PATHOLOGY

• pathos – suffering, logos- study

• study of the structural, biochemical, and functional
changes in cells, tissues, and organs that underlie
disease
• Rudolf Virchow (1821 - 1902)
• father of modern pathology
• proposed that injury to the smallest living unit of the
body, the cell, is the basis of all disease
BRANCHES OF PATHOLOGY
• General pathology- concern with the basic reaction of cells and
tissues to abnormal stimuli that underlie the disease

• Systemic (organ and organ system) pathology- examines the specific

responses of specialized organs to a defined stimuli
 INTRODUCTION TO PATHOLOGY
Tuberculosis
Four aspects of a disease
process that form the core of
pathology

• Etiology : cause
• Pathogenesis : mechanism
• Morphologic changes : structural alterations
• Clinical manifestations:
functional consequences

Normal Lung Tuberculosis

• Etiology: can be genetic or acquired
but most commonly multifactorial Tuberculosis
• Pathogenesis: sequence of events that
follow after injury
• Morphologic changes: remains as a
diagnostic cornerstone
• Clinical manifestation: end result

Normal Lung Tuberculosis

CLINICAL MANIFESTATION
Manifestation
• Observable or measurable characteristics associated with specific type of
pathology (ex: signs, symptoms, laboratory/radiograpic tests)

Sign
• Objective observation that can be seen or measured (high blood pressure,
fever)

Symptom
• Subjective report that can be perceived only by the person affected
(headache, nausea)
DEFINITION OF TERMS
Disease
• Specific set of signs and symptoms seen together frequently and become the
basis for diagnosis

Disorder
• Disruption of the disease to the normal or regular functions in the body

Syndrome
• Disease or disorder that has more than one identifying feature or symptoms
The cell
• Fundamental, functional unit of life that makes up all
living organisms and the tissues of the body
• Rudolf Virchow (1821 - 1902)
• father of modern pathology
• proposed that injury to the smallest living unit
of the body, the cell, is the basis of all disease
GENOME
• Human genome contain roughly 3.2 billion DNA base pairs,
only 1.5% (20,000) of which code for proteins (coding genes),
remaining are non-coding genes
• This coding genome is similar across species, and the
diversity lies in the non-coding genome
• As the complexity of organism increases so does the
proportion of non-coding genome
GENE VS GENOME
EXONS: EXPRESSED, CODING REGIONS
INTRONS: INTERRUPTED, NON-CODING REGIONS
POLYMORPHISM/GENETIC
VARIATIONS
🠶 ANY TWO INDIVIDUALS – 99.5%
🠶 HUMAN AND CHIMPS – 99%
🠶 HUMAN AND CAT – 90%
🠶 HUMAN AND CHICKEN – 60%

🠶 VARIATIONS IN GENOMES ARE DUE TO

🠶 SNP – SINGLE NUCLEOTIDE POLYMORPHISM

🠶 CNV – COPY NUMBER VARIATION
Epigenetics
• Phenomenon in which genetically identical cells or organisms
express their genomes differently causing phenotypic differences

• Heritable changes in gene expression that are not cause by

alteration in DNA sequence
Black
Brown
Skin cells/tissues Pale
Fair
CELLULAR HOUSEKEEPING
A cell can survive only if the following house keeping
functions are performed on a regular basis

• protection from the environment,

• nutrient acquisition,
• communication,
• movement,
• renewal of senescent molecules,
• metabolism
• energy generation
1. PLASMA MEMBRANE
• Protection and nutrient acquisition
• Bilayers of amphipathic phospholipid
• Hydrophobic head
• Hydrophilic tails
• Phosphatidylinositol- inner membrane leaflets
• Phosphatidylserine- negative charge, “eat me” signal when extracellular
• Glycolipids and sphingomyelin- extracellular, negative charge
• Inflammation recruitment
• Sperm-egg interaction
• Proteins and Glycoproteins- transport, receptor
1. Plasma membrane
Functions of plasma membrane

(1) ion and metabolite transport

(2) fluid-phase and receptor mediated uptake of
macromolecules, and
(3) cell-ligand, cell-matrix, and cell-cell interactions
 Passive and Active Transport

