Lecture 1 Flashcards
What is pathology
What disciplines are involved in?
The study of disease (suffering)’Pathos- suffering
Logy-studying
The bridge between the basic sciences and clinical medicine
•The scientific foundation for all of medicine
•Made up of four disciplines ; anatomic pathology, microbiology, hematology and clinical chemistry or chemical pathology
Bridging discipline involving both basic science and clinical practice
•Devoted to the study of the structural and functional changes in cells, tissues, and organs that underlie disease.
•Achieved by the use of molecular, microbiologic, immunologic, chemical and morphologic techniques.
Pathology is the scientific study of disease
• Core of medicine
• Comprises of structural and functional changes
Both gross and microscopic levels of cellular changes
What is general pathology
You’re finding out what happened to the suffering cells from the time they were normal to the time they started suffering till now that the person is exhibiting symptoms
Concerned with the basic reactions of cells and tissues to abnormal stimuli that underlie all diseases.
Concerned with the basic reactions of cells and tissues to abnormal stimuli that underlie all diseases.
What are the four aspects of disease process that form the core of pathology
1.Its cause (etiology),
2.The mechanisms of its development (pathogenesis),
3.The structural alterations induced in the cells and organs of the body (morphologic changes),
4.The functional consequences of the morphologic changes (clinical significance).
Understanding the terminologies is key. Eg
Aetiology - cause
Pathogenesis - mechanisms
Morphological, functional and clinical changes (manifestations)
Complications and sequelae (secondary effect)
Diagnosis (detection)
Prognosis (outcome)
Pathology ( anatomic pathology, microbiology, clinical chemistry and hematology)
•Autopsy ( anatomic pathology led the way)
•Microscopy ( histopathology) is modern
What happened during haruspicy
•Later discipline was fragmented
True or false
Haruspicy- 4th century BC in Babylonia rabbis examined slaughtered animals for evidence of disease
•Talmudic law “Thou shalt not eat anything that dyeth of itself,”
Haruspicy is an ancient practice of divination that involves examining the entrails of sacrificed animals, especially the liver, to predict future events or interpret the will of the gods. This method of divination was particularly prominent among the Etruscans and Romans.
What theories dominated Ancient Greek medicine?
Why is it that autopsy wasn’t done during this period
Humoral theories of disease dominated ancient Greek medicine and discouraged investigation to correlate anatomy with disease.
•Hippocratic physicians were content to observe human anatomy only through wounds(they didn’t want to cut and look deeper)
What was autopsy about in the beginning
Who inspired the study of animal anatomy?
To see for ones’ self
•The ‘thing’ that caused the death of an individual
•‘Thing’ may be supernatural, microbial, environmental, genetic…..
•We want to see what caused death !!!
Aristotle (384-322 BC) inspired the study of animal anatomy and development
•Ptolemy of Macedonia (367-282 BC) created the environment in which pathologic anatomy first flourished at The Alexandria Library
When was the first known dissection done in Japan and why
In China, human dissections were performed occasionally during which dynasty?
What’s the name of the first recorded text dealing with forensic issues
The first known dissection in Japan was in 456 AD when an autopsy done on the body of Princess Takukete following her suicide revealed fluid in the abdomen with a “stone.”
In China, human dissections were performed occasionally during the Sung dynasty.
Around 1250, there appeared a handbook, His Yuan Lu (Washing Away of Wrongs),
•This text described simple autopsy techniques and guidelines,
•It was the first recorded text dealing with forensic issues
•In 1045 AD, over a 2-day period, dissections of the bodies of 56 members of a band of rebels were recorded in an atlas.
Who introduced the art of examining bodies in europe
AUTOPSY PRACTICE- EUROPE
•A Muslim from Tunisia ( Ifriqiya)
•Constantine the African (1020-1087), who had traveled widely arrived in Europe introducing the art of examining bodies
•He translated many works from Arabic to Latin
Confirmed Western physicians in their belief that medicine should be studied as a ‘rational system with close ties to philosophy, grounded in logical order and susceptible to methodical investigation’
What did arcadians believe to be the cause of diseases?
Etiology or cause
•Arcadians (2500 BC), diseases were caused by the patient’s own fault (for having sinned) or the makings of outside agents, such as bad smells, cold, evil spirits, or gods.
According to the modern concept of diseases, what are the two major classes of aetiological factors
Modern concept; two major classes of etiologic factors: intrinsic or genetic, and environmental / acquired (e.g., infectious, nutritional, chemical, physical).
Two Factors work hand in hand.
The Genetic and environmental factors. Either one of both of them happening.
Example: people are genetically predisposed to getting diabetes but if they control their sugar intake,they are less likely to get diabetes.
If you take in a lot of sugar,you will get the diabetes.
If someone isn’t genetically prone to diabetes and person consistently consumes large amounts of sugar,the person will get diabetes
Why is The concept of one etiologic agent for one disease (as produced by Koch postulates )
no longer sufficient
The concept of one etiologic agent for one disease is no longer sufficient because genetic and environmental factors work hand in hand.
•Knowledge or discovery of the primary cause remains the backbone on which a diagnosis can be made, a disease understood, or a treatment developed.
Kochs postulate for microbiology:
-one bacteria causes one diseases
-that one bacteria should be the cause of every manifestation of the disease
-the bacteria should be isolated from the body and grown on culture or media
-the bacteria should be able to be inoculated back into the body to cause the same disease
One agent for one disease as Koch said isn’t sufficient because Two Factors work hand in hand.
What is pathogenesis?
What are morphological changes?
Pathogenesis refers to the sequence of events in the response of cells or tissues to the etiologic agent, from the initial stimulus to the ultimate expression of the disease
•Morphologic changes refer to the structural alterations in cells or tissues that are either characteristic of the disease or diagnostic of the etiologic process
When referring to morphology as a characteristic of a disease, it involves recognizing specific structural changes in tissues or cells that are typical for that disease. These morphological features help distinguish one disease from another and can provide clues to the underlying etiological process.
