4. Irreversible Injury Flashcards

1
Q

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

A

cell death
necrosis
etiologic triggers

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2
Q

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 ____
A

membranes
cytoskeleton
interpendence

accumulated damage
mitochondrial function
membrane proteins
DNA integrity

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3
Q

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

A

pathologic
autolysis
heterolysis

pro-inflammatory
isozymes

calcium deposition

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4
Q

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)

A

enzymes
diagnosis
inflammation

disappear
persist

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5
Q

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

A

defining event

marker

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6
Q
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

A

mitochondrial damage
membrane function
DNA/chromatin

eosinophilia
ER
myelin

pyknosis
karyorrhexis

membranes
myelin

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7
Q

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 ____

A
ATP
ROS
eosin
mRNA
ultrastructure
organelles
calcium
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8
Q

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

A

large
euchromatin
nucleolus
blue

smaller
heterochromatin

hemotoxylin
quiescent

pyknosis
pH
karyorrexhis
karyolysis

smear

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9
Q

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 ____

A

etiology/pathogenesis

enzymatic digestion
protein

steatosis

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10
Q

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)

A
digestion
autolysis
heterolysis
semi-liquid
recognizable
microbial infection

abscess

digested

walled

inflamed tissue

normal

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11
Q

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)

A

heterolysis
proliferative

scar tissue
connective

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12
Q

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)

A

unrecognizable
regenerate

scar tissue

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13
Q

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

A
common
hypoxia
autolysis
pH
denaturation
infarct
eosinophilic
nucleus
days/weeks
phagocytes

bacterial/immunologic
hypoxia

glucose metabolism
denaturation

lysosomes

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14
Q
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

A

perfusion
veins
shunting

oxygenation
ventilate
pump
air

anemia
CO poisoning
affinity

ischemic

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15
Q

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

A

decreased
Na+
Ca++
ribosome

ROS

denatured
limited access

autolytic

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16
Q

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

A

gross
tombstoning
eosinophilia

normal basic outline
nuclei
eosinophilic
borders

17
Q

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

A

RBC

18
Q

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)

A

Tb
fungal

necrotic center

amorphous granular debris
granuloma
outlines

bacterial
cellular

19
Q

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)

A

obliterated
granuloma
merge

20
Q

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
A

clinical term
ischemic
infection

coagulation necrosis
overgrow

liquefactive necrosis
foul

CO2 bubbles

21
Q

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

A

plasma cells
insudation
Type III
hypertension

hyalinization

22
Q

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

A
adipose
focal
pancreatitis
trauma
phospholipases
protease
pancreatic lipase
saponification

blue
irregular chalky white areas

steatosis
soaps
extracellular

23
Q

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

A
locally
necrosis
dysfunction
calcium
phosphorus
hypercalcemia
PTH
bone
vitamin D
renal
calcium phosphate

thin

necrosis

24
Q

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., ____

A

injury
suicide
inflammation

25
Q

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 \_\_\_\_
A

regulated
“intact”
cleared
inflammation

26
Q

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

A

physiologic

pathologic

27
Q

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 (____)

A

proteins
DNA
caspases
phagocytes

intrinsic
survival
misfolded
extrinsic

28
Q

Morphologic Changes Associated with Apoptosis

  • Affects ____ cells
  • Plasma membrane does not ____
  • Cell removed by phagocytes, but does not normally stimulate inflammatory response
  • (NO ____)
A

single
rupture
inflammation

29
Q

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 (____)
A

shrink
condensation
blebs
apoptotic bodies