Oxygen
Carbondioxide
Steroid based –
estradiol, Vit D

Water
Ethanol
Urea

transferrin and
low-density
lipoprotein
(LDL)
UPTAKE OF MACROMOLECULES
• Exocytosis: large molecule exported out of cell
• Transcytosis: movement of endocytosed vesicle between the apical
and basolater compartments
• Endocytosis: uptake of fluid or large molecules
• 1. Caveolea-mediated: use of caveolin for smaller molecules (vitamin A)
: potocytosis- cellular sipping
• 2. Receptor mediated: use of clarithrin-mediated pits for larger molecules (LDL, iron)
: pinocytosis- cellular drinking
2. Cytoskeleton
Roles:
- Ability of cells to adapt to a
particular shape
- Maintain polarity
- Organize relationship of
intracellular organelles
- Cellular movement
2. Cytoskeleton
3 MAJOR CLASSES
• ACTIN MICROFILAMENTS
• Most abundant
• Maintains shape and
movement
• INTERMEDIATE FILAMENTS
• Rope-like
• Use for tensile strength,
bear mechanical stress
• Major protein in hair and
skin
• MICROTUBULES
• Moves vesicles, organelles
or other molecules
• Motile cilia or flagella
• microvilli
Intermediate filaments
• Laminin- nuclear lamina of cells
• Vimentin- mesenchymal cells (fibroblasts and endothelium)
• Desmin- muscle cells
• Neurofilaments- axons of neurons
• Glial Fibrillary Acidic Proteins- glial cells (astrocytes, microglia, oligodendrocytes)
• Cytokeratins: Epithelial cells
CK immunostain DESMIN immunostain
CELL TO CELL INTERACTION
• OCCLUDING (TIGHT) JUNCTION
• Seal adjacent cells, continuous barrier
• ANCHORING JUNCTIONS
(DESMOSOMES)
• Attach cells to another cell
• Attachment between cell and cell matrix
• Spot desmosome or macula densa- cell to cell
• Hemidesmosome- cell to ECM/basement
membrane
• Belt desmosome- cell to cell
• COMMUNICATING (GAP) JUNCTIONS
• Passage of chemical or electrical signals
• Pores: CONNEXONS
3. ENDOPLASMIC RETICULUM
• site for synthesis of all the transmembrane proteins and lipids
for plasma membrane and cellular organelles

• initial site for the synthesis of all molecules destined for export
out of the cell
4. GOLGI APPARATUS
• Prominent in goblet cells,
bronchial epithelium,
plasma cells
5. LYSOSOMES AND PROTEOSOMES
LYSOSOMES
• 40 different acid hydrolases
• Proteases, nucleases, lipases, glycosidases,
phosphatases, sulfatases

PROTEOSOMES
• Digest proteins tagged with ubiquitin
5. LYSOSOMES AND PROTEOSOMES
 PROTEASOMES

•Proteasomes play an important role in degrading cytosolic proteins these

include denatured or misfolded proteins any other macromolecule whose
lifespan needs to be regulated (e.g., transcription factors)