For example, the presence of Reed-Sternberg cells in a lymph node biopsy is a characteristic morphological finding that is diagnostic of Hodgkin lymphoma.
When using morphology as an example, “diagnostic of an etiological process” means identifying the cause of a disease by examining the structural changes in cells or tissues.
For instance, the presence of granulomas (a collection of immune cells) in a tissue biopsy is diagnostic of an infectious etiology such as tuberculosis or sarcoidosis. Here, the specific morphological pattern—granuloma formation—helps determine the underlying cause of the disease.
Which aspect of the disease process influences normal function and determines the clinical features of the disease
functional derangements and clinical manifestations
•The nature of the morphologic changes and their distribution in different organs or tissues influence normal function and determine the clinical features (symptoms and signs), course, and prognosis of the disease.
•Virtually all forms of organ injury start with molecular or structural alterations in cells
Which aspect of the disease process influences normal function and determines the clinical features of the disease
functional derangements and clinical manifestations
•The nature of the morphologic changes and their distribution in different organs or tissues influence normal function and determine the clinical features (symptoms and signs), course, and prognosis of the disease.
•Virtually all forms of organ injury start with molecular or structural alterations in cells
State three things that confine a normal cell too a narrow range of its functions and structure?
What is homeostasis?
normal cell confined to a fairly narrow range of function and structure by its genetic programs of metabolism, differentiation, and specialization; by constraints of neighboring cells; and by the availability of metabolic substrates.
Neighboring cells regulate each other’s growth, function, and survival through direct contact and signaling molecules, ensuring coordinated tissue organization. This prevents abnormal cell behavior, such as uncontrolled proliferation or inappropriate responses, maintaining tissue integrity and homeostasis.
Genetic Programs of Metabolism, Differentiation, and Specialization: Each cell type has a specific genetic blueprint that dictates its metabolic activities, differentiation (development into a specialized cell type), and specialized functions. This genetic programming ensures that cells perform their designated roles effectively and maintain homeostasis.
•Cells able to handle normal physiologic demands, maintaining a steady state called homeostasis(Hemostasis is the physiological process that stops bleeding at the site of an injury while maintaining normal blood flow elsewhere in the circulation)
When cells are exposed to a persistent mild or slowly progressive sublethal stimulus, they undergo cellular adaptations to cope with the stress without dying. These adaptations allow cells to maintain function and survive in the face of adverse conditions.
What are cellular adaptations
Morphological changes seen in adaptive changes include what four main things?
Body response to stress
May be due to physiological stimuli acting in excess or pathological stimuli.
Adaptation Involves an altered steady state, which is POTENTIALLY REVERSIBLE to the normal steady state
• Involves alteration in
• STRUCTURE or MORPHOLOGY
• FUNCTION
Severe physiologic stresses and some pathologic stimuli may bring about a number of physiologic and morphologic cellular adaptations, during which new but altered steady states are achieved, preserving the viability of the cell and modulating its function as it responds to such stimuli
Morphological changes seen in adaptive changes include hypertrophy,hyperplasia and atrophy and metaplasia
Explain the body’s response to stress or injury up till the point of cell death
Depending on the various influences or things that condition cells, what two things may occur in response to abnormal stimuli?
• Depending on the various influences or things that condition cells, the following may occur in response to abnormal stimuli:
• Cellular Adaptation: The result of a number of physiologic and structural cellular changes which occur with development of a new but altered steady state
• Cell Injury: The result of a series of event that occur when adaptation is not possible or fails when the limits of adaptation are exceeded
So for a normal cell, homeostasis is going on well. When there is stress, the cell tries to adapt to it. If it can’t adapt, it leads to cell injury. This injury could be reversible or irreversible. If the injury is (mild,transient), it is reversible. If it is severe and progressive, it becomes irreversible.
If reversible, it’ll go back to the normal way the cell was.
If irreversible, it’ll undergo either necrosis or apoptosis.
If the cell went through an injury or injurious stimulus but not a stress, the cell becomes injured. If the injury is mild,transient it is reversible. If it is severe and progressive, it becomes irreversible.
If reversible, it’ll go back to the normal way the cell was.
If irreversible, it’ll undergo either necrosis or apoptosis
So for stresss, the body adapts or the cell adapts but for a cellular injury, it moves into being reversible or irreversible.
If it can’t adapt, it now becomes a cellular injury and then depending on the kind of injury, it is either reversible or irreversible
What are the five cellular adaptations that occur in cells after a stress?(not an injury. A cell can’t adapt after an injury but it can after a stress. If it tries to adapt but the stress is too severe, it now becomes an injury cuz it can’t adapt again)
Hyperplasia
Hypertrophy
Atrophy
Metaplasia
Dysplasia
What is hypertrophy?
What is the cause of hypertrophy?
Which type of cells does it usually occur in? Give an example
State and explain the two types with examples
Is hypertrophy reversible?
Why will the size of cells increase in hypertrophy?
Pure hypertrophy without accompanying hyperplasia occurs in which two types of muscles?
Which type of muscle is hypertrophied in prolonged exercise?(skeletal,cardiac,smooth)
Which type is hypertrophied in pregnancy?
What pathological event will cause hypertrophy of cardiac muscle?
What pathological events will cause hypertrophy of smooth muscle?
A. arteries in hypertension (medial hypertrophy)
B.gastrointestinal tract proximal to obstruction
C.bladder in outflow obstruction
D. None of the above
E. All of the above
Refers to an increase in the size of cells, resulting in an increase in the size of the organ.
•The hypertrophied organ has no new cells, just larger cells. The increased size of the cells is due not to cellular swelling but to the synthesis of more structural components. This is due to Structural proteins increase in cells causing increased cell size and consequently hypertophy.
