Human Pathology HLSC 4P95

What are the Greek Origins of Pathology?

the study of disease (pathos = suffering, logos = study)

Who is the father of modern pathology?

Rudolph Virchow → discovered cell theory

Cellular pathology

All diseases originate at the cellular level

What is Pathology?

The study of the structural, biochemical, and functional changes in cells, tissues and organs that underlie disease

What does Pathology attempt to explain?

the whys of the signs & symptoms manifested by patients while providing a rational basis for clinical care & therapy

What is General Pathology?

Common reaction of cells and tissue to injury (acute inflammation in response to an infection)

What is Systemic Pathology?

Examines alterations and underlying mechanisms in origin-specific diseases (ischemic heart disease)

What are the 4 aspects of disease?

1. Etiology 2. Pathogenesis 3.Morphological Changes 4. Clinical Manifestations

What is Etiology?

the cause of disease (genetic / acquired)

What is pathogenesis?

biochemical and molecular mechanisms of a disease’s development

Define Morphological Changes

Structural alterations induced in the cells, tissues and organs of the body

Define Clinical Manifestations

Functional consequences which led to clinical symptoms and signs

All diseases are related to what?

disturbances in cell function (in organelles)

What are the Housekeeping functions of cells

Protection from the environment

Nutrient acquisition

Communication

Movement

Renewal of senescent molecules

Molecular catabolism

Energy generation

Cellular communication: Autocrine

Secretion from the cell attaches to own surface receptors (ex: T-cell activation)

Cellular communication: Paracrine

Closely adjacent cells act on one another (ex: biogenic amines)

Cellular communication: Endocrine

hormones are secreted reach target via blood stream (ex: insulin)

Homeostasis

The maintenance of a “steady state” by means of physiological feedback control mechanisms

(Greek, meaning “standing” or “staying similar”)

What alters Homeostasis and what does that cause?

External stimuli can alter homeostasis

Imbalance in homeostasis can cause = Cell injury (reversible or irreversible)

Reversible Cell Injury: Cellular Swelling

Cell response that remains within the range of homeostasis due to an acute exposure to stimuli

What are examples of Hydropic Changes

A. Normal microvilli

B. Swollen microvilli

C. Invagination of cell membrane

D. Swollen mitochondria; dilation of rough endoplasmic reticulum

E. Loss of cell-to-cell contact

What happens if cell injury persists?

leads to irreversible cell injury

Irreversible Cell Injury results from what?

from chronic exposure to insults that the cell cannot recover from

Irreversible Cell Injury is characterized by what?

by nuclear changes or loss of cell integrity (A. Pyknosis B. Karyorrhexis C. Karyolysis )

What is Pyknosis

the condensation of chromatin

What is Karyorrhexis

the fragmentation into smaller particles "nuclear dust"

What is Karyolysis

dissolution of nuclear structure and lysis of chromatin by enzymes (DNase and RNase)

What are some causes of cell injury?

1. Hypoxia: reduced availability of O2 2. Anoxia: complete lack of O2 3. Toxins 4. Microbes 5. Mediators of inflammation 6. Immune reactions 7. Genetic and metabolic disorders

What are some causes of Hypoxia/Anoxia

1. Airway obstruction (choking)

2. Impeded O2 exchange at the lungs (pneumonia)

3. Inadequate O2 transport in blood (Low RBC count, anemia)

4. Blockade of cellular respiration and oxidative phosphorylation (cyanide poisoning)

Definition of Hypoxia/Anoxia: post perfusion injury

Over supply of oxygen once the obstruction is removed damages local cells as a result of oxygen radicals or reactive oxygen species (ROS)

What are the oxygen species that cause post perfusion injury

Hydrogen peroxide (H2 O2 )

Superoxide (O2-)

Hydroxyl radicals (OH•)

What are the types of toxic cell injuries

direct and indirect toxins

Direct toxins of toxic cell injury

heavy metals (i.e., mercury) leads to the disruption of S-S bonds

• alters protein structure, can lead to inactivation of cytoplasmic enzymes

Indirect toxins of toxic cell injury

Must be metabolically activated carbon tetrachloride (component of metal polish) is not toxic itself

• When consumed, metabolized to carbon trichloride (a free radical) which damages cells membranes

Microbial Pathogens: Bacteria produce toxins

Inhibit cellular functions such as protein synthesis or respiration

• E.g., exotoxins causing food poisoning

Microbial Pathogens: Viruses invade cells and “kill from within”

Disrupt nuclear or plasma membrane

• ultimately leads to cell death either from viral expulsion or immune system

What are cell adaptations?

