BIOL 4102 Midterm Study Notes

Generalized Assortment of Information for Studying for BIOL 4102 Midterm According to learning Objectives and self selected pieces of information.

What is the difference between General Pathology and Systemic Pathology?

General Pathology is the study of REACTIONS of CELLS to TISSUES and pathological stimuli

Systemic Pathology is the study of reaction and abnormalities in organs

Both are required when assessing pathology

What are the stages in the development of disease?

They are in order…

1. Etiology (Cause of disease)

2. Pathogenesis (Mechanism of disease)

3. Abnormalities in cells and tissues (be they molecular, functional or morphological)

4. Clinical Manifestations (signs and symptoms)

Cellular Responses To Stress & Noxious Stimuli Included what 4 criteria?

A. Causes of Cell Injury

B. Cell Injury and Cell Death (*Reversible and Irreversible)

C. Mechanisms of Cellular Injury and Death

D. Cellular Adaptations to Stress

What are some of the causes of Cell Injury listed from very common to very uncommon?

• Oxygen Deprivation in the form of Hypoxia and Ischemia

• Toxins (Such as drugs and other environmental agents)

• Infectious agents (Bacteria, viruses, fungi, parasites)

• Immunologic reactions (Allergic reactions and autoimmune reactions)

• Genetic abnormalities (aa substitution, protein misfolding)

• Nutritional imbalances (malnourishment vs over consumption)

• Physical agents (temperature, trauma, radiation, electrical shock)

• Aging

At what is that relationship between reversible and irreversible cell injury with morphology and function?

Reversible cell injuries tend to preserve cell function more so that irreversible cell injuries. In this similar vein, they are also more morphologically observable, requiring less tools to asses. On the contrary, Irreversible cell function can can lead more towards cell death as the morphological changes become less apparent to more apparent as the duration of the injury increases.

What are the Two Main types of Reversible Cell Injury?

1. Cellular Swelling

• Failure of ion pumps in membrane to maintain ionic and fluid balance, leading to possible lysis and endosmosis occurs resulting from cell presence in hypotonic solution

2. Fatty change (Steatosis)

• form of Hypoxic Injury, although can have various metabolic and toxic injury types

• contains lipid vacuoles in cytoplasm

• common in cells involved in lipid metabolism such as hepatocytes or myocardial cells

In the Proximal Rabbit Kidney Tubule Example, what caused the loss of microvilli and blebbing of the membrane?

Reperfusion following ischemia

What are some other morphological changes seen in cell injury?

Eosinophilia in cytoplasm which gets emphasized more in necrotic cells.

Myelin figures, which are collections of phospholipids resembling myelin sheaths that are derived from damaged cells can be found in both irreversible and reversible cell injuries.

What is Necrosis?

Necrosis is when a severe disturbance or action of a toxin causes a quick and uncontrollable cell death.

Often called “accidental cell death”

What happens during necrosis?

• Loss of membrane integrity

• Leaking of cellular contents → enzymatic digestion of organelles & cytosolic components

• Increased eosinophilia via ↓ cytoplasmic RNA

• Myelin figures

• Patterns of nuclear changes (due to breakdown of DNA & Chromatin)*

• Inflammation (at late stages)

• Cellular Swelling

What are the Three Patterns of nuclear changes that can occur during Necrosis*

Pyknosis - Nucleus shrinks and chromatin clumps, making it highly basophilic

↓

Karyorrhexis - Chromatin dissolution due to action of DNAses and RNAses = Pyknosis nucleus fragments

↓

Karyolysis - Fading of basophilia (Loss of DNA due to endonucleases)

What are the Five different patterns of tissue injury related necrosis?

• Coagulative Necrosis

• Liquefactive Necrosis

• Caseous Necrosis

• Fat Necrosis

• Fibrinoid Necrosis

What is Coagulative Necrosis?

Coagulative Necrosis is a common type of necrosis that is known for its presence of infarcts (area of ischemic death) that is present in all solid organs EXCEPT the brain.

It has architecture of dead tissue that is preserved.

