heart attack) > ____: enzymes that have same function but slightly different in molecular weight and these are used diagnostically
Fate: degradation of FA (bind calcium, and form a lattice) and ____ after the tissue has been removed
pathologic
autolysis
heterolysis
pro-inflammatory
isozymes
calcium deposition
Necrosis (accidental death)
- Spectrum of morphologic changes that follow irreversible injury that are recognized as cell death
- Most changes result from progressive degradative action of ____ (both intra- and extracellular) on the cell
- Necrotic cells are unable to maintain membrane integrity; as a result, contents often leak out:
- Important for ____
- Stimulates ____
• Fate: digested by enzymes and ____; or ____. Degradation to fatty acids and binding of Ca (calcification)
enzymes
diagnosis
inflammation
disappear
persist
Irreversible cell injury
There isn’t a ____ that separates reversible injury from irreversible injury; there is no single ____
Changes in PM, or lysosomal membranes; cytoskeleton can be affected by enzymes escaping from the lysosome
Irreversible injury occurs when the cell cannot restore mitochondrial function; and loss of structure of function of membrane protein and DNA; but there isn’t one single event characterizing irreversible injury
defining event
marker
Necrosis • Phenomena most often observed: – Inability to reverse \_\_\_\_ – Profound disturbances in \_\_\_\_ – Loss of \_\_\_\_ integrity
• Changes in cellular morphology
– Cytoplasmic: ____, mitochondrial swelling,
loss of ____, calcification, ____ figures
– Nuclear (DNA breakdown): ____, karyolysis, ____
• Ultrastructural changes:
– Discontinuities in ____, mitochondrial dilation, ____ figures
mitochondrial damage
membrane function
DNA/chromatin
eosinophilia
ER
myelin
pyknosis
karyorrhexis
membranes
myelin
Necrosis
Most common change > mitochondrial damage > not producing ____ and may be generating ____ > switch to glycolysis
Cytoplasmic level > eosinophilic (when tissue stained with H/E, increase with ____ staining, and a decrease in hemotoxylin due to decreased levels of ____ because the nucleus has been comprimised); myelin figures may be seen at light microscope, but more prominent at ____ > swirls of laminated tissue > remnants of ____
You don’t need ultrastructural assessment to see they’re irreversibly injured, however, discontinuities in membrane result from enzymes that are activated from excess ____
ATP ROS eosin mRNA ultrastructure organelles calcium
Nuclear Status
• Busy cells: – \_\_\_\_ nuclei – \_\_\_\_ – \_\_\_\_ – \_\_\_\_ cytoplasm (mRNA) • Non-busy cells: – \_\_\_\_ nuclei – \_\_\_\_
Busy cell: DNA unpacked = euchromatin; nucleus of active cell takes up more ____
Non-busy is viable but ____; just looking at a nucleus you can tell busy vs non-busy
Dead cell shows one of three changes: clump (____) because of change in ____ as switches to glycolysis, or enzymes that breakdown the structure; DNA may break up due to nucleases (____); nucleus may dissolve and totally degrade (____); all three of these changes are irreversible, if seen in tissue the cell is dead
Karyorrhexis is not the same as what you see during apoptosis; not organized, all kinds of nucleases attack > results in a ____ instead of an organized ladder of DNA during electrophoresis
large
euchromatin
nucleolus
blue
smaller
heterochromatin
hemotoxylin
quiescent
pyknosis
pH
karyorrexhis
karyolysis
smear
Patterns of Necrosis
Severe pathologic conditions lead to large areas of tissue necrosis: Morphologically distinct changes result from progressive degradative action of enzymes on dead cells; these patterns provide some insight into ____
____ (autolysis, heterolysis) vs
____ denaturation
Fat necrosis is not ____
etiology/pathogenesis
enzymatic digestion
protein
steatosis
Liquefactive necrosis
- Involves complete ____ (Liquefy)
- Result of hydrolysis: ____ along with ____ (enzymatic digestion is predominant)
- Loss of cell architecture: tissue converted into a ____ mass (no longer ____)
- Often associated with ____-strong inflammatory stimuli; PMN derived lysosomes
____: swollen, inflamed because of a microbial infection > production of pus (inflammatory exodate)
Stimulant: bacteria (kills some of normal tissue), causes influx of neutrophils > engulf bacteria; surrounding tissue is also destroyed > tissue will be ____ (semi-liquid mass)
On right: tissue has been converted to semi-liquid mass, and dots are invading neutrophils; local accumulation of bacteria that has been ____ off by inflammatory process: abscess
Collagen makes up most of connective tissue, tissue is perfused with BV (in a biopsy won’t see them common, isn’t enough blood in body to perfuse all tissue; pre-cap sphincters that open and close, selectively when the tissue requires it); however, in ____ you will see presence of BV (neutrophils invade)
Cannot identify the ____ tissue type; all different tissue types of liquefactive necrosis look identical (kidney looks like liver, etc)
