Cell Injury 1-3 Flashcards
Cellular Responses to Stress and Injurious Stimuli
1) Altered Physiologic Stimuli;
Nonlethal injurious Stimuli:
=> Cellular Adaptation
2) Increased Demand,
Increased Stimulation
(e.g. Growth Factors, Hormones):
=> Hyperplasia, Hypertrophy
3) Reduced Oxygen Supply;
Chemical Injury;
Microbial Infection:
=> Cell Injury
4) Acute and Transient:
=> Acute, Reversible Injury;
Cellular Swelling,
Fatty Change
5) Progressive and Severe (e.g. DNA Damage): => Irreversible Injury: ==> Cell Death: Necrosis Apoptosis
6) Metabolic Alterations (Genetic or Acquired);
Chronic Injury:
=> Intracellular Accumulations;
Pathologic Calcification
7) Cumulative Sublethal injury over Long Life Span:
=> Cellular Aging
Adaptations
= Reversible changes in Size, Number, Phenotype, Metabolic Activity, or Functions of cells in response to changes in their environment.
Types: _Hypertrophy _Hyperplasia _Atrophy _Metaplasia
Atrophy, Hypertrophy, and Hyperplasia *Can all be *Normal Physiologic processes.
Hypertrophy and Hyperplasia *May Occur Together.
ALWAYS ABNORMAL:
_Metaplasia
_Dysplasia
Hypertrophy
= Compensatory Increase in Cell *Size,Typically of
*Terminally *Differentiated Cells that *CAN’T Divide.
Mechanism:
_Hypertrophy results from increased production of Cellular Proteins.
Physiologic:
_Increased Work Demand:
(1) Increased muscle mass with Exercise,
(2) Increased Size of Remaining Kidney after Nephrectomy,
(3) Increased Breast Size during Pregnancy.
Pathologic:
_Cardiac Hypertrophy in Hypertension
_Bladder Muscle Hypertrophy due to Obstruction (BPH)
Hyperplasia
= Compensatory *Increase in Cell *NUMBER, Typical of
*Cells that *CAN Divide
Mechanism:
_Hyperplasia results from growth factor-driven proliferation of mature cells and, in some cases, from increased output of new cells from tissue stem cells.
Physiologic:
_Occurs due to action of Hormones or Growth Factors
(1) To increase functional capacity of hormone-sensitive organs:
_e.g. Increased Breast tissue in Pregnancy for Lactation
(2) Need for compensatory increase after Damage or Resection:
_e.g. Liver cell Regeneration in Cirrhotic liver to compensate the Loss of normal cells.
Pathologic Hyperplasia:
_Due to Continued, Excessive Abnormal Stimulus (Inappropriate actions of Hormones or Growth Factors):
(1) *Endometrium in Response to *Abnormal *Estrogen Levels
(2) *Squamous Epithelium in Response to *Viral Infection
(Human papillomavirus, HPV)
(3) *Benign Prostatic Hyperplasia (BPH)
***Potential Precursor to Neoplasia
(so-called ** “Atypical” Hyperplasia)
Atrophy
= Compensatory *Decrease in *Size and *Activity of the cell
Physiologic:
_e.g. Muscle fibers decrease in size with Lack of Exercise
Pathologic:
_e.g. Pressure (Tissue compression, such as from a benign tumor), Chronic Injury (Chronic Gastritis), Compressed Nerve, Lack of use when bed-bound or immobilized, Alzheimer’s etc.
Metaplasia
= **One Cell Type REPLACES Another Cell Type
by *STEM CELL *Reprograming in Response to Chronic Irritation.
*Metaplastic Cell Type is *More Capable of Dealing with the *Stimuli
(1) Columnar to Squamous:
(Most common Epithelial metaplasia)
(Stratified Squamous)
_*Respiratory Epithelium becomes *Squamous in Response to *Smoking
_Bladder in response to Stone Obstruction
_Cervix in response to HPV or Herpes
(2) Squamous to Columnar:
_Barrett Esophagus
Esophageal squamous epithelium is replaced by Intestinal-like Columnar cells in response to Gastric Reflux.