•Occurs in nondividing cells (e.g., myocardial fibers)
•May be pathological or physiological
Physiologic (example: increased uterus size during pregnancy) and pathological hypertrophy(example: left ventricular hypertrophy. Hypertrophy of left ventricle due to increased workload on the heart)
Means increase in size of cells in a tissue or organ
An organ or tissue showing hypertrophy has increased size due solely to increase in size of its constituent cells.
The stimulus may be:
•an increased demand function, or
•hormonally induced
•physiologic, e.g. skeletal muscles of athletes, or
•pathologic, e.g. left ventricle in ventricular overload states.
This is a reversible process.
The increase in size of cells is not due to increased intracellular water but there is increase in intracellular organelles with:
•increased RNA synthesis,
•protein synthesis,
•and uptake of amino acids and oxygen.
Pure hypertrophy without accompanying hyperplasia occurs only in cardiac and skeletal muscle, which are composed of permanent cells with no ability to divide.
The stimulus is always mechanical.
PHYSIOLOGIC
• Skeletal muscle - after prolonged exercise
• Smooth muscle – in pregnancy
PATHOLOGIC
•Cardiac Muscle - usually chronic haemodynamic overload.
- left ventricle in systemic hypertension, aortic valve disease, mitral incompetence, high output states.
- hypertrophic cardiomyopathy –due to idiopathic causes
•Smooth Muscle
- arteries in hypertension (medial hypertrophy)
- gastrointestinal tract proximal to obstruction
- bladder in outflow obstruction
What is hyperplasia?
In which cells does hyperplasia usually takes place?
State the types we have
Hyperplasia is an increase in the number of cells in an organ or tissue, usually resulting in increased volume of the organ or tissue
•Hyperplasia takes place if the cellular population is capable of synthesizing DNA, thus permitting mitotic division. Always occurs in a cell capable of replicating. If the cell is not capable of replicating, it’ll increase in size instead(hypertrophy)
•Hyperplasia can be physiologic or pathologic.
Means increase in number of cells
A hyperplastic organ or tissue is increased in size due to an increase in the number of constituent cells
The process occurs in tissues or organs containing stable or labile cells, which retain the ability to divide
The response is also due to increased demand for function or hormonal stimulation but may be idiopathic eg. BPH.
Hyperplasia may be physiologic or pathologic.
Pathologic - here stimulus is often physiological one acting in excess
Those due to a specific stimulus persist only so long as the stimulus remains - reversible.
Explain the types of hyperplasia and give examples of each
Physiologic hyperplasia
•Grouped into;
1.Hormonal hyperplasia e.g. pregnancy changes in the uterus and breasts
2.Compensatory hyperplasia e.g. regeneration of the liver after partial hepatectomy
Mechanism; increased local production of growth factors, increased levels of growth factor receptors on the responding cells, or activation of particular intracellular signaling pathways
Pathologic hyperplasia
•Pathologic hyperplasia; constitutes a fertile soil in which cancerous proliferation may eventually arise, e.g. patients with hyperplasia of the endometrium are at increased risk for developing endometrial cancer
Endocrine glands
•adrenal cortex:
- ACTH secreting pituitary adenoma
- congenital adrenal hyperplasia
•parathyroids:
- idiopathic hyperplasia
- secondary to hypocalcaemia
•thyroid:
- Grave’s disease
Endocrine target organs
•breast:
- puberty, pregnancy, lactation these are physiological
- proliferative breast disease (fibrocystic disease) this is pathological
•endometrium:
- cystic hyperplasia from excess oestrogens
•prostate:
- benign nodular hyperplasia
•myometrium:
- pregnant uterus. This is physiological
Skin:
•hyperplasia of the epidermis (acanthosis) occurs in many disease
- chronic inflammation and chronic irritation:
- the common corn from ill-fitting shoes
- papillomavirus infection (wart)
Bone marrow:
- secondary to haemolysis, infection
- hypoxia which is compensatory; physiological
Lymph nodes
- secondary to antigenic stimulation e.g. infection
Connective tissue
- wound healing
Explain the mechanism of pathological hypertrophy of the heart muscles
Pathological Hypertrophy of heart muscle mechanism:
Anytime there is a mechanical stretch of the heart muscle.
Hypertension increases the stretch on the heart muscles increasing EDV. (End-diastolic volume (EDV) is the amount of blood in the ventricles at the end of diastole, just before the heart contracts. It is a key parameter in cardiac physiology and is often used to assess the heart’s filling capacity.
Key Points about End-Diastolic Volume (EDV):
• Filling Stage: During diastole, the heart’s ventricles are relaxed, and blood flows into them from the atria. The EDV represents the maximum volume of blood that the ventricles hold just before they contract) Left ventricle pumps blood to the entire body and is able to do that due to the elasticity of the heart muscles and the volume of blood that comes in. CO=SVxHR MAP=COxTPR
The mechanical stretch on the heart muscles causes signals to be sent to the cardiomyoctes which activates alpha adrenergic agonists and the hormones and receptors for growth factors such as insulin like growth factor 1.
This causes signal transduction.
Transcription factors are produced to:
- [ ] Induction of fetal genes: not used to level of work adult cardiac cells do. So there’s increased sketching and decreased something so it can contain the amount of work
- [ ] Increased synthesis of contractile proteins: To handle increased mechanical load, cardiomyocytes enhance the synthesis of contractile proteins like actin and myosin, which are crucial for muscle contraction. This increase helps the heart muscle contract more effectively in response to higher demands.
- [ ] Increased production of growth factors : Growth factors such as IGF-1 play a significant role in cardiac hypertrophy by promoting cell growth and survival. The production of these growth factors stimulates autocrine and paracrine signaling pathways that further enhance hypertrophy and survival signals within the heart muscle cells.