Protein denaturation PREDOMINATES over heterolysis or autolysis

What is Liquefactive Necrosis?

Liquefactive Necrosis is a type of necrosis that is often seen at sites of bacterial or fungal infections that result due to an accumulation of inflammatory cells (leukocytes, among others) and enzymes that quite literally “liquefy” them.

Hypoxic Cellular Death in CNS is a good example of this

This results in the formation of abscesses which are creamy yellow pus spots where dead cells are completely digested.

Is where Heterolysis or Autolysis PREDOMINATES over protein denaturation

What is Caseous Necrosis?

Caseous Necrosis is a type of necrosis which in some ways can be thought of as an furtherance of coagulative necrosis, with the distinct trait that tissue architecture and cellular outlines are not able to be discerned.

This necrosis is characteristic for its foci of tuberculosis infection, forming a friable yellow-white “cheese-like” appearance on the surface of the lung.

Often associated with granuloma (will get into more later)

What is Fat Necrosis?

Fat Necrosis is a focal area of fat destruction seen in cases of abdominal trauma or acute pancreatitis.

It is caused by lipase activation from the pancreas, which happens when enzymes leak out of the damaged pancreatic acinar cells and ducts and begin to digest fat cells and their contents including triglycerides.

The fat combined with calcium results in the formation of white soapy deposits

What is Fibrinoid Necrosis

Fibrinoid Necrosis is a special form of necrosis that can only be seen in a light microscopy.

It may result when complex antigens and antibodies are deposited in the walls of blood vessels and in severe hypertension.

Deposited immune complex and plasma proteins that have leaked into the wall of injured vessels produces Bright Pink amorphous ring called a fibrinoid.

Often seen in cases of vasculitis and in transplanted organs undergoing rejection.

Continue with Apoptosis

Continue On Slide 18 and textbook page 23

What is Apoptosis?

Apoptosis is.

• Regulated Cell Death

• Involves Enzymatic Degradation

  • Nuclear DNA & proteins

  • Cytoplasmic proteins

• Forms cytoplasmic blebs and apoptotic bodies

• Apoptotic bodies targeted for phagocytosis

• No Inflammation

• Can coexist with necrosis

What are some important Pathological Causes of Apoptosis?

• DNA Damage

• Accumulation of misfolded proteins

• Infections, especially Viral Infections

Cell Survival and Apoptosis Pathways

What are the Two Major Mechanisms of Apoptosis

1. Mitochondrial (Intrinsic Pathway)

   • Cell survival vs. death is determined by membrane permeability of mitochondria

   • Controlled by more than 20 proteins (Bcl-2 Family)

   • Bcl-2 and Bcl-x are anti apoptopic while Bax and Bak are pro apoptotic

2. Death receptor (Extrinsic Pathway)

   • Death receptor expressed on cell surface can trigger apoptosis

   • tumor necrosis factor (TNF) receptor family

     • cytoplasmic regions contain a conserved “death domain”

Close Up On Death Receptor Pathway

In Example Checkpoint, TNFa acts as ligand for a TNF receptor similar to how FasL acts as a receptor to Fas (CD95) or Type 1 TNF receptors

Death Domain Explained

What is TP53 and why is it called the guardian of the genome?

The TP53 gene encodes p53, a crucial tumor suppressor protein often referred to as the "guardian of the genome." This designation stems from its pivotal role in preserving genomic stability by preventing the accumulation of mutations that can lead to cancer. TP53 is one of the most frequently mutated genes in human malignancies, emphasizing its importance in cell cycle regulation, DNA repair, and apoptosis.

What does FLIP do to caspase stimulation?

FLIP works as a caspase antagonist, blocking activation of downstream effects of death receptors

These are often produced by Viruses in order to keep infected cells alive.

What type of chemical is responsible for the clearance of of Apoptotic material?

the “eat me” aka, phosphatidylserine that signals phagocytic cells

Is present on outer leaflet of cell membrane

Note: dying cells also secrete soluble factors that recruit phagocytes

What are the General Principles for the Mechanisms of cell injury and cell death?