•Proteasomes digest proteins into small (6 to 12 amino acids) fragments

that can subsequently be degraded to their constituent amino acids and
recycled
6. MITOCHONDRIA
• Contains their own DNA which is maternally inherited
• Mitochondrial disordered are X-liked or maternally inherited
• Inner membrane- folded into cristae, bulk of the enzymes
• Intermediate space- site of ATP synthesis
• Outer membrane- studded with porins
• Thermogenin: inner membrane protein use to generate heat
• Has a role in cell death either necrosis or apoptosis
6. MITOCHONDRIA
CELLULAR ACTIVATION
1. Damage to neighboring cells and pathogens- danger signals
2. Contact with neighboring cells- gap junction signaling
3. Contact wit ECMs- mediated through integrins
4. Secreted molecules- cytokines, growth factors and
hormones
Mechanism chemically-mediated cell
to cell communication
GROWTH FACTORS
• role of growth factors is to stimulate the activity of genes that are required
for cell growth and cell division
• Hepatocyte growth factor- promotes differentiation and migration
so called “scatter factor”
• Vascular endothelial growth factor
• VEGF-A: major angiogenic factor
• VEGF-B: embryonic vessel development
• VEGF-C and VEGF-D: angiogenesis and lymphatic development
• Hypoxia- inducer/trigger
• Transforming growth factor-B
• Scar formation, fibrosis, anti-inflammatory
EXTRACELLULAR MATRIX
• Network of interstitial proteins that constitute a significant proportions of any tissue
• Functions:
• Mechanical support
• Control of cell proliferation
• Scaffolding for tissue renewal
• Establishment of tissue microenvironments
• Two forms
• Interstitial matrix- synthesize by mesenchymal cells (fibroblasts)
• Basement membrane- synthesized by overlying epithelium
COMPONENTS OF ECM
THREE GROUPS OF PROTEINS
1. Fibrous structural proteins- collagen, elastin
2. Water-hydrated gels- proteoglycans and hyaluronan
• Resistance to compressive forces
• Lubrication
• More abundant in joints, intervertebral disc
3. Adhesive glycoproteins
• Fibronectin- major component of interstitial matrix
• Laminin- major component of basement membrane
• Integrins- adhesion receptors
Types of Collagen
CELL CYCLE
• Maintain cell population
• Key element in cell proliferation
• Senecence: non-replicative state
• CDK inhibitors: cell cycle checkpoints
• G1: presynthesis phase
• S: DNA synthesis
• G2: premitotic phase
• M: mitotic phase
TYPES OF TISSUES ACCORDING TO PROLIFERATION
STEM CELLS
During development, stem cells give rise to all
the various differentiated tissues
In the adult organism, stem cells replace
damaged or senescent cells
Stem cells are characterized by two important
properties:
• Self-renewal, which permits stem cells to
maintain their numbers
• Asymmetric division, in which one daughter cell
enters a differentiation pathway and gives rise
to mature cells, while the other remains
undifferentiated and retains its self-renewal
capacity
 STEM CELLS
STEM CELL VARIETIES

1. EMBRYONAL STEM CELLS

• Most undifferentiated
• Give rise to every cell
• Aka TOTIPOTENT stem cells
2. TISSUE STEM CELLS
• Adult stem cell
• Aka PLURIPOTENT STEM CELL
• Protected in specialized tissue
• Skin stem cell- hair follicle
• Small intestine- near base of the crypt
• Liver- canals of Herring
Regenerative medicine

• identify, isolate, culture, and transplant stem cells

• a handful of genes have been identified whose products
can—remarkably—reprogram somatic cells to achieve the
“stem-ness” of ES cells
• Eg. insulin-secreting β-cells in a patient with diabetes
GERM LAYER DERIVATIVES
DEFINITION OF TERMS: DEVELOPMENTAL DEFECTS
• Aplasia: incomplete or defective development of an organ
• Atresia: failure to form an opening
• Hypoplasia: failure of an organ to reach its matured size
• Agenesis: complete non-appearance of an organ
SHORT EXERCISE: THE CELL
1. LDL uptake A. Plasma membrane
2. Microvilli B. Proteosome
3. Initial site for synthesis of all molecules C. Mitochondria
4. Has its own DNA, maternally inherited D. Endoplasmic reticulum
5. Modify proteins for packing E. Golgi bodies
6. Cillia and flagella F. Cytoskeleton
7. Active and passive transport G. Lysosome
8. Composed of acid hydrolases
9. Identifies ubiquitin
10. thermogenin
11. Eat me signal for phagocytes
12. Desmin
SHORT EXERCISE: DEFINITION OF TERMS
1. Part of the DNA molecule that contains the hereditary elements
2. Total DNA molecule that comprises the coding and non-coding protein elements
3. Two individual shares their DNA sequence by how many percent?
4. Phenomenon in which genetically identical cells or organisms express their
genomes differently causing phenotypic differences
5. promotes differentiation and migration so called “scatter factor”
6. Two forms of extracellular matrix
SHORT EXERCISE: TYPES OF TISSUES
1. Skeletal muscle A. Stable tissues
2. Hepatocytes B. Labile tissues
3. Skin epithelium C. Permanent tissues
4. Cardiac muscle
5. Smooth muscle
6. Neurons
7. Hematopoietic cells
8. Endothelium
9. Fibroblasts