Transcript Veterinary Profession

Today’s Quranic verse
For Muslim men and women,- for
believing men and women, for
devout men and women, for true
men and women, for men and
women who are patient and
constant, for men and women who
humble themselves, for men and
women who give in Charity, for
men and women who fast (and
deny themselves), for men and
women who guard their chastity,
and for men and women who
engage much in God's praise,- for
them has God prepared forgiveness
and great reward. [033:035]
Overview of Inflammation
• Inflammation as one of the Tissue
Response to Injury
• The most important topic in Pathology
• “If you understand Inflammation you
understand Pathology”
• “Otherwise you do so at your own risk”
• A complex set of tissue response to injury
at the site of injury involving 4 sets of
tissue response and 4 stages
• I = D+N+CD+GD+IIC
• SOI=TC+VC+EnP+RnR
Tissue Response to Injury
(Histopathological Concept)
STIMULUS
1.DEGENERATION
NORMAL
CELL
RESPONSE
TO THE
NECROTIC
TISSUES
2.NECROSIS
MOLECULAR
LESIONS
9.PIGMENTATION
NECROSIS
3.INFLAMMATION=COMPLEX
SETS OF TISSUE RESPONSE
TO INJURY AT SITE OF INJURY
=D+N+CD+GD+IIC
4.CD=D OF CVS
5.GD=CHANGE IN NUMBER, SIZE,
TYPE AND ARRANGEMENT
IIC=INCREASED INFLAMMATORY
CELLS
GD→DYSPLASIA→6..NEOPLASIA
GD→FOETAL STAGE →7.CONGENITAL
ANOMALIES
CHEMICAL+PHYSICAL STIMULI
→8.TRAUMA
PIGMENTS→9.PIGMENTATION
OTHERWISE 10.MISCELLANEOUS
Overview of Inflammation
(Robbins, 2:33)
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The same stimuli that cause cell injury also elicit inflammation
Inflammation is a protective response intended to eliminate the initial
cause of cell injury as well as the necrotic cells and tissues resulting
from the original insult.
Inflammation accomplishes its protective mission by diluting,
destroying, or otherwise neutralizing harmful agents.
Iinflammation then sets into motion the events that eventually heal and
reconstitute the sites of injury
Inflammation is intimately interwoven with repair process whereby
damaged tissue is replaced by the regeneration of parenchymal cells,
and/or by filling of any residual defect with fibrous scar tissue
The inflammatory response involves circulating cells and plasma
proteins, vascular wall cells, and cells and extracellular matrix of the
surrounding connective tissue
The broad outline of inflammation are as follows:
An initial inflammatory stimulus triggers the release of chemical
mediators from plasma or connective tissue cells.
The mediators amplify the initial inflammatory response and influence
its development by regulating the subsequent vascular and cellular
responses.
The inflammatory response is terminated when the injurious stimuli is
removed and the inflammatory mediators catabolized or inhibited.
Inflammation is divided into 2 basic patterns: acute or chronic
Acute inflammation is of relatively short duration, lasting from a few
minutes up to a few days, and is characterized by fluid and plasma
protein exudation and a predominantly neutrophilic leukocyte
accumulation.
Chronic inflammation is of longer duration, days to years, and is
typified by influx of lymphocytes and macrophages with associated
vascular profileration and scarring.
‫اﷲ‬
Pathogenesis and Sequelae of Inflammation
(a complex set of tissue response to injury at the site of injury involving 4 tissue responses with 4 stages and increased inflammatory cells )
Capillary,Venules,Arterioles
Chemical Mediators (13)
Vasodilation-Arteriolar Dilatn
Endothelial Integrity
Vascular Permeability
Bld Flow- Axial,,LaminarFlow
Bld Pr
Labile
Stable cells
Permanent cells
ECM
Interstitial Tissue
Interstitial Tissue space
Blood/Vessel
(Haemodynamics)
PMN-Nuet,Eos,Baso
MNC- L,Mono,Histo,Plasma cell
Macrophages,Giant Cells,Mast c
Chemical Mediators,Cytokines
Exudation,Infiltration
Proliferation
Phagocytosis
Non specific Immune Response
Inflammatory cells
(10 Types)
Stimulus
(Infectious,physical,chemical)
Tissue
(Cell Types)
Stages of Inflammation (4)
1.Tissue Changes=Tissue Injury=Degeneration → Necrosis
2.Vas. Changes=CD=Vasodilation → V. Perm. → Oedema
3.Exudation + Infiltration=Increased Inflammatory Cells
4.Regeneration + Repair=GD=Hyperplasia + Fibroplasia
Acute Inflammation AI(≈3 days)
Mediated by 13 mediators (Histamine, Serotonin,
Bradykinin, C3a, C5a, Prostaglandins,
Leukotrienes C4, D4, E4, Oxygen metabolites,
and PAF).