The above three factors contribute to the increase in the size of the cardiomyocytes.
Induction of fetal genes:
1. Under stress, adult cardiomyocytes often revert to expressing a set of genes that are normally active during fetal development. These genes produce proteins that are less efficient at supporting the workload required by adult cardiac cells. The activation of these fetal genes can lead to increased cell growth, but they often provide a temporary adaptation that may not sustain the high functionality needed in adult hearts. This adaptation can lead to increased stretching and decreased efficiency in contraction as the cells are not optimally configured for high workload.
2.
What is metaplasia
Why does it occur?
What’s the difference between metaplasia and dysplasia
What is neoplasia
A reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type.
•It may represent an adaptive substitution of cells that are sensitive to stress by cell types better able to withstand the adverse environment.
•The influences that predispose to metaplasia, if persistent, may induce malignant transformation in metaplastic epithelium..
Means the replacement of one fully differentiated cell type by another fully differentiated cell type
May represent an adaptive substitution of cells more sensitive to the injurious stimulus which induced the change by cells better suited to withstand the stimulus
Usually a response to chronic inflammation or irritation
Is reversible but may undergo further indirect transformation to neoplasia through dysplasia
Metaplasia: uncontrollable increase in number of cells. The cell look like the normal cell morphology.
When it moves into the blood vessels or crosses basement membrane into the connective tissues and surrounding areas that’s when you say the cancer has metastized
Cells have the normal morphology in metaplasia while cells have a different morphology in dysplasia. Dysplasia: uncontrollable increase in number of cells with a change in structure of normal cells or differences in the normal structure of the cells
Neoplasia is the process of abnormal and uncontrolled cell growth that leads to the formation of a mass or tumor, known as a neoplasm
What is atrophy
What are the types of atrophy
Why are atrophic tissues sometimes brown in color?
Shrinkage in the size of the cell by loss of cell substance.
•When a sufficient number of cells are involved, the entire tissue or organ diminishes in size, or becomes atrophic.
H Means decrease in size of a cell and/or in number of cells
When enough functional cell mass is involved leads to decrease in size of organ or tissue.
Atrophy is an important adaptive response to decreased demand for function of a particular cell, tissue or organ.
In addition to being smaller in size, atrophic tissue and organs are sometimes brown in colour (brown atrophy) due to accumulation in the cytoplasm of residual bodies called lipofuscin, a pigment derived from lipids which are resistant to digestion by lysosomal enzymes.
In pathologic states, the process may represent a reduction to a size at which survival is still possible; further reduction will lead to cell death
•Can be physiologic or pathological. Physiologic example is aging(organs and tissues decrease in size as aging occurs. This is called senile atrophy. It involves loss of muscle mass). Another example is the return of the uterus to the normal size after giving birth(involution)
Pathological:
Disuse atrophy, reduced blood flow to the area cause reduced usage,etc
That’s correct! Muscle atrophy, also known as muscle wasting, occurs when there is a loss of contractile proteins, leading to a reduction in muscle size and strength.
In atrophy, the following changes occur:
- Loss of contractile proteins: Actin and myosin filaments are broken down, leading to a decrease in muscle fiber size and number.
- Reduced muscle protein synthesis: The rate at which new muscle proteins are built decreases, contributing to muscle loss.
- Increased muscle protein degradation: Muscle proteins are broken down more quickly, leading to a net loss of muscle tissue.
- Disruption of muscle fiber structure: The organization and alignment of muscle fibers are disrupted, leading to a loss of muscle function.
As a result, the muscle reduces in size, and its strength and function are impaired. Atrophy can occur in various contexts, such as:
- Disuse (e.g., immobilization or prolonged bed rest)
- Aging (sarcopenia)
- Malnutrition or inadequate protein intake
- Certain diseases (e.g., muscular dystrophy, cancer cachexia)
- Hormonal imbalances (e.g., testosterone deficiency)
In atrophy, the structural proteins (like collagen and elastin) may also be affected, leading to changes in muscle tissue architecture and function.
Great question! Let me know if you’d like more details on muscle atrophy or related topics!
State six causes of atrophy
What is sarcopenia
Decreased workload (atrophy of disuse)
• Loss of innervation (denervation atrophy).
• Diminished blood supply.
•Inadequate nutrition
•Loss of endocrine stimulation.
•Aging (senile atrophy).
•Pressure.
How diminished blood supply causes atrophy:
- [ ] By causing Tissue hypoxia leading to reduced oxygen in cells that is used for their cellular function leading to shrinking of the cells
- [ ] It can also cause decreased workload cuz reduced blood supply to a certain part makes it difficult to use that part of the body
So when the cell loses its function or is unable to perform its function, it leads to atrophy.
Thymus gland is almost vanished due to atrophy in aging people
Senile Atrophy:
• Definition: Senile atrophy is a type of atrophy that occurs as a natural part of aging. It affects various organs and tissues, such as muscles, the brain, skin, and bones. • Mechanism: Aging leads to a gradual decrease in cell size and number due to a combination of factors, including reduced blood supply, decreased hormonal stimulation, and accumulation of cellular and molecular damage over time. • Examples: • Brain: In the elderly, there is a decrease in brain size due to the loss of neurons, which is evident in conditions like Alzheimer’s disease. • Muscles: Age-related muscle wasting, known as sarcopenia, is another example, where muscle fibers shrink and are replaced by fat and fibrous tissue. • Skin: The skin may become thinner, less elastic, and more prone to injury as cells decrease in number and collagen production declines.
- Pressure Atrophy:• Definition: Pressure atrophy is the reduction in the size of a tissue or organ due to persistent and prolonged pressure. This pressure disrupts normal blood flow, leading to ischemia (reduced oxygen supply), which in turn causes tissue shrinkage.
• Mechanism: When an organ or tissue is subjected to continuous pressure, cells can be damaged, and nutrient and oxygen supply to the cells is impaired. Over time, this causes cells to shrink or die, leading to atrophy.