Cancers can arise here.
Can be a Precursor to further changes, such as Dysplasia, leading to Neoplasia.
Also, may result in reduced functions with that cell type.
Dysplasia
= **Disorderly Growth Pattern in an *Epithelium.
_In Response to *Prolonged Abnormal Stimulation or Injury:
e.g. *Cervical Squamous Dysplasia in response to Human *Papillomavirus (HPV)
_***Can Lead to Additional Changes that Progress to Cancer!!
Irreversible Cell Injury
Cell Cannot Recover => Cell Death
_*Holes in *Cell Membrane _*Calcium Influx with _*Poisoning and *Swelling of *Mitochondria _*Lysosome Swelling with Enzyme Leakage _*Shrunk, Pyknotic Nucleus _Critically *Depleted ATP _*Excessive Free Radical Generation
Changes such as Dilated ER or Shrunken Internal Mitochondrial Membrane are Reversible.
Mechanisms of Cell Injury
▪ ATP depletion: failure of energy-dependent functions → irreversible injury → necrosis
▪ Mitochondrial damage: ATP depletion → failure of energy-dependent cellular functions → ultimately, necrosis; under some conditions, leakage of mitochondrial proteins that cause apoptosis
▪ Influx of calcium: activation of enzymes that damage cellular components and may also trigger apoptosis
▪ Accumulation of reactive oxygen species: covalent modification of cellular proteins, lipids, nucleic acids
▪ Increased permeability of cellular membranes: may affect plasma membrane, lysosomal membranes, mitochondrial membranes; typically culminates in necrosis
▪ Accumulation of damaged DNA and misfolded proteins: triggers apoptosis
Free Radicals
= *Oxidants produced in response to _*Radiant Energy _*Ischemia _*Metabolism of Toxins _*Inflammatory Cell Products _*Aging
To *Degrade Free Radicals:
- *Cells Contain
(1) **Antioxidants, such as **Glutathione, and
(2) Enzymatic Pathways, such as **Catalase and **Superoxide Dismutase.
Severe Prolonged Injury May Generate More Free Radicals than the Cells can Handle.
Free Radicals Can Damage Cells Via:
_Membrane Lipid Peroxidation
_Oxidation of Protein’s Amino Acid Side Chains
_Inducing DNA Breaks
Cell Death
2 Major Mechanisms:
Necrosis: = **Pathological or **Accidental Cell Death,
Due to **Lethal Stimuli that
*Increase Plasma Membrane Permeability
_Cellular contents leak via the damaged plasma membrane into the extracellular space, eliciting inflammation.
(Note: moderately increased permeability is initially reversible, as is intracellular edema)
Apoptosis: = **Physiological or **Pathological Cell Death,
Due to **Stimuli that **Activate an Intrinsic Genetic Program of Cell Death:
“Programmed Cell Death”
“Cell Suicide”
_When cell’s DNA or proteins are damaged beyond repair. There is cell shrinking without complete loss of membrane integrity. Rapid removal of cellular debris. No cellular leakage, so there is no inflammatory reaction.
Morphologic Changes in Cell Death
1) Cell Size:
_Necrosis: Enlarged (Swelling, Edema)
_Apoptosis: Reduced (Shrinkage)
2) Nucleus:
_Necrosis: Pyknosis –> Karyorrhexis –> Karyolysis
_Apoptosis: Fragmentation into nucleosome-size fragments
3) Plasma Membrane:
_Necrosis: Disrupted
_Apoptosis: Intact. Altered structure, especially orientation of lipids.
4) Cellular Contents:
_Necrosis: Enzymatic Digestion. May Leak out of Cell.
_Apoptosis: Intact. May be Released in Apoptotic Bodies.
5) Adjacent Inflammation:
_Necrosis: Yes, Frequent.
_Apoptosis: No.
