The presentation is about the general concepts of Pathology from Robbin and Cotran, featuring the organization of the cell, injury & adaptation, and inflammation & repair

1. COMPETENCY GROUP1A
ALLADO | CABATINGAN | LAGARTO | FABROS
General
Pathology

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The Cell as a Unit
of Health and
Disease
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BACKGROUND
Pathology
patho – suffering; logos – study
Cellular Pathology – Virchow – study of cellular abnormalities

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Genome
• 🠶 Human genome contain roughly 3.2
billion DNA base pairs, only 1.5% (20,000) of
which code for proteins (coding genes), the
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.
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The organization of nuclear DNA
VS.
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Central dogma of molecular biology
$2Bn
20YY 20YY
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WE ARE 99.9% SIMILAR
❑ ANY TWO INDIVIDUALS – 99.9
❑ HUMAN AND CHIMPS – 99.5
❑ HUMAN AND CAT - 90
❑ HUMAN AND CHICKEN – 60
❖ THE DIFFERENCE IS DUE TO
VARIATIONS IN GENOMES CALLED:
▪ SNP – SINGLE NUCLEOTIDE
POLYMORPHISM
▪ CNV – COPY NUMBER VARIATION

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EPIGENETIC FACTORS
🠶 HISTONES
🠶 DNA in cell is wound around these proteins
🠶 Not uniformly wound – Heterochromatin and Euchromatin
🠶 Histone acetylation and methylation can cause neoplasia
🠶 NON CODING RNAs – microRNAs and long RNAs

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miRNA
🠶 Primarily involved in gene silencing, if doesn’t work, can lead to
neoplasia
🠶 That means it’s a tumor suppressor

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Long non coding RNA (lncRNA)

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🠶 A cell can survive only if the following housekeeping functions are
performed on a regular basis
🠶 protection from the environment,
🠶 nutrient acquisition,
🠶 communication,
🠶 movement,
🠶 renewal of senescent molecules,
🠶 Molecular catabolism,
🠶 energy generation.
Cellular Housekeeping

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PLASMA MEMBRANE

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Passive diffusion
Active transport
Oxygen
Carbon dioxide
Steroid based –
estradiol, Vit D
Water
Ethanol
Urea
transferrin and
low-density
lipoprotein (LDL)

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Cell Injury, Cell
Death,
and Adaptations
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Stages of the cellular response to stress and
injurious stimuli

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Cellular responses to Injury

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Cellular responses to Injury

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➔Hypoxia
➔Physical Agents
➔Chemical Agents
➔Infectious agents
➔Immunologic reactions
➔Nutritional Imbalances
➔Genetic derangements
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Causes and morphologic alterations of Cell
Injury

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Reversible Injury
- Cell swelling
- Fatty change
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REVERSIBLE CELL INJURY

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IRREVERSIBLE CELL INJURY

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Mechanisms of Cell Injury

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• Ischemic and Hypoxic Injury
• Ischemia-Reperfusion Injury
• Chemical (Toxic) Injury
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Examples of Cell Injury and Necrosis

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APOPTOSIS

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• Cell shrinkage,
• Chromatin condensation and fragmentation,
• Cellular blebbing and fragmentation into apoptotic bodies, and
• Phagocytosis of apoptotic bodies by adjacent healthy cells or
macrophages.
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Morphologic Features Of Apoptosis

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Apoptosis is a cascade of molecular events that can be initiated by a
variety of triggers.
• Initiation phase, when caspases become active
o Intrinsic mitochondrial pathway
o Extrinsic death receptor-mediated pathway
• Execution phase, when the enzymes cause cell death.
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Mechanisms of Apoptosis

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Mechanisms of Apoptosis

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1. Growth Factor Deprivation
2. DNA Damage
3. Protein Misfolding
4. TNF Family Receptors
5. Cytotoxic T Lymphocytes
6. Disorders Associated with Dysregulated Apoptosis
a. Disorders with defective apoptosis and increased cell survival
i. cancers
ii. autoimmune disorders
b. Disorders with increased apoptosis and excessive cell death
i. neurodegenerative diseases
ii. ischemic injury
iii. death of virus-infected cells
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Apoptosis in Health and Disease

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NECROPTOSIS
Also called “programmed necrosis,” necroptosis:
• Morphologically resembles necrosis
• Mechanistically resembles apoptosis
• Activate receptor-interacting protein kinases
• Evokes an inflammatory response.
Necroptosis is involved in physiologic events as well as pathologic
processes. It is also a fail-safe form of cell death for certain viral
infections that encode caspase inhibitors.

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“Self-eating”
• Autophagy is a characteristic feature of atrophy but is also involved in the
normal homeostatic turnover of organelles and in clearing intracellular
aggregates that occur with aging, cellular stress, and disease states.
• It also plays a role in host defense by degrading certain intracellular
pathogens.
• It can also be associated with cell death, as in several neurodegenerative
disorders.
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AUTOPHAGY

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Cells may accumulate abnormal amounts of various substances.
• A normal endogenous substance is produced at a normal rate,
with the metabolic rate inadequate to remove it.
• An abnormal endogenous substance accumulates because of
defective folding or transport and inadequate degradation.
• A normal substance accumulates because of genetic or
acquired defects in its metabolism.
• Abnormal exogenous substances may accumulate in normal
cells because they lack the machinery to degrade such
substances
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INTRACELLULAR ACCUMULATIONS

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1. Lipids
a. Steatosis
b. Cholesterol and Cholesterol Esters
2. Proteins
3. Hyaline Change
4. Glycogen
5. Pigments
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INTRACELLULAR ACCUMULATIONS