• Examples:
• Kidneys: In hydronephrosis, where there is a blockage of urine flow, the build-up of urine puts pressure on kidney tissues, causing them to atrophy.
• Skin and Subcutaneous Tissue: Prolonged pressure in bedridden patients can cause pressure ulcers (bedsores), where the skin and underlying tissues atrophy due to sustained pressure.
Generally, excessive use of an organ or tissue does not cause atrophy; Pressure atrophy results from prolonged pressure on tissues, leading to a reduction in size due to impaired blood flow and oxygen supply.
When does cell injury occur?
What are the two types of cell injury
Cell injury results when cells are stressed so severely that they are no longer able to adapt or when cells are exposed to inherently damaging agents
•Injury may progress through a reversible stage and culminate in cell death
•Injury is grouped into ;
1.Reversible cell injury
2.Irreversible injury and cell death
What are the hallmarks of reversible cell injury?
How are stress proteins produced?
Are stress proteins produced in reversible cell injury or irreversible cel injury
Reversible injury; the hallmarks of reversible injury are
reduced oxidative phosphorylation(this is the process by which mitochondria produces ATP),
adenosine triphosphate (ATP) depletion,
and cellular swelling caused by changes in ion concentrations and water influx. In addition: ATP DEPLETION, Impaired mitochondrial function
4. Increased ROS production
5. Disrupted electron transport chain
Further understanding:
So oxidative phosphorylation will be reduced because there is reduced ADP generation. ADP is the substrate for ATP synthase. ATP synthase uses ADP and inorganic phosphate to produce ATP. With less ADP available, the enzyme has less substrate to work with, reducing the rate of ATP synthesis and reducing oxidative phosphorylation
Reversible cell injury refers to cellular damage that can be reversed if the harmful stimulus is removed. The hallmarks of reversible cell injury primarily reflect early cellular responses to stress or injury
The key features include:
- Cellular Swelling: Due to the failure of ion pumps in the plasma membrane, especially the Na+/K+ ATPase pump, leading to an influx of sodium and water into the cell.
- Fatty Change (Steatosis): Accumulation of lipid droplets within the cytoplasm, often seen in organs involved in lipid metabolism, like the liver.
- Membrane Blebbing: Formation of protrusions or blebs in the plasma membrane due to cytoskeletal disruption.
- Mitochondrial Swelling: Swelling and distortion of mitochondria, which may lead to decreased ATP production but are not yet irreversibly damaged.
- Dilation of the Endoplasmic Reticulum: Expansion of the ER, leading to detachment of ribosomes and disruption of protein synthesis.
- Detachment of Ribosomes from the Rough ER: Leading to impaired protein synthesis.
- Chromatin Clumping: Aggregation of nuclear chromatin due to changes in ionic balance, especially pH.
- Cellular and Organelle Disorganization: Initial reversible changes in the structure and function of various organelles within the cell.
- Increased Plasma Membrane Permeability: Leading to an imbalance of ions and water across the membrane, contributing to cellular swelling.
- Accumulation of Intracellular Ions: Particularly calcium, which can activate various enzymatic pathways that can lead to further cell damage if not controlled.
These changes are generally reversible if the injurious stimulus is removed and the cell can restore homeostasis.
Reversible cell injury changes are first seen:
ultra structurally, later on…
light microscopy
Reversible cell injury is a Redemption mechanism:
Stress response: most genes are inactivated and a set of inducible genes are expressed resulting in synthesis of intracellular “stress proteins” or “heat shock proteins” (HSP)
Stress proteins are involved in the cell’s defense mechanisms against stress and are produced during reversible cell injury to help the cell adapt and recover.
• In the context of irreversible cell injury, while stress proteins may still be produced, their protective effects are insufficient to prevent cell death.
What are the hallmarks of irreversible cell injury
What is indicative of severe mitochondrial damage
Irreversible injury; structural changes (e.g., amorphous densities in mitochondria, indicative of severe mitochondrial damage) and functional changes (e.g., loss of membrane permeability) are indicative of cells that have suffered irreversible injury.
Irreversible cell injury refers to a state where cell damage has progressed to a point beyond recovery, ultimately leading to cell death. Several hallmark features characterize this irreversible injury, distinguishing it from reversible damage. These hallmarks include:
- Irreversible Mitochondrial Dysfunction: Mitochondria lose their ability to produce ATP. Significant mitochondrial damage includes the loss of membrane potential and the formation of mitochondrial permeability transition pores, leading to the release of pro-apoptotic factors.
- Plasma Membrane Disruption: Loss of membrane integrity leads to an uncontrolled influx of calcium and other ions, as well as leakage of cellular contents into the extracellular space.
- Lysosomal Membrane Damage: Release of lysosomal enzymes into the cytoplasm, causing enzymatic digestion of cellular components.
- Pyknosis: Nuclear shrinkage and increased basophilia due to chromatin condensation.
- Karyorrhexis: Fragmentation of the nucleus into smaller pieces.
- Karyolysis: Dissolution of the nuclear structure, resulting in a loss of chromatin staining.
- Increased Eosinophilia: The cytoplasm appears more pink when stained with hematoxylin and eosin (H&E) due to the denaturation of proteins and loss of RNA.
- Cytoplasmic Vacuolization: Formation of large vacuoles within the cytoplasm as a result of autophagy and other degradative processes.
- Leakage of Intracellular Enzymes: Enzymes and proteins, such as lactate dehydrogenase (LDH) and creatine kinase (CK), are released into the extracellular space and bloodstream, serving as markers of cell death and tissue damage.
- Functional Impairment: Complete loss of specific cellular functions, such as contraction in muscle cells or electrical activity in neurons
When I mentioned “increased basophilia” in the context of pyknosis, I was referring to the fact that the condensed chromatin in the nucleus becomes more intensely stained with basic dyes.