• Type, duration and severity of injury

  • may affect how cell respond to injurious stimulus

• Type, status, adaptability & genetic make up of the injured cell

  • may effect degree of cellular damage. ie think of skeletal muscle vs cardiac muscle

• Functional and biochemical abnormalities

  • may affect essential cellular components causing further injury and death

• One injurious stimulus may trigger multiple mechanisms

Explain Mitochondrial Damage and Dysfunction related cell injuries

• Mitochondria affected by Hypoxia and ischemia

  • Compensated for by TF of the hypoxia-inducible factor 1 (HIF-1) Family

  • Synthesis of proteins to help with cell survival in low oxygen

• Effect ATP Generation leading to ATP depletion, disrupting membrane transport, protein synthesis and lipogenesis

Ischemia can cause necrosis by…

Note: Injures tissues faster than hypoxia

What are the two mechanism by which a reperfusion injury can take place after an Ischemic episode

• Increased Generation of ROS due to …

  • mitochondrial damage

  • Loss of antioxidant defence mechanism

  • leukocyte infiltration

• Inflammation leading to tissue injury

  • increased influx of leukocytes and plasma proteins (chapter 2)

  • increases release of products of activated leukocytes

  • complement activation and by-products

How is Oxidative Stress related to cell Injury

Oxidative stress refers to cellular damage induced by accumulation of ROS, in the form of free radicals.

Involved in cell injuries such as:

• hypoxia

• ischemia reperfusion

• chemical and radiation

• tissue injury via inflammatory cells

• cellular aging

may cause necrosis, apoptosis, or necroptosis

What are the two major pathways of ROS production?

1. Normal Redox reaction in mitochondrial metabolism

2. Respiratory burst in phagocytic cells

Free Radicals involved in Cell Injury

What are the systems used to remove free radicals from a cell?

Superoxide dismutase in the mitochondria and cytosol

glutathione peroxidase in the mitochondria and cytosol

Catalase in peroxisomes

That are the pathological effects of ROS?

• Lipid peroxidation of membranes

  • DB are susceptible to attack by ROS leading to unstable peroxides and unstable membrane

• Protein modifications

  • promote sulfhydryl induced protein crosslinking which enhances degradation or loss of enzyme activity

  • Direct effect on polypeptide fragmentation leading to protein misfolding

• DNA Damage

  • ROS binds to thymine which targets and breaks single stranded mitochondrial and nuclear DNA

  • Implicated in apoptosis cell death

How is Chemical Injury related to Cell injury and cell death?

Directly and Indirectly

Directly due to chemicals binding to critical molecular components, such as the cases of mercury and anticancer drugs.

Indirectly due to biologically inactive chemicals being converted to reactive toxic metabolites and the function of cytochrome p-450 mixed oxidases

metabolites might cause membrane damage and cell injury by bind to proteins and lipids they shouldn’t

How does ER Stress relate to cell injury and cell death?

• Accumulation of misfolded proteins in cells leaking to ER Stress

• This causes an increased production of misfolded proteins

  • such happens in aging and genetic mutations

• Reduced ability to eliminate misfolded proteins

• Induce “unfolded protein response” as a protective mechanism, causing an increased production of chaperones and decreases protein synthesis

• Apoptosis by mitochondrial (Intrinsic) pathway activated when cellular adaptive response in inadequate

  • activation of proapoptotic sensors via the BH-3 family

  • direct activation of caspases

  • observable in neurodegenerative disorders.

How is DNA Damage related to Cell injury and death?

Mainly being caused by Radiation, chemotherapy, ROS and mutations

Prevents cells from becoming a tumor if the p53 gene is able to act functionally, as MDM2 will targets p53 for destruction

Repair via p53 also possible, as p53 arrests the cell cycle at G1 to allow for repair

Mitochondrial Damage and Dysfunction

Defects in Membrane Permeability

Cellular Adaptations to Stress (reversible) can cause changes to cell…

• Size

• Number

• Phenotype

• Metabolic Activity

• Function

• Environmental Changes

What are the FOUR ways cells may respond to stress?