6) Physiologic or Pathologic Role:
_Necrosis: Invariably Pathologic (Culmination of Irreversible Cell Injury)
_Apoptosis: Often Physiologic, means of eliminating unwanted cells. May be Pathologic after some forms of Cell Injury, especially DNA Damage.
Necrosis
**Autolysis: General term describing the **Dissolution of **Cell Structure, Characterized by: (1) *Nuclear Pyknosis (2) *Nuclear Karyorrhexis (3) *Nuclear Karyloysis (4) *Cytoplasmic Swelling (Intracellular Edema) and Organelle Loss
Pyknosis: Nuclear Shrinkage.
DNA condenses into shrunken basophilic mass. Denser and Darker.
Karyorrhexis: Nuclear Fragmentation.
Pyknotic Nuclear Membrane Ruptures and Nucleus Fragments.
Karyolysis: Nuclear Fading.
Chromatin Dissolution due to Action of DNAases and RNAases (endonucleases).
Lab Findings in Cellular Necrosis
**Damaged cells Leak their Contents into the Bloodstream.
*Enzymes measured in Serum may indicate which organ is damaged:
- CK-MM: Muscle
- CK-MB: Heart
- Troponin I: Heart
- ALT: Liver
- AST: Liver and others
- Lipase: Pancreas
- Amylase: Pancreas
- LDH: Kidney, Heart, RBCs, others
Tissue Necrosis
**Extensive Cellular Damage Leads to Tissue Necrosis:
(1) Coagulative Necrosis
(2) Liquefactive Necrosis
(3) Fat Necrosis
(4) Caseous Necrosis
(5) Gangrenous Necrosis
Coagulative Necrosis
(Most common form of Necrosis)
a.k.a. **Ischemic Necrosis
Typically caused by
*Loss of Blood Supply and *Subsequent Hypoxia
Cellular Proteins are Denatured, but
*Cellular Outlines Initially Remain.
_Anucleate cells persist for some days or weeks, before they are ultimately phagocytosed and digested.
_The affected tissues exhibit a firm texture.
Gross: **Localized Area of Coagulative Necrosis is called an *Infarct.
Infarction
*Pale Tan/White Appearance.
Wedge-Shaped
_Infarcts have a Distribution that coincides with the Blood Supply to Parts of an Organ.
(Pinker infarcts are more recent)
Infarcts are Typical for Ischemic Necrosis of Most Solid Organs, such as Heart, Kidney, Spleen.
Liquefactive Necrosis
Seen with **Destruction of Tissues that Contain Lots of Lipids, e.g. **Brain
Seen with **Tissue Destruction by **Bacteria or Inflammatory cells with *Release of *Proteolytic Enzymes, as in an **Abscess.
In contrast to coagulative necrosis, Liquefactive is characterized by Digestion of the Dead cells, resulting in transformation of the tissue into a liquid viscous mass.
Fat Necrosis
= **Destruction by Enzymes Digesting Fat
Gross: *Soaps are Present
as Chalky-white areas.
Typical of Injury to
(1) **Breast
(2) **Pancreas
Caseous Necrosis
= **Combo of Coagulative and Liquefactive Necrosis.
Gross: **Cheese-Like Appearance
Micro: Acellular areas of Necrosis Surrounded by Granulomatous Inflammation.
Typical of **Granulomas Formed in Response to
**Tuberculosis or **Fungal infection.
Gangrenous Necrosis
= *Necrosis of a *Body Part
**Dry Gangrene:
= Ischemia with Coagulative Necrosis predominates.
**Wet Gangrene:
= Infection with Liquefactive Necrosis predominates.
Ischemia
= Loss of Blood Flow to a Tissue or Organ
When Ischemia Persists, there is Hypoxia because Less Oxygen is Reaching the Tissues.
- Global Ischemia:
e. g. Shock, Loss of Blood Pressure - Focal Ischemia:
e. g. Occlusion of a Blood Vessel, such as a Coronary Artery
2 Most Common Organs:
_Heart
_Brain
*Recovery Depends on the *Time Frame
Worst Case Scenario:
_**After Cardiac Arrest, There are **3-5 Minutes to Restore Circulation
in order to **Avoid Irreversible Brain Injury in an Adult.