Basophilia is a term used to describe the ability of a substance to attract basic dyes, such as hematoxylin and eosin (H&E). In the context of histology and cytology, basophilia is often used to describe the staining properties of cellular structures.
In the case of pyknosis, the condensed chromatin becomes more basophilic because the DNA and associated proteins are packed more tightly together. This increased density of negatively charged molecules (such as phosphate groups in DNA) creates a stronger attraction for positively charged basic dyes.
As a result, the pyknotic nucleus appears more intensely stained with basic dyes, often appearing dark blue or purple under a microscope. This is in contrast to the surrounding cytoplasm, which may appear more pale or eosinophilic (staining with acidic dyes).
So, to summarize:
- Basophilia refers to the ability of a substance to attract basic dyes.
- In pyknosis, the condensed chromatin becomes more basophilic due to the increased density of negatively charged molecules.
- This results in the pyknotic nucleus appearing more intensely stained with basic dyes under a microscope.
State six causes of cell injury
1.Oxygen deprivation-
2.Physical agents- too hot too cold temperatures cuz the cells were to best at optimum temp
Which is often 37 degrees celcius. PHYSICAL
A.Extremes of temperature - cell injury and/or cell death result if tissue is maintained at a level greater than 5°C above (hyperthermia) or 15°C
below (hypothermia) normal body temperature.
B. Mechanical causes; Mechanical -
•abrasions (tearing of epidermal cells by friction)
• contusions/bruises
• lacerations
• incisions
• stab (pressure produced by pointed objects)
C. Light - photopathy (pathologic effect produced by light): photalgia (pain in eye caused by light); photonosus (any disease due to excess light)
D. Pressure - high pressure may cause injury.
E.Sound - may damage hearing causing hearing impairment
F.Radiation - x-rays, gamma rays, alpha and beta particles, ultra-violet rays, etc. - result in damage to DNA and mutations
3.Chemical agents and drugs: The number of chemicals capable of causing cell injury is too vast to enumerate. Some, even in very small amounts, can cause death to enough cells in the body within minutes to hours, killing the whole organism – “poisons”.
4.Infectious agents-HIV destroying cells. BIOLOGICAL (INFECTIVE) AGENTS
Bacteria - production of exo- and endo-toxins and other virulence factors
Viruses, Clamydiae, Rickettsiae - direct cell lysis, cytopathic effects e.g. syncytial giant cell formation, inclusions, DNA alteration.
Yeasts and fungi - chronic inflammation with fibrosis, hypersensitivity reactions.
Parasites - cell lysis, tissue destruction by enzymes, competition for nutrients
5.Immunologic reactions-Allergic reactions and SLE. IMMUNOLOGICAL REACTIONS
Hypersensitivity reactions - complement, T lymphocytes, Macrophages, chemical mediators of inflammation
Autoimmune diseases – reactions of the immune system to self antigens
Immunodeficiency – inherited and acquired (e.g. HIV infection)
6.Genetic derangements: GENETIC ABNORMALITIES
DNA damage may lead to cell death, alteration of metabolic pathways (including synthesis of abnormal products or reduced or total lack of synthesis), or neoplastic transformation.
7.Nutritional imbalances:
8.Ageing
Why is reversible cell injury reversible?
Irreversible cell injury: Loss of membrane permeability means the cell isn’t able to control what goes in and out of it. There is lysosome rupture. Lysosomes contain certain chemicals that destroy the cell
One of the reasons reversible cell injury is reversible is cuz the damage isn’t as bad and lysosomes don’t rupture
Diff between reversible and irreversible cell injury
Cell response to injurious stimul depends on what three things?
Consequences of cell injury depend on what three things?
Cell Injury results from what abnormalities?
Mechanisms of cell injury
1.The cellular response to injurious stimuli depends on the type of injury, its duration, and its severity.
2.The consequences of cell injury depend on the type, state, and adaptability of the injured cell.
3.Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components(next slide).
Cell response to injurious stimul depends on what three things?
Consequences of cell injury depend on what three things?
Cell Injury results from what abnormalities?
Mechanisms of cell injury
1.The cellular response to injurious stimuli depends on the type of injury, its duration, and its severity.
2.The consequences of cell injury depend on the type, state, and adaptability of the injured cell.(example is the cells in the lungs. They are used to oxygen so oxygen deprivation in the lungs for even ten seconds will give you an exaggerated effect as compared to oxygen deprivation of the same amount of time in the liver. Hepatocytes will be more adapted to oxygen deprivation stress than the lungs )
3.Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components
State five important targets of injurious stimuli
Important targets of injurious stimuli
1.Aerobic respiration involving mitochondrial oxidative phosphorylation and production of ATP
2.The integrity of cell membranes, on which the ionic and osmotic homeostasis of the cell and its organelles depends(attack to this area by injurious stimuli leads to high sodium in cells due to failure of Sodium potassium pumps leading to swelling of cells)
3.Protein synthesis-components in cell are held together by proteins. Example is the cytoskeleton. Problem in protein synthesis can cause deranged enzymes such as derangement in enzymes in glycolytic pathway (example streptokinase) so the cell isn’t able to produce the mediators for ATP synthesis
4.The cytoskeleton
5.The integrity of the genetic apparatus of the cell.(Example is radiation causing injury to DNA which will affect integrity of genetic apparatus
Summary:
Injury to membrane or cell affects these key areas or causes:
1.Mitochondrial damage leads to reduced ATP production and then loss of energy dependent cellular functions like sodium potassium atpase pumps.
2.Injury to lysosomes causing enzymatic digestion of cellular components
3. Injury to plasma membrane causing loss of integrity of plasma membrane leading to loss of cellular contents
4. Increased intracellular calcium leading to protein breakdown and dna damage
5. Release or ROS such as nitric oxide,hydrogen peroxide,hydrochloride also leading to protein breakdown and dna damage
What kind of injuries are usually associated with deceased ATP synthesis and depletion?ATP depletion to less than five percent to ten percent of normal levels results in what five things?