• Hypertrophy

• Hyperplasia

• Atrophy

• Metaplasia

What is Hypertrophy

Increase in size of cells, leading to an increased organ size

Caused by an increase in structural proteins and organelles

Occurs when cells are UNABLE to divide

Physiological: Uterus growth during pregnancy

Pathological: Cardiac Hypertrophy due to hypertension or aortic valve disease

Cardiac Example Hypertrophy

protein and signalling pathway hypertrophy explanation

What is Hyperplasia

An increase in the number of cells leading to an increased organ size

Occurs due to proliferation and differentiation of cells

Two Physiological Forms:

• Hormonal Hyperplasia

  • Hormones increase functional capacity when needed

  • increased in glandular epithelium

  • ie/ breast tissue during puberty

• Compensatory Hyperplasia

  • Increase in tissue mass after damage or partial resection

  • ie/ Liver resection

• Pathological Hyperplasia

  • due to excess hormones or growth factors

  • normal regulatory process

  • risk for developing cancers increases

  • ie/ endometrial hyperplasia and benign prostatic hyperplasia (BPH)

What is Benign Prostatic Hyperplasia?

A form of nodular pathological hyperplasia that occurs in males over 50 years old.

Etiology & Pathogenesis:

• Benign proliferation of stromal and glandular elements

• Central role of dihydrotestosterone (DHT) - androgen derived testosterone

Clinical Features:

• Nocturia

• Poor Urinary Stream

• Acute Urinary Retention

Treatments:

• α1 adrenergic receptor blockers

• inhibitors of 5-α reductase

• transurethral resection of prostate (TURP) and surgical alternatives

How are Stromal cells and Epithelial cells interacting with testosterone that leads to Benign Prostatic Hyperplasia?

What is Atrophy?

• a decrease in the size of cells, leading ot a reduction in organ size

• results in decreased protein synthesis with decreased metabolic activity

• increased protein degradation in cells via Ubiquitin-Proteasome pathway

Causes:

• decreased workload, loss of innervation, decreased blood supply, inadequate nutrition, loss of endocrine stimulation, aging

Physiological Atrophy

• atrophy of endometrium, breast and vaginal epithelium after menopause

Pathological Atrophy

• decreased workload - disuse atrophy

• damage to nerve supplying skeletal muscle - denervation atrophy

• Diminished blood supply, ie/ cerebral atrophy

• Inadequate nutrition eg. Marasmus, Kwashiorkor, Cachexia

Similarities and differences between Marasmus, kwashiorkor and cachexia

First important to understand what PEM is: Protein Energy Malnutrition

Marasmus

• Insufficient calories overall (wt. < 60% normal)

• Somatic protein compartment severely depleted

• Pronounced muscle wasting

• loss of subcutaneous fat (via cortisol-induced lipolysis)

kwashiorkor

• protein deprivation relatively greater than loss in calories

• visceral protein compartment (most likely liver) more severely depleted

• generalized edema masks a decrease in body weight

• enlarged fatty liver

Cachexia is PEM in advanced cancer or aids

What is Metaplasia?

Reversible change from one adult cell (epithelial or mesenchymal) to another cell type.

• Occurs due to reprogramming of stem cells, phenotypic change of differentiated cells by cytokines and growth factors

• May initiate malignant transformation if signals for metaplastic changes persist

• Most common in columnar to squamous epithelium

example. Epithelial metaplasia in respiratory tract of habitual smoker

What are the FOUR main pathways that lead to abnormal intracellular accumulations?

• Abnormal Metabolism ex. Fatty liver (steatosis)

• Defect in protein folding/transport/secretion ex. alpha1-antitrypsin

• Inherited enzyme deficiencies ex. “storage diseases”

• Ingestion of indigestible materials ex/ accumulation of carbon/silica particles

What are the FOUR main types of intracellular accumulation?

• Lipid

• Protein

• Glycogen

• Pigment

Examples of Lipid Accumulation and how its related to Intracellular Accumulation?