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The abnormal tissue deposition of calcium salts:
• Dystrophic calcification arises in nonviable tissues in the
presence of normal calcium serum levels occurs in arteries
in atherosclerosis, in damaged heart valves, and in areas of
necrosis
• Metastatic calcification happens in viable tissues in the
setting of hypercalcemia. calcium deposits occur as
amorphous basophilic densities that can be present widely
throughout the body.
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PATHOLOGIC CALCIFICATION

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CELLULAR AGING
Cellular Aging—reflecting the progressive accumulation of sublethal
cellular and molecular damage due to both genetic and exogenous
influences leading to cell death and diminished capacity to respond to
injury; it is a critical component of the aging of the entire organism.
Aging can potentially be parsed into definable mechanistic alterations:
• Genomic instability
• Cellular senescence
• Defective protein homeostasis
• Deregulated nutrient sensing

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CELLULAR AGING

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Inflammation and
Repair
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Inflammation is a response of vascularized
tissues that delivers leukocytes and molecules
of host defense from the circulation to the
sites of infection and cell damage in order to
eliminate the offending agents.
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Inflammation

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Five classic clinical signs of inflammation

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Causes of Acute and Chronic Inflammation
Causes:
❖Infection
❖Tissue Necrosis
❖Foreign Bodies
❖Immune reactions

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Features of Acute and Chronic Inflammation

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ACUTE INFLAMMATION

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➔ Changes in Vascular Flow and
Caliber
➔ Increased Vascular Permeability
(Vascular Leakage)
➔ Responses of Lymphatic Vessels
and Lymph Nodes
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Reactions of Blood Vessels in Acute Inflammation

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Leukocyte Recruitment to Sites of Inflammation

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Leukocyte Adhesion and Migration

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After exiting the circulation, leukocytes
move in the tissues toward the site of
injury by a process called chemotaxis,
which is defined as locomotion along
a chemical gradient.
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Chemotaxis of Leukocytes

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Phagocytosis and Clearance of the Offending
Agents

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Vasoactive Amines
- Histamine
- Serotonin
Arachidonic Acid Metabolites
- Prostaglandins
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Mediators of inflammation

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Cytokines
- proteins produced principally by activated lymphocytes and
macrophages
- modulate the function of other cell types
- Other Cytokines in Acute Inflammation : IL-6 and IL-7
Chemokines
- cytokines that also stimulate leukocyte movement (chemotaxis)
- classified into four major classes: CXC chemokines, CC chemokines,
C chemokines and CX3C chemokine is fractalkine
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Cytokines and Chemokines

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COMPLEMENT SYSTEM

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• Platelet-Activating Factor
• Product of Coagulation
• Kinins
• Neuropeptides
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OTHER MEDIATORS OF INFLAMMATION

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• Serous Inflammation
• Fibrinous Inflammation
• Purulent (Suppurative) Inflammation and
Abscess
• Ulcers
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MORPHOLOGIC PATTERN OF ACUTE INFLAMMATION

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MORPHOLOGIC FEATURES
• Infiltration with mononuclear inflammatory cells, including
macrophages, lymphocytes, and plasma cells
• Tissue destruction, induced by persistent injury and/or
inflammation
• Attempts at healing by connective tissue replacement,
accomplished by vascular proliferation (angiogenesis) and
fibrosis
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CHRONIC INFLAMMATION

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Cells and Mediators in Chronic Inflammation:
• Macrophages
• Lymphocytes
• Eosinophils
• Mast cells
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CHRONIC INFLAMMATION

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Systemic Effects of Inflammation
These represent responses to cytokines produced either by bacterial
products or by other inflammatory stimuli.
The acute phase response consists of several clinical and pathologic
changes:
• Fever
• Acute Phase Proteins
• Leukocytosis
• Sepsis
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SYSTEMIC EFFECT OF INFLAMMATION

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OVERVIEW OF TISSUE REPAIR
regeneration can occur through the proliferation of adjacent surviving
cells or through the activity of tissue stem cells.
In most cases healing is some combination of regeneration and scar;
the outcome will be affected by
(1) proliferative capacity of the damaged tissue,
(2) integrity of the ECM, and
(3) the chronicity of the associated inflammation.
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TISSUE REPAIR

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Liver Regeneration Through Hepatocyte Proliferation

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STEPS IN REPAIR BY SCAR
FORMATION
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REPAIR BY CONNECTIVE
TISSUE DEPOSITION

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Angiogenesis is the process of new blood vessel growth
from existing vessels.
• Vasodilation in response to NO and increased permeability
in response to VEGF
• Separation of pericytes from the vessel wall and basement
membrane breakdown allowing vessel sprouting
• Migration of endothelial cells toward the area of tissue
injury
• Proliferation of endothelial cells
• Remodeling into capillary tubes
• Recruitment of periendothelial cells
• Suppression of endothelial proliferation and migration,
and
• redeposition of the basement membrane
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ANGIOGENESIS

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• Nutritional status of the host.
• Metabolic status
• Circulatory status or vascular adequacy.
• Hormones
• Size and location: Well-vascularized tissues heal faster;
Inflammation in tissue spaces develops exudates that can either
resolve or undergo organization.
• Type of tissue: Labile and stable tissues have better tissue
regeneration, whereas permanent tissues form only scar.
• Local factors that delay healing include infections, ischemia,
• mechanical forces, and foreign bodies.
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FACTORS THAT INFLUENCE TISSUE REPAIR

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• Deficient Scar Formation
• Excessive Repair
• Formation of Contractures
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ABNORMALITIES IN TISSUE REPAIR

62. Thank
You
Jens Martensson
jens@bellowscollege.com
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