Cell and Tissue Injury Flashcards
In cellular adaptation to stress, what does adaptation means?
What are some examples?
It refers to reversible changes in number, size, phenotype, metabolic activity or functions of cells in response to changes in their environment, they can be:
•Physiologic
•Pathologic
–Hypertrophy, Hyperplasia, Atrophy, Metaplasia
What is hypertrophy?
Can hypertrophy and hyperplasia occur together?
Can a limit be reached?
•Increase in the size of cells resulting in increase in size of organ (could be due to functional demand or growth factor or hormone stimulation)
–Physiologic (e.g. gravid uterus; enlargement of the uterus during pregnancy)
–Pathologic (e.g. Left ventricular hypertropy due to hypertension)
*Note, hypertrophy and hyperplasia can occur together
•Eventually limit is reached where enlargement cannot compensate for increased burden (–> injury)
What is hyperplasia?
What are some physiolgical examples?
Pathological?
Can hyperplasia go away?
It is the Increase in number of cells in response to stimulus or injury.
– Physiologic
- Hormonal (e.g. female breast)
- Compensatory (e.g. liver regeneration)
–Pathologic**
- Excessive hormonal or GF stimulation (e.g. endometrial hyperplasia (Estrogen), BPH-Benign Prostatic Hyperplasia (DHT)
- If stimulation removed, hyperplasia should abate (contrast with cancer).
What is atrophy?
Physiologic examples?
Pathologic?
What is the mechanism?
•Decrease/shrinkage in size and functional capacity of cell
–Physiologic (e.g. loss of hormone stimulation in menopause, decreased workload, aging)
–Pathologic (e.g. denervation or diminished blood supply)
–Mechanisms: decreased protein synthesis and i_ncreased protein degradation_ (ubiquitin-proteasome pathway)
Skeletal muscle atrophy due to decreased innervation
What is metaplasia?
Why does this occur?
•Reversible change in which one adult/differentiated cell type is replaced by another adult/differentiated cell type.
–Cell type sensitive to a particular stress is replaced by another cell type better able to withstand particular stress
R-eversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type, typically as an adaptive measure in response to injury or environmental changes. Examples:
1) Replacement of the ciliated columnar epithelium of the bronchus by squamous epithelium in response to injury from noxious chemicals in cigarette smoke.
2) Replacement of the squamous epithelium in the distal esophagus by columnar intestinal epithelium in chronic reflux esophagitis (so‐called intestinal metaplasia in Barrett’s esophagus).
Types of adaptations shown:
What defines a reversible injury?
What are the types of irreversible injury?
–It has to be recoverable if damaging stimulus is removed
–Injury has not progressed to severe membrane damage and nuclear dissolution
Irreversible injury
–Necrosis
–Apoptosis
What are some of the reversible morphological features of cell injury?
What is cellular swelling and what causes it?
Describe eosinophilia in staining?
Reversible
–Cellular swelling
•Failure of energy dependent ion pumps in plasma membrane –> disrupted ionic and fluid homeostasis.
- Cell membranes. The cell membrane is perhaps the most important target for both reversible and irreversible injury. The outer cell membrane directly interacts with the environment is usually the first cellular component to be damaged.
In addition, the lipid within the membrane is easily oxidized and supports an oxidative chain reaction called lipid peroxidation. ——=–Damage to the membrane may physically break the membrane or inactivate the ion pumps that control the ionic concentrations in the cytoplasm. *Cell swelling is a common morphologic change seen in nearly all types of injury. Recall that in the normal cell there are impressive Na+, K+ and Ca++ concentration gradient across the membrane. Outside the cell, the Ca++ is approximately 10‐3M while within the cytoplasm, the Ca++ is approximately 10‐7M. In the injured cell, the accumulation of Na+ leads to an increase in H20 and cell swelling.
Eosinophilia
Eosinophilic (meaning loves eosin) refers to the staining of certain tissues, cells, or organelles after they have been washed with eosin, a dye.
Eosin is an acidic dye; thus, the structure being stained is basic and as a corollary, is acidophilic.
Eosinophilic describes the appearance of cells and structures seen in histological sections that take up the staining dye eosin. This is a bright-pink dye that stains the cytoplasm of cells, as well as extracellular proteins such as collagen.[1]
What are some of the reversible morphological features of cell injury?
What is fatty change?
Why does it happen?
Fatty change
- Accumulation of lipid vacuoles within cytoplasm of cells (typically those participating in fat metabolism such as hepatocytes, myocardial cells).