digestion autolysis heterolysis semi-liquid recognizable microbial infection
abscess
digested
walled
inflamed tissue
normal
Liquefactive Necrosis
Looking within a tubule, abundance of inflammatory cells and eventually the tubule will be digested via ____; already eosinophilic and nuclei are affected
In the skin, the necrosis will resolve because the skin is ____
In the kidney, the inflammatory cells will disappear, but ____ will remain (permanently non-functional ____ tissue)
heterolysis
proliferative
scar tissue
connective
Liquefactive Necrosis
Stimulus is unknown; tissue injury to hepatocytes > resulted in an influx of neutrophils > conversion to semi-solid tissue (____ as liver)
Necrotic change occurs after death > in the liver, it will most likely ____
Abscess formation in lung (arrows); influx of neutrophils > tissue is being digested > formation of ____ (limited capacity to proliferate)
unrecognizable
regenerate
scar tissue
Coagulative necrosis
• Most ____ form of necrosis - associated
with ____
• Complete ____ of cells is blocked with
persistence of their shape:
– low ____
– protein ____ (inactive degradative
enzymes)
– limited availability of lysosomes
• Localized area of coagulative necrosis due to loss of blood supply is referred to as an ____ (also, ischemic necrosis)
• Fate: cells are ____, lack ____ and persist for ____; eventually digested by ____
Liquefactive is more so ____; coagulative is a result of ____
Lack of oxygen is going to cause the cell to use ____ (glucose to ATP) instead of respiratory metabolism; resulting in a pH drop, which results in irreversible injury in low pH (generation of lactate) > protein ____ (autolytic or heterolytic enzymes) > tissue is not digested
Also occurs in tissues with low level of ____ > cell cannot undergo autolysis
common hypoxia autolysis pH denaturation infarct eosinophilic nucleus days/weeks phagocytes
bacterial/immunologic
hypoxia
glucose metabolism
denaturation
lysosomes
Hypoxia “too little oxygen in tissues” • Ischemia (deficient \_\_\_\_ of tissues): – occlusion of \_\_\_\_ – occlusion of veins – \_\_\_\_ of arterial blood
• Hypoxemia (deficient ____ of blood):
– failure to properly ____ lungs
– failure of lungs to properly oxygenate blood
– failure of heart to ____ enough blood thru lungs
– too little oxygen in ____
• Hemoglobin problems:
– inadequate red cell mass (____)
– inability of hemoglobin to carry oxygen (e.g. ____)
– high ____ hemoglobins
Infarction: localized area of ____ necrosis
perfusion
veins
shunting
oxygenation
ventilate
pump
air
anemia
CO poisoning
affinity
ischemic
Hypoxic Injury – Critical Events
Mitochondrial dysfunction (decrease ATP)
– increase glycolysis (____ pH)
– decrease ____ pump (swelling)
– increase intracellular ____
– ____ detachment (decreased protein syn.)
• Membrane injury: – loss of phospholipids – \_\_\_\_ generation – lipid breakdown products – cytoskeletal abnormalities
- Lysosomal enzymes ____
- Inflammatory cells have ____
Lack of oxygen, no aerobic respiration > glucose to pyruvate to lactic acid > drop in pH > non-functional ____ enzymes
decreased
Na+
Ca++
ribosome
ROS
denatured
limited access
autolytic
Coagulative necrosis (ischemic necrosis)
• Morphological changes:
• ____:
—• pale/firm, tissue retains basic outline
• Microscopic:
- –• cell architecture remains; “____” reveal structure of living tissue
- —– ____
- –• nucleus
- —– pyknosis
- —– karyorrhexis
- —– Karyolysis
• Fate: necrotic tissue removed by phagocytes
Recognizable as kidney; the tissue has retained its ____ > but has a “tombstoning” appearance (non-functional) > cannot see the presence of any ____ and the tissue is purely ____ > within tubules you can’t see distinct ____
Proteolytic (autolytic) enzymes degraded by low pH, and no inflammatory cells because there is no blood supply; eventually, the inflammatory cells will invade from adjacent tissue and break down the necrotic tissue > formation of scar tissue
gross
tombstoning
eosinophilia
normal basic outline
nuclei
eosinophilic
borders
Myocardial infarct
On the right: eosinophilic, see some ____ because of hemorrhage early in the lesion, the tissue here is dead (still recognizable as myocardium)
Eventually digested by inflammatory cells that invade from adjacent tissue
RBC
Caseous necrosis
- Characteristic of a subtype of immune injury; generally seen in certain granulomatous diseases such as ____ and some ____ infections (coccidioidomycosis, blastomycosis, histoplasmosis)
- Gross: Cheesy, white appearance of ____ area
- Microscopic: Necrotic center (____ and coagulated cells) is enclosed within ____. Tissue architecture is obliterated-no cellular ____
Tb produces waxy cell wall that cannot be degraded, and induces a form of inflammation (not many neutrophils)
Necrotic center > granular debris (____ and ____ debris)
Tb
fungal
necrotic center
amorphous granular debris
granuloma
outlines
bacterial
cellular
