Lectures 2 and 3 - Cell Injury and Necrosis I and II Flashcards
What can cause cell injury?
- Lack of oxygen
- Lack of nutrients
- Extreme pH
- Electrolyte imbalances
- Toxins
- Free radical damage
- Physical disruption
Reversible changes:
- Cellular swelling
- Cell membrane blebs
- Detached ribosomes
- Chromatin clumping
- Lipid deposition
- Vacuole formation
Irreversible changes:
- Lysosomes rupture
- Dense bodies in mitochondria
- Cell membrane rupture
- Karyolysis, karyorrhexis, pyknosis
Karyolysis:
Karyorrhexis:
Pyknosis:
- Chromatin dissolves
- Chromatin breaks
- Condensation of chromatin (followed by karyorrhexis)
Neurons are damaged in…
Myocardium, hepatocytes, renal epithelium in…
Fibroblasts, epidermis, skeletal muscle in…
- 3-4 min
- 30 min - 2hr
- Many hours
3 ways to move from cell injury to cell death:
- Require continuous ATP, so irreparable damage to mitochondria
- Holes in membranes (ion transport, can’t exclude Ca2+ and Na+)
- Activation of self-digestion (proteinases, lipases, endonucleases)
List 6 pathways of cell injury:
- ATP depletion
- Irreversible mitochondrial damage
- Disrupted Ca2+ homoeostasis
- Free radical formation
- Defects in cell membrane permeability
- Accumulated DNA and protein damage
What can cause ATP depletion?
Lack of O2, lack of substrates, decrease in mitochondrial function
What does ATP depletion do exactly?
- Can’t pump out Na+ or maintain Ca2+ homeostasis –> swelling issues
- Switch to anaerobic glycolysis (lactic acid build-up) –> chromatin clumping
- Damage to protein synthesis (ribosomes detach RER…lack of O2 leads to misfolded proteins) –> lipid deposition
What produces free radicals?
Normal metabolism and neutrophils (superoxide anion), hydrogen peroxide, toxins and environmental agents
What do free radicals do?
Cause lipid peroxidation of membranes and formation of thymidine dimers and single-stranded DNA breaks (cancer)
also, chain breakage in proteins
What protects from oxygen free radicals?
Catalase, superoxide dismutase, antioxidants and scavengers (Vitamins E and A, ascorbic acid), glutathione peroxidase, binding of metals such as copper and iron
Membrane damage can be caused by a host of things, such as…
ROS, decreased O2, increase in cytosolic Ca2+
What is the “point of no return”?
Damage to mitochondria and inability to make ATP
…also loss of structural integrity; leakage
List causes of hypoxia:
- ischemia
- low oxygen tension (hypoxia)
- CO poisoning
- severe anemia
Ischemia tends to be more damaging than simple hypoxia (added decrease in delivery of metabolic requirements, and accumulation of metabolic waste)
Hypoxia causes:
- Anaerobic metabolism
- Impaired Na+ pump
- Disaggregation of ribosomes
Cancer associated with chronic inflammation examples (ROS):
- chronic hepatitis C
- smoking
- gastric reflux, chronic gastritis
What is hemochromatosis?
Hereditary disease that leads to deposition of iron in many tissues (liver, heart, pancreas, etc.)
- Chronic tissue damage
- “Bronze diabetes” - cirrhosis, diabetes, skin pigmentation, heart failure, maybe liver cancer
What is reperfusion injury?
Re-establishing blood flow to ischemic area may enhance damage initially (ultimately saves tissue)
- O2 converted to ROS, re-establish metabolic pathways that make ROS
Antioxidants help
What causes contraction bands?
Reperfusion injury, cocaine, chronic catecholamines
Carbon tetrachloride yields ROS CCl3- and…
Fulminant liver damage and necrosis
- Lipoprotein synthesis damage –> fatty liver
- Lipid peroxidation
What is the timeline of cell injury?
- Biochemical and functional changes (minutes)
- Ultrastructural changes (hours)
- Microscopic changes (hours to days…at least 4 hrs.)
- Gross tissue changes (days)
What is “ballooning degradation” indicative of?
Viral illness. Swollen eosinophilic cytoplasm w/o vacuoles
Lymphocytic infiltration.
Fatty changes are _______.
Reversible! From damage to lipoprotein synthesis. Cells are still intact.
But eventually will die. Alcoholism.
Irreversible injury is:
- Enzymatic digestion
- Denaturation of proteins, lipids, nucleic acids
- Disruption of membranes
What necrotic changes are seen under a light microscope?
- Increased eosinophilia (loss/dissolution of RNA/ribosomes)
- Hyalinization - glassy/homogenous (loss of glycogen and organelles)
- Vacuolization
- Calcification
- Pyknosis, Karyorrhexis, Karyolysis
Pyknosis:
Solid, shrunken basophilic mass
Increased basophilia
Karyorrhexis:
Pyknotic nucleus undergoes fragmentation
Karyolysis:
Dissolving nucleus into amorphic mass
- Decreased basophilia
- Activation of DNAase
There is a _____ danger period following MI for rupture when the heart wall is soft
4-5 day
What are some characteristics of coagulative necrosis?
Absent or karyorrhexic nuclei; eosinophilic
Softens after several days
Mechanism of coagulative necrosis?
Intracellular acidosis denatures proteins and proteolytic enzymes…autolysis minimal and architecture left intact
Characteristic of most hypoxic tissue death, except in brain
What are some characteristics of liquefactive necrosis?
Infiltration by neutrophils, architecture destroyed, pus
What is a special case of liquefactive necrosis?
CNS - no collagenous stabilizing tissue (just neurons, astrocytes) so softens, yellow/tan, liquefies
What is gangrenous necrosis?
Coagulative necrosis associated with loss of blood supply. First dry, usually associated with limbs.
What is wet gangrene?
Secondary liquefactive necrosis (secondary bacterial infection; often in diabetes)
What is caseous necrosis?
Type of coagulative; Associated with Mycobacterium and fungal infection (blasto, histo)
Yellow-white, cheese-like material
Often nodules
What are characteristics seen in caseous necrosis?
Central areas of amorphous eosinophilic granular material
- Cell outlines indistinct, but not liquefied
- Macrophages and multinucleated giant cells
- Granulomatous inflammation
Type IV hypersensitivity
What is fat necrosis?
Destruction of adipose tissue; uncommon; coagulative
- Breast (trauma)
- Pancreatitis (abnormal release of pancreatic lipases)
- -> saponification
What is saponification?
Soap formation from calcium and lipids
Characteristics of fat necrosis?
- Eosinophilic “ghost” outlines of necrotic adipocytes
- Basophilic Ca2+ deposits
- Inflammation
- No nuclei
What is fibrinoid necrosis?
Special form; necrosis within walls of blood vessels
- Immune-mediated vasculitis (Type III)
- Deposit immune/antibody complexes with fibrin