• Examples include steatosis and Cholesterol and cholesteryl ester accumulation

• Steatosis is accumulation of triglycerides in parenchymal cells that can happen at any stage be it uptake, catabolism or secretion.

  Cholesterol & cholesteryl ester can be atherosclerosis where foam cells from macrophages and smooth muscle cells filled with cholesterol form

• May also be xanthomas

  • tumorous masses of subepithelial connective tissue of skin and tendons

Examples of Protein Accumulation

Caused by excess production but not morphologically visible

Examples

• Alpha 1 antitrypsin

  • secretory protein that inhibits proteases ie/ neutrophil elastase

  • Autosomal recessive disorder results in mutant proteins misfolding and polymerizing causing impairment in migration from the ER to the golgi

  • this disease causes low circulating levels of this protein

  • Mutation overall leads to pulmonary emphysema leading to lack of destructive proteases

  • also has hepatocellular accumulation of misfolded a1AT protein, which leads to nonfunctional proteins stores in hepatocytes that can cause apoptosis

  • deficiency is commonly diagnosed in infants

• Reabsorption of protein droplets in nephrotic syndrome

• neurofibrillary tangles in Alzheimer’s disease

How is Alpha-1 Antitrypsin Deficiency characterized in the Liver?

Globular Inclusions in Hepatocytes that ate PAS positive and diastase resistant

Periportal hepatocytes affected early and central lobular later as severity continues

Other features include hepatitis, fibrosis, to full blown cirrhosis

NOTE: MAKE NOTES ABOUT ASSIGNMENT 1 PRESENTATION DISEASES AS THESE MIGHT SHOW UP ON THE MIDTERM

What is Glycogen Accumulation

Excess glycogen deposit associated with abnormal metabolism of glucose and glycogen

Common in Diabetes mellitus when its poorly controlled, resulting in abnormal glucose metabolism and accumulation in the renal tubular epithelia, cardiac myocytes and beta cells of the islets of langerhans

What is Pigment Accumulation and what are the two types?

Exogenous:

Carbon and coal dust causing anthracosis

Endogenous:

Melanin causing Brown black pigmentation of skin

Freckles for instance

help protect skin against harmful UV radiation

Other examples could include Lipofuscin and Hemosiderin

What is Lipofuscin

A pigment that is found as a marker of past free radical injury and lipid peroxidation

called a wear and tear pigment

In liver and brain

What is Hemosiderin

Hb derived, golden yellow to brown pigment

Ferritin micelles form hemosiderin granules

Accumulates due to local excess (such as a hemorrhage)

Or

Systemic excess (Such as hemolytic anemia, hereditary hemochromatosis)

What Pathologic Calcification

• Common process in disease states

• Abnormal depositions of calcium salts

• can be two forms

In DEAD and DYING CELLS = Dystrophic

In normal tissues = Metastatic

Dystrophic Calcification

• Normal calcium metabolism but it deposits in injured or dead tissue (e.g. areas of necrosis)

  • Arterial lesions of atherosclerosis

• May cause organ dysfunction

  • Important cause of aortic stenosis in the elderly

Metastatic Calcification

• In normal tissue during hypercalcemia

  • Affects the tissues of the vasculature, kidneys, lungs

  and gastric mucosa

  • Causes:

  • Increased PTH secretion (hyperparathyroidism, PTH

    secreting malignancy)

  • Bone destruction (tumors in bone, Paget disease)

  • Vit D related disorders (vit D intoxication, sarcoidosis)

  • Renal failure

    • Phosphate retention = secondary hyperparathyroidism

Paget Disease

Cellular Aging

Acute Vs Chronic Inflammation

Disorders Causes by Inflammatory Reactions

What are the cardinal signs of inflammation?

• Heat

• Redness

• Swelling

• Pain

• Loss of function

What are some of the causes of inflammation?