Caseous necrosis
Tissue is ____ without an abscess, instead with a unique lesion; lesions are ____ > serves a structure, surrounded by collagen fiber with an abundance of inflammatory cells; eventually the granulomas ____ (can be seen microscopically but not gross, until they all fuse)
obliterated
granuloma
merge
Gangrene (Gangrenous necrosis)
- Not a separate kind of necrosis; ____ often applied to limb (lower)
- ____ (coagulative) necrosis with superimposed ____ (liquefactive necrosis of saprophytic bacteria (e.g. Clostridium)
- Dry gangrene: tissue is dry, black and shriveled (mostly ____; bacteria haven’t had chance to ____)
- Wet gangrene: mostly ____ with several kinds of bacteria; ____ smelling (liquefaction due to inflammatory cells)
- Gas gangrene: ____ produced by bacteria
clinical term
ischemic
infection
coagulation necrosis
overgrow
liquefactive necrosis
foul
CO2 bubbles
Fibrinoid Necrosis
• Refers to damage to walls of arteries which allows ____ to seep into and precipitate in the media (____)
• Often associated with immune injury (____) and accumulation of immune complexes; also seen in severe ____
Not a true form of necrosis
Insudation > ____ > homogenous, glassy, pink appearance
plasma cells
insudation
Type III
hypertension
hyalinization
Fat Necrosis
- Occurs only in ____ tissue; descriptive of ____ areas of fat destruction
- Occurs in association with ____ or ____ which results in the release of lipases:
- ____ and ____ attack plasma membrane of fat cells (release triglyceride stores)
- ____ hydrolyze triglycerides yields free fatty acids
- fatty acids are precipitated as calcium soaps (____)
• Appear as amorphous ____ areas in H/E sections; gross exam appears as ____
Not a form of ____; more so descriptive, can see both histologically and gross
Dark purple/blue areas (____); ____ areas
adipose focal pancreatitis trauma phospholipases protease pancreatic lipase saponification
blue
irregular chalky white areas
steatosis
soaps
extracellular
Pathologic Calcification
• Dystrophic Calcification – takes place \_\_\_\_, often seen in areas of \_\_\_\_ – frequently cause of organ \_\_\_\_ – occurs in the presence of normal \_\_\_\_ -\_\_\_\_ metabolism
Metastatic Calcification
– Occurs in normal tissue when there is ____: serum calcium and or phosphate ion concentration is elevated (increased ____ secretion, destruction of ____ tissue, ____ disorders, ____ failure
Involves the formation of ____ mineral (similar to hydroxyapatite of bone)
Dystrophic > occurs in injured tissue (undergone necrosis) and will become calcified > organ dysfunction (not a result of abnormal metabolism, but necrotic tissue acting as an attractant of calcification); calcification will act upon the infarct located on ____ wall of the heart and it will blow out
Metastatic > not associated with ____ > occurs in normal tissue as a result of hypercalcemia, or increased hormonal secretion
locally necrosis dysfunction calcium phosphorus
hypercalcemia PTH bone vitamin D renal calcium phosphate
thin
necrosis
Apoptosis (Programmed Cell Death)
Cells die by one of two mechanisms – necrosis or apoptosis:
– Necrosis – death by ____
– Apoptosis – death by ____
Apoptosis and necrosis have different characteristics and outcomes particularly with respect to induction and outcome, i.e., ____
injury
suicide
inflammation
Apoptosis = Program Cell death
• A pathway of cell death • Tightly \_\_\_\_ intracellular program • Leads to activation of enzymes that degrade DNA and protein • Plasma membrane remains \_\_\_\_ • Apoptotic cells are rapidly \_\_\_\_ • Generally does not induce \_\_\_\_
regulated
“intact”
cleared
inflammation
Apoptosis may be due to physiologic or pathologic causes:
• ____ apoptosis:
– Serves to eliminate unwanted or potentially harmful cells and to maintain a steady number of cells in tissues
• ____ apoptosis:
– Removal of cells that are damaged beyond repair
physiologic
pathologic
Summary of Apoptosis
- Regulated mechanism of cell death that serves to eliminate unwanted and damaged cells
- Characterized by enzymatic degradation of ____ and ____
- Initiated by ____
- Recognition of dead cell and apoptotic bodies by ____
• Two major pathways:
– Mitochondrial (____) triggered by loss of ____ signals, DNA damage and accumulation of ____ proteins
– Death receptor pathway (____)
proteins
DNA
caspases
phagocytes
intrinsic
survival
misfolded
extrinsic
Morphologic Changes Associated with Apoptosis
- Affects ____ cells
- Plasma membrane does not ____
- Cell removed by phagocytes, but does not normally stimulate inflammatory response
- (NO ____)
single
rupture
inflammation
Morphologic Changes Associated with Apoptosis (continued)
- Cells ____-cytoplasmic and nuclear condensation
- Chromatin ____-peripheral aggregation and eventually DNA fragmentation
- Cell eventually breaks up into membrane bound ____ containing containing DNA and cytoplasmic organelles (____)
shrink
condensation
blebs
apoptotic bodies