Reduced Oxygen Delivery means Reduced Oxidative Phosphorylation to Produce ATP!
(1) *Loss of ATP Leads to
(2) *Failure of Sodium Pump
–> (3) with *Influx of Sodium and Water.
Failure of Sodium Pump Leads to
–> (4) *Cell Swelling and
–> (5) *Subsequent Cell Organelle Swelling (Edema)
–> Severe *Swelling Leads to
(6) *Membrane Damage,
(7) *Calcium Influx,
(8) and **IRREVERSIBLE Cell Injury
Reperfusion Injury
Quick *Restoration of Blood Flow ordinarily limits cell damage.
However, Cells that are Close to Necrosis may be Pushed “Over the Edge” to Irreversible Injury DUE TO Restoration of Blood Flow.
This is because Restoration of Blood Flow:
(1) *Leads to *Inflammation from Cell Surface Adhesion Molecules and from Complement Components that Attract Inflammatory cells such as Neutrophils.
(2) *Increases *Free Radical Formation
(Released by the inflammatory cells)
Reversible Cell Injury
Cellular Swelling:
_Occurs when cell cannot maintain ionic and fluid homeostasis.
_Results from Failure of Energy-Dependent Ion Pumps in the Plasma Membrane
- Plasma membrane alterations, such as blebbing, blunting, and loss of microvilli
- Mitochondrial changes, including swelling and the appearance of small amorphous densities
- Dilation of the ER, with detachment of polysomes; intracytoplasmic myelin figures may be present (see later)
- Nuclear alterations, with disaggregation of granular and fibrillar elements
Apoptosis
Programmed Cell Death _Controlled, Non-accidental _ Orderly, natural process with _Very Focal, **Individual Cell Death (not parts/all of tissues) _Typically followed by Phagocytosis
Programmed in:
(1) Embryogenesis:
Disappearance of Embryonic Structures in Normal Development
(2) Response to Selective Viral infection
(3) Immunologic Reactions, as in
Graft vs. Host Disease (GVHD)
(4) Response to Hormonal Influences:
e. g. Menstruation with Endometrial Sloughing
Occurs with the Normal Ongoing Destruction and Phagocytosis in Tissues:
Cellular Recycling
_Lack of Apoptosis has been Recognized in Neoplasms, as in some Chronic Leukemias.
_Some Forms of Cancer Chemotherapy work mainly by more Selectively Inducing Apoptosis in Tumor cells.
_**Also Seen in Senescent (Old) Cells with *Short Telomeres After *80-100 Cell Divisions.
Morphologic Changes in Apoptosis
1) **Cell Shrinkage and Condensation:
_Densely eosinophilic,
_Cell Junctions Broken,
_Preserved Mitochondria and Ribosomes
2) **Chromatin Condensation with *Blebs under *Nuclear Membrane Followed by *Fragmentation:
_Membrane Blebs Followed by Cytoplasmic Fragmentation into
**Apoptotic Bodies
_Apoptotic Bodies undergo Phagocytosis
DNA is broken down by Endonucleases into specific Fragment sizes that are characteristic on Gel Electrophoresis, called “Ladders.”
_First to Large 50-300 Kbp
_Then to 180-200 bp or multiples of this.
Triggers of Apoptosis
1) Can be Triggered by Compounds Extrinsic to the Cell that contact the Cell Surface Receptors to initiate the Apoptotic sequence.
2) Can be Triggered by Mitochondrial Changes that are Tightly Regulated by Protein Products of Genes that are Pro-Apoptotic and Anti-Apoptotic.
Heterophagocytosis
Lysosomal Functions
Macrophages eat up the Debris of damaged cells or eat Foreign material (e.g. Bacteria) to form a Phagosome that fuses with Lysosomes.
This is a typical body response to clearing up a mess from cellular injury.