• Infection

• Cell Injury and tissue necrosis

  • Ischemia, physical and chemical injury

• Foreign bodies

  • dirt, sutures, crystal deposits, splinters

• Immune reactions

  • hypersensitivity reaction against

    • self tissues (AI diseases) or

    • Environmental substances (eg. Allergies)

How are microbes and damaged cells recognized?

• Pattern Recognition Receptors

  • Recognize “danger signals” from many microbes or injured cells

• 2 Important Families

  • Toll-like Receptors (TLRs)

  • Inflammasome

TLR Recognition of microbes and damaged cells

Inflammasome Recognition of microbes and damaged cells

are cytoplasmic and can recognize exogenous antigens and intracellular molecules

Main Features, Steps and Outcomes of Acute Inflammation

Main features:

• vascular changes

• cellular response

Steps:

• Recognition of injurious agent

• Recruitment of leukocytes

• Removal of injurious agent

• Regulation of response

• Resolution (repair)

Outcome:

• Elimination of injurious stimuli followed by tissue repair

• Persistent Injury leads to chronic inflam

Vascular Changes include…

• Vascular flow and diameter

  • Stasis

    • Vascular congestion & erythema

    • Leukocyte margination & recruitment

• Increased vascular permeability

• Lymphatic vessels & lymph node responses

What chemical mediators cause vasodilation in arterioles and what clinical signs show up as a consequence?

• Histamine

• NO

Increased blood flow causes Redness (erythema) & warmth

Vascular Permeability is caused by what THREE things

1. Retraction of Endothelial Cells

   a. Increase Interendothelial spaces

   b. Due to Inflam Mediators (eg. Histamine, bradykinin, leukotrienes) - rapid, transient

   c. Cytokines (TNF, IL-1) - slower, prolonged response (Hrs)

2. Direct endothelial cell injury

   a. neutrophils’ ROS Production

   b. Burns

3. Increased transcytosis of proteins thru EC

   a. Increased venular permeability

Increased Vascular Permeability causes what?

Edema, which is an increase in interstitial fluid

• Protein-rich fluid (exudate) into extravascular tissues

• Pus = purulent exudate

  • Inflammatory exudate with leukocytes, microbes and dead cells

Effects of Vascular Changes could include…

• Changes in appearance of stasis (due to viscosity Increase and Decrease circulation)

• Vascular congestion

• Increased leukocyte accumulation along vascular endothelium margination

Lymphatic Vessel Responses In Acute Inflammation include…

• Increased Transport

• Lymphangitis

  • Secondary Inflam of lymph vessels

  • Characterized by red streaks in the skin

• Lymphadenitis

  • Inflammation of draining lymph nodes

What are the two components of cellular response?

• Leukocyte Recruitment

• Leukocyte Activation

What are the four steps of Leukocyte Recruitment?

1. Margination & Rolling

2. Firm Adhesion

3. Transmigration

4. Chemotaxis

1. Margination and Rolling

2. Firm Adhesion

3. Transmigration (emigration)

4. Chemotaxis of Leukocytes

Leukocyte Activation

• Recognition through receptors

• Results in an enhanced

  • 1. Phagocytosis

  • 2. Killing and degradation of phagocytosed microbes

    • secretion of microbicidal agents from granules

    • ROS

    • Lysosomal enzymes

    • NETs

  • 3. Inflammatory mediator release = amplify inflammatory response

Intracellular Effects

What are the General Properties and Chemical Classifications of Inflammatory Mediators?

The general properties are sourced as…

• Cell-derived

• Plasma-derived

Released/Activation Induced by Injury/Inflammation

Short Lived

Stimulate Other mediators

Chemical Classes

• Vasoactive amines

• Lipid products (arachidonic acid metabolites)

• Cytokines

• Products of complement activation

Vasoactive amines

Arachidonic Acid Metabolites

Arachidonic Acid

Phospholipase A2 Pathways

Principal Actions of Arachidonic Acid Metabolites in Inflammation

Prostanoid biosynthesis ***

Leukotriene/Lipoxin Biosynthesis ***

Corticosteroids

Cytokines and Chemokines

Cytokines and Inflammation Systemic Protective Effects and Pathological Effects