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.