Extrinsic: Apoptosis
(1) When **Pro-Apoptotic Fas (Cell Membrane Receptor) is Bound to **Fas-ligand on the @ Cell Surface, a series of Caspase Enzyme Activations occur.
**Caspases are Enzymes that Signal Apoptosis and Cell Breakdown.
(2) Inflammatory processes can lead to increased production of TNF.
**TNF Can Bind to Cell Surface Receptor **TNFR1 to Initiate Apoptosis.
(3) Other Pro-Apoptotic molecules can signal the same pathway through different specific receptors.
Intrinsic: Apoptosis
Cell Stress Results in a
1) Decrease (Downregulation) in the **Anti-Apoptotic Bcl-2 Proteins on @Mitochondrial Membranes.
2) Subsequent Leakage of Mitochondrial Cytochrome C Complexes with Apaf-1 Activates **Caspases
==> Apoptosis.
Role of Hormones in Apoptosis
Physiologic Hormone Levels can maintain cell function.
Withdrawal of Hormones or Physiologic Cycling can Induce Apoptosis.
Examples:
Hormone Withdrawal During Menstrual Cycle
==> Endometrial Apoptosis
==> Menstruation
DNA Damage in Apoptosis
Low Level DNA Damage occurs Constantly.
The p53 Gene is Turned ON with DNA Damage.
_p53 Protein Accumulates to Cause Cell Cycle Arrest,
_Preventing Abnormal DNA Replication
_And Allowing Time for DNA Repair.
***Failure of DNA Repair Results in the p53 Protein Triggering Apoptosis.
_This effect can be utilized by Therapeutic Radiation and Chemotherapy to Trigger Death of Cancer Cells by Exposing them to radiation or chemotherapy to cause irreparable DNA damage.
Cytotoxic Lymphocytes and Apoptosis
As part of an immune response, some lymphocytes are programmed to react to cells that have been damaged.
*CTLs Recognized Abnormal Cells and Release Enzymes:
including **Perforins and **Granzymes.
**CTLs Have Fas-Ligand @ their Cell Surfaces and Can Trigger Apoptosis by Contact with Target Cell!!
Autophagy
= Cell Eats its own contents to survive starvation.
Can result in Genetically Controlled Cell Death Distinct from Necrosis or Apoptosis.
1) *Intracellular Debris is Sequestered in Autophagosomes and Fused with Lysosomes to form Autophagolysosomes for Digestion.
2) * “Residual Bodies” of Material that Cannot be completely Digested May Remain
_called Lipochrome (Lipofuscin) Pigment on Light Microscopy.
Autophagocytosis is a Key Part of:
_Cell Differentiation
_Cell Injury (Gradual or Long Term)
_Cell Atrophy
Cytoskeletal Elements
Intermediate Filaments are Between the Size of Thin (Actin) Filaments and Thick (Myosin) Filaments.
They play a role in Movement of the Cell:
Best example: Chemotaxis
Accumulations Occur in Response to Injury. Examples:
_Mallory Bodies (Alcoholic Hyaline) @ Liver
(Alcoholic Liver Disease)
_Neurofibrillary Tangles
(Alzheimer’s Disease) @ Brain
Fatty Change
a.k.a. **Fatty Metamorphosis
or **Steatosis
or Fatty Degeneration.
Basic Problem:
_Lipid Accumulates in Cytoplasm, either as Small Vesicles or Large Droplets.
Etiology:
_Impaired Intracellular Metabolism or Lipoprotein Transport.
Steatosis: _*Best Known as *Morphologic Change @ in *Hepatocytes. _Caused By: (1) Toxic Injury: *Alcohol (Alcoholic Liver Disease, Drug-induced Hepatitis)
(2) Genetic Diseases:
Galactosemia from lack of an Enzyme for Metabolism of Galactose.
(3) Nutritional: *Kwashiorkor from Lack of Sufficient Dietary Protein.
________
Lipid Accumulation:
_Atheromatous Plaques Collect Lipid, Mainly Cholesterol.
_Macrophages that Phagocytize Dead Cells Accumulate Cytoplasmic Lipid.