Decreased ATP synthesis and depletion are frequently associated with both hypoxic and chemical (toxic) injury
H Hypoxic Injury: A lack of oxygen reduces oxidative phosphorylation in mitochondria, sharply decreasing ATP production. Cells switch to anaerobic glycolysis, which is much less efficient and produces minimal ATP.
• Chemical (Toxic) Injury: Toxic substances can damage mitochondria, inhibit key enzymes in ATP production pathways, increase mitochondrial membrane permeability, or cause oxidative stress, all of which impair ATP synthesis.
• ATP depletion to <5-10% of normal levels result in;
1.Reduction in the activity of the plasma membrane energy-dependent sodium pump (ouabain-sensitive Na+,K+-ATPase) which leads to increased sodium,water and calcium influx and increased potassium efflux causing ER swelling and the whole cell to swell up
2.Altered cellular energy metabolism-reduced ATP means now the cell has to undergo anaerobic glycolysis instead of aerobic. More of the ATP or high amounts of it is produced from aerobic glycolysis in the cristae of the mitochondria. This anaerobic glycolysis leads to reduced glycogen,reduced ph and then clumping of nuclear chromatin
3.Failure of the Ca2+ pump leads to influx of Ca2+, with damaging effects on numerous cellular components
4.Structural disruption of the protein synthetic apparatus, manifested as detachment of ribosomes from the rough endoplasmic reticulum and dissociation of polysomes into monosomes, with a consequent reduction in protein synthesis and increased lipid deposition
5.Unfolded protein response is triggered
cristae **: The folds of the inner mitochondrial membrane where the electron transport chain and ATP synthesis take place.
- Matrix: The innermost part of the mitochondrion where the Krebs cycle occurs.
What four things causes damage to the mitochondria
The damage to mitochondria results in what two major events ?
State the things that are released to cause apoptosis when there is damage to my he mitochondria
Increases of cytosolic Ca2+
•Oxidative stress
•Breakdown of phospholipids
•Lipid breakdown products
Damage RESULTS IN;
1.Formation of a high-conductance channel in the mitochondrial membrane, called the mitochondrial permeability transition pore
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Mitochondrial Permeability Transition (MPT) pore formation: A high-conductance channel forms in the mitochondrial membrane, allowing solutes and water to flow into the mitochondria, leading to:
- Mitochondrial swelling
- Mitochondrial dysfunction
- Release of pro-apoptotic factors
2.Sequestration between the outer and inner membranes of the mitochondria of several proteins that are capable of activating apoptotic pathways( cytochrome c and proteins that indirectly activate apoptosis inducing enzymes called caspases). The statement you’ve provided refers to a critical step in the intrinsic (mitochondrial) pathway of apoptosis, where certain proteins sequestered between the outer and inner membranes of the mitochondria are released to initiate the apoptotic process. Here’s a breakdown:
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Sequestration of Proteins:
- Under normal conditions, proteins like cytochrome c and others that can promote apoptosis are sequestered in the intermembrane space of the mitochondria (the space between the outer and inner mitochondrial membranes).
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Release of Cytochrome c:
- In response to apoptotic stimuli (e.g., DNA damage, oxidative stress), the mitochondrial outer membrane becomes permeable.
- This permeability allows cytochrome c and other pro-apoptotic proteins to be released into the cytoplasm.
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Activation of Caspases:
- Once in the cytoplasm, cytochrome c interacts with a protein called Apaf-1 (Apoptotic protease activating factor-1) to form a complex known as the apoptosome.
- The apoptosome then recruits and activates procaspase-9, which is cleaved to form active caspase-9.
- Caspase-9 subsequently activates other caspases (like caspase-3), which are responsible for executing the cell death program by degrading cellular components.
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Apoptotic Pathway:
- The release of cytochrome c is a key event in the intrinsic apoptotic pathway.
- This pathway is tightly regulated and ensures that cells undergo controlled, programmed cell death in response to internal stress signals.
- Cytochrome c: A protein normally involved in the electron transport chain, but also crucial for the activation of the intrinsic apoptotic pathway when released into the cytoplasm.
- Caspases: A family of protease enzymes that play essential roles in programmed cell death (apoptosis). They are activated in a cascade, leading to the systematic dismantling of the cell.
- Sequestration of apoptotic proteins like cytochrome c within the mitochondria keeps the apoptotic machinery in check.
- Release of these proteins into the cytoplasm triggers the activation of caspases, leading to apoptosis.
This process ensures that cells can be efficiently and systematically eliminated when they are damaged or no longer needed, preventing potential harm to the organism.
Sequestration of pro-apoptotic proteins*: Between the outer and inner mitochondrial membranes, several proteins are sequestered, including:
- Cytochrome c: A key electron transport chain protein that can activate caspases and induce apoptosis
- Pro-apoptotic Bcl-2 family members: Proteins like Bax, Bak, and Bid, which can activate caspases and induce apoptosis
These sequestered proteins can then be released into the cytosol, triggering apoptotic pathways and ultimately leading to programmed cell death (apoptosis).
S several key factors responsible for triggering apoptotic pathways are located in the mitochondria. These factors include:
- Cytochrome c: A protein that’s normally involved in the electron transport chain, but when released into the cytosol, it activates caspases and triggers apoptosis.
- Smac/DIABLO: A protein that inhibits the activity of IAPs (inhibitors of apoptosis proteins), allowing caspases to activate and drive apoptosis.
- Omi/HtrA2: A serine protease that can activate caspases and trigger apoptosis.