- Due to increased entry and synthesis of free fatty acids and decreased fatty acid oxidation.
Intracellular changes with reversible injury:
What are myelin figures?
•Intracellular changes associated with reversible injury:
- Plasma membrane alterations (blebbing, blunting, distortion of microvilli, loosening of intercellular attachments); myelin figures = phospholipid masses derived from damaged cellular membranes
- Mitochondrial changes (swelling and appearance of phospholipid-rich amorphous densities)
- Dilation of the ER with detachment of ribosomes and dissociation of polyribosomes.
- Nuclear alterations with clumping of chromatin
**Note, if any of these changes persist (especially severe mitochondria damage and disturbances in membrane function) irreversible injury can ensue
Describe Necrosis in terms of:
Cell size is_____1______.
Nucleus is_____2_______
Plasma membrane is ____3______
Cellular contents______4_______
Adjacent inflammation_____5________
Physiologic or pathologic role____6_____
1- Enlarged (Swelling)
2- Pyknosis–>karyorrhexis–>karyolysis
3- Disrupted
4- Enzymatic digestion occurs and cellular content may leak out of the cell
5- Frequent
6- Pahologic invariably (culmination of irreversible cell injury)
Describe Apoptosis:
Cell size is_____1______.
Nucleus is_____2_______
Plasma membrane is ____3______
Cellular contents______4_______
Adjacent inflammation_____5________
Physiologic or pathologic role____6_____
1- reduced (shrinkage)
2- Fragmentation into nucleosome size fragments
3- intant, but altered structure specially the orientation of lipids
4- Intact, may be released in apoptotic bodies
5- No adjacent inflammation
6- often physiologic and means of eliminating unwanted cells; may be pathologic after some forms of cell injury, specially DNA and protein damage
What are some intracellular changes associated with irreversible injury?
Cytoplasmic changes?
Nuclear changes?
What is pyknosis?
What is Karyorrhesis?
Karyolysis?
•Intracellular changes associated with irreversible injury:
–Cytoplasmic changes: increased eosinophilia (increased binding of eosin to denatured cytoplasmic proteins) and loss of RNA basophilia in cytoplasm.
–Nuclear changes: breakdown of DNA and chromatin
•Pyknosis
–Nuclear shrinkage and increased basophilia (DNA condenses)
•Karyorrhexis
–Pyknotic nucleus fragments
•Karyolysis
Dissolution of nucleus (basophilia of chromatin fades secondary to deoxyribonuclease activity – breakdown of denatured chromatin)
What are some of the mechanisms of injury of cells?
Explain ATP depletion:
By what two pathways is ATP produced?
Which tissues can withstand ischemic injury better?
Which tissue is the most susceptible to ischemic damage in a short period of time?
What tissues can withstand hours of ischemic disease?
- ATP produced via oxidative phosphorylation of ADP in mitochondria OR glycolytic pathway in absence of oxygen
- Tissues with greater glycolytic capacity better able to withstand ischemic injury
- Neurons…
3 to 5 min
•Cardiac myocytes, hepatocytes, renal epithelium…
30 min to 2 hr
•Cells of soft tissue, skin, skeletal muscle…
many hours
Influx of calcium
Ischemia and toxins lead to a release of:
- Ordinarily substantial calcium gradient between extracellular and intracellular calcium
- Ischemia and toxins –> release of Ca2+ from intracellular stores and increased influx across plasma membrane.
Accumulation of ROS
Damage characterized by?
What are the two major pathways that form radicals?
- Cell injury involves damage by free radicals
- Two major pathways:
1) All cells during reduction-oxidation (redox) reactions during mitochondrial respiration
2) Phagocytic leukocytes (neutrophils and macrophages) as mechanism for host defense
What are the consequences of free radicals?
What leads to oxidative stress?
How are they removed?
- Damage is determined by rate of production vs. removal
- Increased production or ineffective scavenging
–> oxidative stress
•Removal via spontaneous decay and specialized enzymatic systems
–> the hydroxyl radical (OH-) is the one capable of producing the most damage since it is not converted to other compounds that easily.
When there are defects in membrane permeability, what are important sites of membrane damage?
Important sites of membrane damage:
1)Mitochondria
2)Plasma membrane
3)Lysosome
Coagulative Necrosis
Damages both what?
How do death cells remain?
Where can it commonly be seen following ischemia?