They are functional & structural responses to changes in physiological states

What causes cell adaptations?

Result from prolonged exposure to adverse or exaggerated normal stimuli

Cell Adaptations: Atrophy

Decrease in size of cell, tissue, organ, or entire body

• Physiological & predictable (age-induced)

Causes of Pathological Atrophy

• Lack of nutrition

• Chronic ischemia

• Denervation

• Inactivity

Cell Adaptations: Hypertrophy

Increase in size of cell, tissue, organ, or entire body

• hypertrophy of the heart during hypertension

• hypertrophy of skeletal muscle in body builders

• hypertrophy is often combined with hyperplasia

Cell Adaptations: Hyperplasia

Increased number of cells found within a t issue or organ

• Endometrial hyperplasia caused by estrogen

• Benign prostatic hyperplasia in elderly men

• Callus on hands or on heels

Cell Adaptation: Metaplasia

Characterized by the change of one cell type into another

• Prolonged cigarette smoke irritation results in normal ciliated columnar bronchial epithelial cells to turn into squamous epithelium

Cell death occurs through 2 mechanisms, what are they?

1. Necrosis

2. Apoptosis

Necrosis

Exogenously induced (come in contact with some form of stimuli)

• Localized death of tissue in living organisms

Apoptosis

Endogenously induced

• Programmed cell death of single cells within an organism

• Active form of cell death mediated by intracellular programming

• Energy-dependent process that activates so-called “suicide” genes and synthesis of proteolytic enzymes

Coagulative Necrosis

• Most common form of necrosis (often caused by anoxia)

• Characterized by rapid inactivation of cytoplasmic hydrolytic enzymes

• Prevents the lysis of tissue, which retain their original form

• Typically involves solid internal organs, such as the heart, liver and kidneys

Liquefactive Necrosis

• Dissolution of tissues (Become soft and diffluent)

• Most common in the brain, where cells lose their contours and are “liquefied” (Semifluid mush)

• Typically due to brain infarcts

• Consequence of leukocytes releasing lytic enzymes which turn solid tissue into liquid pus

Caseous Necrosis

• Special form of coagulative necrosis with limited liquefaction

• Center of a tuberculosis granuloma becomes necrotic (mycobacteria)

• Tissue is yellow-white and appears as a “cheesy” consistency

• Common in fungal infections

Enzymatic Fat Necrosis

• Special form of liquefactive necrosis caused by the action of lipolytic enzymes

• Limited to fat tissue, usually around the pancreas (Pancreatic enzymes degrade adjacent fat t issue into glycerol and free fatty acids (FFA))

• FFA bind calcium forming calcium soaps (Liquified necrosis with calcium soaps)

Dystrophic Calcification

• high accumulation of free fatty acids

• Secondary changes

• Necrotic tissue attract calcium salts in the absence of systemic mineral imbalances

What is inflammation?

a non-specific, predictable response that can be acute or chronic

Cardinal signs of inflammation

1. Calor – heat

2. Rubor – redness

3. Tumour – swelling

4. Dolar – pain

5. Functio laesa – loss of function

Pathogenesis of Inflammation Involves

1. Circulatory changes

2. Vascular changes

3. Mediators of inflammation

4. Induced cellular response

Circulatory Changes: 1st response to injury involves what?