- Bcl-2 family members: A family of proteins that regulate apoptosis by either promoting (pro-apoptotic) or inhibiting (anti-apoptotic) mitochondrial outer membrane permeabilization (MOMP).
These mitochondrial factors are normally sequestered within the mitochondria, but when the mitochondria are damaged or dysfunctional, they can be released into the cytosol, triggering apoptotic pathways
Sequestration of proteins refers to the process by which proteins are selectively bound or trapped by other molecules, such as lipids, nucleic acids, or other proteins, and removed from their normal cellular environment or activityh
The MPT pore formation and protein sequestration are critical steps in the mitochondrial pathway of apoptosis, which is a key mechanism of cell death in response to cellular stress, injury, or damage.
State four causes of defects in membrane permeability
CAUSES OF DEFECTS IN MEMBRANE PERMEABILITY
•Mitochondrial dysfunction-losss of sodium potassium atpase causing cell membrane to swell up
•Loss of membrane phospholipids
•Cytoskeletal abnormalities.
•Reactive oxygen species.
•Lipid breakdown products.
Here are some ways in which lipid breakdown products can disrupt membrane permeability:
- Lysophospholipids: These products of phospholipid breakdown can insert into the mitochondrial membrane, causing it to become more permeable.
- Fatty acid derivatives: Certain fatty acid derivatives, such as palmitate, can alter the fluidity and permeability of the mitochondrial membrane.
- Oxidized lipids: Oxidized lipids, such as oxidized cholesterol, can disrupt the mitochondrial membrane structure and function, leading to increased permeability.
- Ceramide: This sphingolipid breakdown product can form channels in the mitochondrial membrane, leading to increased permeability
What two phenomena consistently characterize irreversibility of the cell
The best available definition of cell death is the irreversible loss of certain integrated cellular functions. State five of them
Two phenomena consistently characterize irreversibility;
1.The inability to reverse mitochondrial dysfunction (lack of oxidative phosphorylation and ATP generation) or when Mitochondria is destroyed
2.Profound disturbances in membrane function.-Membrane of cell is destroyed
The best available definition of cell death is the irreversible loss of integrated cellular function:
Boundary functions (cell membrane)
Energy production/metabolism
Protein synthesis
Maintenance of cell shape (Cytoskeleton)
Cell function control and modulation (RNA/DNA)
State two light microscopic changes in the cell that are seen in reversible cell injury
State four ultra structural changes seen in reversible injury
Two light microscopic changes are recognizable;
1.Cellular swelling and bleb formation
2.Fatty change and fatty deposits especially in the hepatocytes
Ultrastructural changes in reversible injury include:
1.Plasma membrane alterations
2.Mitochondrial changes
3.Dilation of the endoplasmic reticulum-this displaces the ribosomes on it
4.Nuclear alterations
I checked this when I asked whether bleb formation was irreversible or reversiboe and the thing said it’s an early sign of reversible cell injury but it can also occur in latter parts of irreversible cell injury so it gave me the below to understand better.
When selecting an option for an MCQ that involves bleb formation, here’s how to approach it:
1. Question Context: Determine whether the question is asking about early or late features of cell injury. If it focuses on early signs, bleb formation can be associated with both reversible and irreversible cell injury. 2. Specificity: • If the question specifies irreversible cell injury or cell death, choose that option as bleb formation can occur during the transition to irreversible damage. • If the question is general and does not specify the stage of injury, note that bleb formation can occur in both reversible and irreversible cell injury. 3. Definitive Signs: • For irreversible cell injury: Look for additional definitive signs like severe mitochondrial damage, extensive membrane rupture, or nuclear changes (e.g., pyknosis). • For reversible cell injury: If only bleb formation is mentioned without other irreversible changes, it’s more likely to indicate reversible injury or early reversible injury.
Example MCQ Scenario:
• Question: “Which of the following is an early sign of cell injury?” • Options: • A. Bleb formation • B. Pyknosis • C. Karyorrhexis • D. Karyolysis • Best Answer: A. Bleb formation, because it can occur early in both reversible and irreversible cell injury. • Question: “Which of the following indicates irreversible cell injury?” • Options: • A. Bleb formation • B. Cellular swelling • C. Pyknosis • D. Fatty change • Best Answer: C. Pyknosis, as it is a definitive sign of irreversible cell injury and cell death, though bleb formation is also relevant as part of the broader context of injury.
Reversible and irreversible cell injury involve distinct cellular changes. Here’s a comparison:
- Cellular Swelling: Early sign, caused by impaired ion pumps (e.g., Na+/K+ ATPase) leading to an influx of water.
- Fatty Change: Accumulation of lipid droplets in the cytoplasm due to impaired lipid metabolism.
- Loss of Microvilli: Changes in the cell membrane structure.
- Mitochondrial Swelling: Mild swelling and aggregation of mitochondrial granules.
- Chromatin Clumping: Chromatin becomes more condensed and clumped, but this is reversible if the stress is removed.
- Cell Death: Irreversible injury leads to cell death via apoptosis or necrosis.
- Severe Mitochondrial Damage: Loss of mitochondrial function and release of pro-apoptotic factors (e.g., cytochrome c).
- Severe Plasma Membrane Damage: Loss of membrane integrity leads to leakage of cellular contents.
- Lysosomal Membrane Damage: Enzymes leak out, causing digestion of cell components.
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Nuclear Changes:
- Pyknosis: Nuclear shrinkage and increased basophilia.
- Karyorrhexis: Fragmentation of the nucleus.
- Karyolysis: Dissolution of the nucleus.
- Reversible Injury: Characterized by early changes that are potentially recoverable if the stress is removed. It involves cellular swelling, fatty change, and mild structural changes.
- Irreversible Injury: Characterized by severe damage leading to cell death. It involves significant mitochondrial damage, membrane rupture, and severe nuclear changes.
Understanding these distinctions helps in diagnosing and managing cell damage in various pathological conditions.