- Tissue architecture preserved for at least several days (due to damage to both structural proteins and enzymes)
- Dead cells remain – pale “ghost-like”
- Characteristic of infarcts
–Classically seen in heart following myocardial infarction
–Can be seen in any solid organ following ischemia
Coagulative necrosis ‐ form of necrosis in which tissue architecture is preserved for at least several days (presumably due to damage to both structural proteins and enzymes‐‐this damage to enzymes precludes immediate proteolysis of dead cells). The dead cells remain, therefore, often appearing as pale, ghost‐like remnants of their former selves. Eventually leukocytes are recruited and dead cells are digested by lysosomal enzymes of leukocytes. This form of necrosis is characteristic of infarcts and is classically seen in the heart following a myocardial infarction (“infarction” means “necrosis” secondary to vascular insufficiency).
What is liquefactive necrosis?
In what kind of infections can it be seen?
Who eats/digests the tissue?
- Seen in focal bacterial or occasional fungal infections
- Microbes stimulate the accumulation of inflammatory cells and leukocyte enzymes digest the tissue
- Also seen in hypoxia in CNS
Caseous Necrosis:
Characterized by what infection?
How does the necrotic area appears as?
- Necrosis characteristic of tuberculosis infection (among others; e.g. histoplasmosis, etc.)
- “Caseous” derived from the white appearance of the area of necrosis.
- Microscopically the necrotic area appears as a collection of fragmented or lysed cells and amorphous granular debris enclosed within a distinctive inflammatory border (granulomatous inflammation)
–>Caseous necrosis ‐ seen in tuberculosis infection. The central portion of the infected tissue is necrotic (attributed to toxic effects of mycobacteria) with fragmented cells and amorphous debris surrounded by granulomatous inflammation. On gross examination the necrosis has a chalky white appearance, not unlike the milk protein casein.
Fat Necrosis
Fats are destroyed by who? Following what?
- Fat destruction, typically resulting from release of activated pancreatic lipases (following acute pancreatitis or trauma).
- Fats hydrolyzed into free fatty acids which precipitate with calcium to produce a chalky gray material
Fibrinoid Necrosis
Where are complexes of antigens and antibodies deposited?
Deposited immune complexes combine with what?
Seen in what?
- Immune reaction in which complexes of antigens and antibodies are deposited in the walls of arteries
- Deposited immune complexes combine with fibrin and produce bright pink and amorphous appearance on H&E
- Seen in certain vasculitis (e.g. polyarteritis nodosa)
Apoptosis pathologic causes:
Pathologic
- DNA damage (radiation, cytotoxic drugs, temperature extremes, hypoxia) where repair mechanisms inadequate – better to eliminate cell than risk propagating mutated DNA
- Accumulation of misfolded proteins (ER stress)
- Cell injury in certain infections (especially viral)
- Pathologic atrophy in parenchymal organs after duct obstruction (pancreas, parotid, kidney)
Apoptosis mechanisms
What are the two pathways?
Mention the anti-apoptotic cytokines?
Mention the Pro-apoptotic cytokines?
- Activation of caspases (cysteine proteases that cleave proteins after aspartic residues)
- Two main pathways
1)Mitochondrial (intrinsic) pathway
- Anti-apoptotic: BCL2, BCL-XL, MCL1
- Pro-apoptotic: BAX, BAK
2)Death receptor (extrinsic) pathway
More on mitochondrial pathway:
What is the executioner caspase?
What is the apoptosis caspases?
•Mitochondrial and death receptor pathways lead to activation of initiator caspases: caspases-9 and -8, respectively: executioner caspases, apoptosis.
What is autophagy?
•Process in which cell eats its own contents
–Adaptive response / survival mechanism in times of nutrient deprivation
–Dysregulation implicated in many disease including cancers, inflammatory bowel disease, and neurodegenerative disorders
–Role in host defense: some pathogens degraded by autophagy (e.g. mycobacteria, HSV-1, etc.)
Steatosis
Steatosis (also called fatty change, fatty degeneration, or adipose degeneration) is the process describing the abnormal retention of lipids within a cell.
It reflects an impairment of the normal processes of synthesis and elimination of triglyceride fat.
Accumulation of glycogen
Lipofuscin
It is a marker of what type of injury?
“wear and tear pigment” – accumulates as function of age or atrophy – complexes of lipid and protein – marker of past free radical injury
Melanin
Hemosiderin
Accumulates due to excess of what?
Cholesterolisis