_Inborn Errors of Metabolism can Lead to Intracellular Accumulations of Complex Lipids.
____
Fatty Change Must be Distinguished from Fatty Accumulation (*Fatty Infiltration), which is simply increased fat cells in tissues, usually from Obesity.
Protein Accumulations
1) Amyloid:
Abnormal Protein products Accumulate
2) Hyaline:
** “Pink-Staining Stuff” in Tissues.
_Is the *Byproduct of *Protein Breakdown
3) Immunoglobulins:
Russell Bodies can form in @Plasma Cells
4) Alpha-1-Antitrypsin:
* Globules Accumulate within @Hepatocytes when AAT is not properly excreted from the Cell.
Excessive Spillage of Protein into the Urine Damages Renal Tubules Trying to Reabsorbe the Protein.
_____
Protein Processing:
_Accumulation of Improperly Processed Intracellular Proteins can lead to Cell Damage.
_Abnormal Proteins accumulating in Neurons can lead to Formation of Neuritic Plaques of Alzheimer’s Disease.
_If the Protection Afforded by Heat Shock Proteins is Exceeded, then Ubiquitin Directs the Abnormal Proteins for Clearance in Proteasomes.
___And if this is Exceeded, then Apoptosis may be Triggered.
Carbohydrate Accumulations
May Result From:
1) **Glycogen Storage Diseases:
Inherited (Genetic) Enzyme Disorders
2) **Altered Metabolism:
**Glycosylation of Proteins in Tissues
_Seen in Poorly-controlled Diabetes Mellitus.
Lipochrome
= Intracellular Accumulation of Autophagolysosomes.
Etiologies:
_Aging
_Atrophy (Brown Atrophy of Heart)
Iron Accumulations
Localized Accumulation of Hemosiderin:
(1) *Tissue Hemorrhage:
_Occurs with Breakdown of RBCs into Heme and Globin.
(2) The *Heme is *Broken Down and Collects as *Hemosiderin Granules, which may eventually be Recycled.
Example: Bruise
Systemic Accumulation of Hemosiderin:
1) Reticuloendothelial Tissues
(Bone Marrow, Liver, Spleen) or elsewhere if severe.
_Prussian Blue Stain stains the Iron Blue.
*Hemosiderosis: Simply an Accumulation of Iron.
**Hemochromatosis: When the Iron Accumulation Interferes with Organ Function. _Causes Include: (1) Genetic (Hereditary Hemochromatosis) (Increased Iron Absorption) (2) Hemolytic Anemias (Premature Lysis of RBCs) (3) Chronic Transfusion Therapy for Anemia (4) Excessive Dietary iron Intake
Bilirubin
Accumulation of this bile pigment leads to *Jaundice.
*Icterus = the Yellowish color caused by bilirubin accumulation.
_Best seen @ Sclera and @ Skin
Bilirubin is Measured in Serum as “Direct” and “Indirect” Bilirubin.
RBC Recycling produces Bilirubin that is
(1) Taken up by Hepatocytes,
(2) Conjugated to Diglucuronide,
(3) and Excreted into Bile.
Excessive Bilirubin can Spill through the Glomerulus into the Urine.
Jaundice Can Result From:
(1) Problems with Excretion of Bile from Liver or Biliary Tract,
(2) Liver Injury,
(3) Excessive Recycling of RBCs from Hemolysis (RBC Destruction)
Anthracosis
= Accumulation of **Carbon Pigment @ Lungs and @ Lymph Nodes.
From Inhaled Dust Particles in the Air. (Air Pollution)
Calcium
***Dystrophic Calcification:
_Calcium is Deposited in
@ *Necrotic or *Damaged Tissues,
Irrespective of Blood Calcium Levels.
_Seen in any type of Necrosis.
_Almost always present in the atheromas of Advanced Atherosclerosis.
_Also seen in Aging or Damaged Heart Valves, e.g. Aortic Valve.
Metastatic Calcification:
_Calcium may be Deposited in Normal Tissues due to Hypercalcemia.