Transient vasoconstriction of arteriolar smooth muscles followed by vasodilation, Active hyperemia, Slowdown of circulation

formation of rouleaux

1. Margination of WBC

2. Adhesion of platelets

3. Pavementing of WBCs

Vascular Changes

1. Increased hydrostatic pressure

2. Slowing down of the circulation

3. Adhesion of leukocytes and platelets to endothelial cells

4. Release of soluble mediators of inflammation

Mediators of Inflammation (2 classes)

• Cell-derived (stored) • Plasma-derived (require activation)

Arachidonic Acid Derivatives

1. Phospholipases break down membrane phospholipids to arachidonic acid (AA)

2. Arachidonic acid feeds into either the cyclooxygenase, lipoxygenase or cytochrome P450 pathway

3. Cell type, type of stimuli and several other factors determine how AA is metabolized

Bradykinin

Plasma protein with similar action to histamine but slower acting Activation pathway: Hageman factor > kallikrein > kininogen > bradykinin Induces pain (dolar) Sensitization of nerve endings Hageman factor also acts on clotting, fibrolytic systems of the blood

Histamine

Stored in cytoplasmic granules of platelets, basophils, eosinophils, and mast cells

4 different receptors

Complement System Outcomes

1. Opsonization (C3b): facilitated phagocytosis of bacteria 2. Anaphylaxis (C3a, C5a): act on endothelial cells and cause histamine release – increase vascular permeability 3. Chemotaxis: migration of leukocytes 4. Cell lysis (C5-C9): formation of the membrane attack complex

Cellular Responses

Transudate, Exudate, Emigration of Leukocytes

Emigration of leukocytes

A. Adhesion of PMNs to endothelial cells (margination)

B. Insertion of cytoplasmic pseudopods between junctions of endothelial cells

C. Passage through the basement membrane (diapedesis)

D. Amoeboid movement from the vessel to the site of inflammation (chemotaxis)

E. Phagocytosis (or other cellular functions)

Cells of Inflammation

Granulocytes (Neutrophils, Eosinophils, Basophils, Mast Cells)

Macrophages

Adaptive lymphocytes

Innate lymphocytes

Platelets

Classification of Inflammation

1.Duration: acute of chronic 2.Etiology: infectious, chemical, physical, foreign bodies, or immune causes 3.Location: localized or widespread (systemic) 4.Pathological features: morphology

Morphology of Inflammation

• serous exudate = clear fluid

• fibrinous = large plasma proteins

• purulent = pus forming bacteria, forms abscess

• ulcerative = defect involving the epithelium

• pseudomembranous = Combination of ulcerative inflammation and fibrinopurulent exudation

• granulomatous = cell-mediated hypersensitivity reaction

Purulent Inflammation

Abscess: accumulation of pus in a newly formed t issue space

Sinus: cavity at the previous site of an abscess which drains to the surface or the tissue

Fistula: channel formed between two preexisting cavities, hollow organs, preexisting cavity and the surface of the body

Caseous Necrosis

Special form of coagulative necrosis with limited liquefaction Center of a tuberculosis granuloma becomes necrotic Tissue is yellow-white and appears as a “cheesy” consistency Also common in fungal infections (histoplasmosis)

Healing and Repair

Continuously dividing cells (stem cells) • Labile cells ex., epithelial cells that make up the skin and gastrointestinal tract

Quiescent facultative mitotic cells (stable cells) • Adult stem cells, muscle cells (satellite cells)

Nondividing postmitotic cells (permanent cells) • Neurons, myocytes, some kidney cells and adipocytes

Cells Participating in Wound Healing

• Polymorphonuclear (PMN) leukocytes

• Macrophages

Wound Healing — First intention (sharp, sterile, surgical wounds)

A. Incision site

B. Formation of scab & scavenger action of PMN leukocytes

C. Formation of granulation tissue

D. Scarring

Wound Healing — Secondary intention (large defects, infected wounds)

• Myofibroblasts cannot close the wound and infection can be present • Granulation tissue exposed • Prolonged healing • Scaring is more prominent

Determinants of Wound Healing

1. Site of wound (tissue type)

2. Size of the wound

3. Mechanical factors (margins, movement)

4. Infection

5. Circulatory status (ischemia = poor healing)

6. Nutritional and metabolic factors

7. Age

Complications of Wound Healing

• Deficient scar formation

• Excessive scar formation (keloid)

What are the 3 layers of host defense

1. physical barrier

2. innate immune response

3. adaptive immune response

What does the physical barrier of host defense consist of

Mechanical barriers; epidermis, ciliated cells

Chemical barriers; protective proteins and chemical secretions

• Properdin in plasma activates complement system

• Lysozymes in body fluids (saliva, tears, respiratory tract), kill bacteria

What does the innate immune response of host defense consist of

Phagocytic cells (neutrophils, macrophages, dendritic cells, natural killer cells)

What does the adaptive immune response of host defense consist of

Lymphocytes (T and B cells)

Cells of the immune system originate from where?

Originate from hematopoietic stem cells in the bone marrow

What are the 2 lineages of stem cells from bone marrow

1. Lymphocytes: lymphoid cells (primary cells)

2. Nonlymphoid cells (myeloid): PMNs, eosinophils, basophils, macrophages, megakaryocytes

Describe Innate Immunity

• Inherited and operational at birth

• Fast to act and nonspecific → Recognizes conserved pathogen patterns (PAMPs)

• Response to repeat infection remains relatively the same → Trained immunity (epigenetic changes)

What 3 mechanisms does Innate Immunity use to protect the body?

1. Initiating inflammation 2. Combating infections (bacterial, fungal etc.) 3. General response to damaged cells

What are some examples of innate immunity cells

Neutrophils Basophils Eosinophils Mast cells Macrophages Natural killer cells Dendritic cells

Describe Adaptive Immunity

AKA acquired immunity

• Ability to distinguish “self” from “non self”

• Specific response elicited by antigens requires time (5-7 days) → “Lock and key” receptor-antigen interactions

• Immunological memory → rapid and effective response upon subsequent exposure to the same pathogen

• Mediated by T and B cells; antigen specific receptors and antibodies

Where do T cells mature?

thymus (thymus = T-cells)

Where do B-cells mature?

Bone marrow (B cells = Bone marrow)

What are the sites of lymphoid maturation?

primary lymphoid organs

Secondary lymphoid tissue =

site of lymphoid cell activation (spleen, lymph nodes, peyers patches, adenoids, tonsils)

Cluster Differentiation (CD) antigens

• T and B cells cannot be distinguished based on morphological differences

• CD antigens – unique markers on the cell surface

• Expressed during lymphocyte development and when mature

• Markers specific to T cells (CD3, CD4, CD8) and B cells (CD19)

• Characterized via fluorescence activated cell sorting

T-Lymphocytes

T helper cells, Cytotoxic T cells, Healthy CD4

Natural Killer (NK) Cells

• Similar surface markers to T cells but do not have T cell receptor gene rearrangement

• Mediate innate immune functions and are not involved in T/B cell reactions

• Similar function to T cells – react to virus infected cells and kill tumor cells/transplanted cells

• Contain lytic granules to destroy foreign substances

B-Lymphocytes

• Essential for the production of antibodies

• Activated B-cells differentiate into plasma cells

• Plasma cells have increased ribosomes and RER for protein production/release

Antibodies

• Serum proteins secreted by plasma cells

• Comprised of 4 polypeptide chains → 2 light chains and 2 heavy chains

• Fab (variable) region is antigen specific

• Fc (constant) region

5 classes of immunoglobulins

IgM, IgG, IgA, IgE, IgD

What are the functions of Antibodies

1. B cell receptors

2. Opsonin – increase phagocytosis

3. Neutralizes antigen by binding

4. Directs immune cell effector function

5. Activates mast cells during allergy

6. Activates complement

Major Histocompatibility Complexes (MHC) — What are the 2 groups?

1. MHC class I: all nucleated cells, receptors for CD8 activation – presents intracellular antigens (viruses, cancer).

2. MHC class II: present on specialized cells to bind to CD4, links macrophages to helper T cells

What are Hypersensitivity Reactions?

Abnormal immune response to exogenous antigens or endogenous auto-antigens

What are the types of Hypersensitivity Reactions

Type I: Immediate anaphylactic or atopic (allergies)

Type II: Cytotoxic antibody mediated

Type III: Immune complex mediated

Type IV: Cell mediated, delayed type

What is the 2 step process of Type I Hypersensitivity

1. Primary exposure (sensitization): primes the immune response to produce IgE antibodies that bind to mast cells

2. Secondary (subsequent exposure): Results in mast cell activation

• Immediate response i.e., mast cell degranulation (histamine)

• Late phase (6-9 hours) cytokines, arachidonic acid (leukotrienes, prostaglandins