Types of AI based on exudates and lesion
7 main Mechanisms of AI (Stages):
1.Tissue Injury: (refer to SAF on Cell Injury)
5 main mechanisms:ATP Depletn, Reactive O
sp.,Loss of Ca homeostasis, Defects in Plasma
memb.Perm., Mitochondrial Damage
2.Vasodilation: 3 main mechanisms:
Preformed mediators eg Histamine,Serotonin
NewlySynthMediators eg Prostaglandin,Cytoki
SystemicMediators eg Bradykinin,C3a,C5a
3.Oedema: (refer to SAF on Oedema (IP))
5 Mechanisms of Inc. Permeability (IP) at
endothelia: EC, JR, DI, LDL, RE
4.Exudation: 4 main mechanisms(stages):
Endo.Activatn, LeukocyteRolling,FirmAdhesn,
Transmigratn.
5.Phagocytosis: 4 main mechanisms(steps):
Recognitn, Engulfmt, Killing, Degradatn.
6.Regeneration: (refer to SAF on Regeneration)
(Mechanisms of Hyperplasia)
7.Repair: (refer to SAF on Wound Healing)
(Mechanisms of Fibroplasia)
Chronic Inflammation CI(>2 weeks)
Haemodynamic Changes
Blood vessels
Stimuli
Mediators
Vasodilation
↓ Velocity
margination
↑ BP
↑ V. Perm.
↑ outflow
exudation
cells
fluid
↑ IC (PMN+MNC)
oedema
proliferation
fibrin
infiltration
AI
- ±Persistence +
↑ PMN
CI
↑ MNC
IT=Interstitial Tissue
V. Perm.=Vascular Permeability
IC=Inflammatory Cells
ITS=IT Space
BP=Bld Pr
SAF=Sys.App.Flowchart
Hypoxia/Hypoglycaemia
Free radical:O2÷,H2O2,OH•
Trauma, Temperature extremes
Virus, Bacteria, Fungi, Parasites, Toxins,
Poisons, Drugs,Allergens,
Similar mechanisms to AI but Stimuli Persistent.
Continuation after AI
Types of CI based on cell types (Mainly MNC)
Granulomatous Inflammation (GI)- Lymphocytes,
Plasma Cells, Epithelioid Cells, Giant Cells,
Fibrpblasts
5 Main Mechanisms of CI:
1.Mechanisms of Persistence:
i. Agent Evasion
ii.Autoimmune reactions (Delayed
Hypersensitivity)
iii.Prolonged Exposure
2.Mechanisms of Granulomatous Inflammation:
i.Caseous necrosis – Hypersensitivity Reactn
ii.Fibrosis
iii.Angiogenesis
3.Mechanisms of Macrophage Proliferation:
i. Continued recruitment from blood
ii.Local Proliferation
iii.Immobilization
4.Mechanisms of Tissue Injury in CI:
Toxic O2 metabolites, Proteases,Neutrophil
Chemot. Factor, Coagulation factor,
Arachidonic Acid(AA) metabolites, NO
5.Mechanisms of Macrophage-Lymphocyte interaction:
Activated Lymphocytes and macrophages
influence each other and also release
mediators that affect other cells.
LESIONS: based on the type of exudates
1.Suppurative- ↑ neutrophils with liquefactive necrosis →abscess
2.Fibrinous – predominantly fibrin + PMN
3.Haemorrhagic – predominantly RBC + PMN
LESIONS: based on the type of exudates
1.Predominantly MNC with caseous necrosis→granuloma
2.Fibrosis
3.Autoimmune reactions
SIGNS: 5 cardinal signs of inflammation →Redness,Heat,Swelling,
Pain, Loss of Fn.
Systemic Effects: Pyrexia, Malaise, Anorexia, Nausea, Wt. loss, LN
hyperplasia, splenomegaly
Haematological: Inc. ESR, leukocytosis, Anaemia,
SIGNS: based on the organs affected
Systemic Effects: Pyrexia, Malaise, Anorexia, Nausea, Wt. loss, LN
hyperplasia, splenomegaly
Haematological
SEQUELAE: based on type of inflammation and organ affected
Resolution, Suppuration, Organisation, Fibrosis →CI
SEQUELAE: based on the organ affected
Fibrosis and Adhesions of organs
Chulan2005
‫ﺍﷲ‬
Pathogenesis of Cellular Injury
(cellular injury as reversible or irreversible conditions which occur after the limits of adaptive response to a stimulus are exceeded)
Agents
(Infectious)
Environment
(Non-infectious)
Virus
ADVERSE
Rickettsiae
Hypoxia/Hypoglycaemia
INTERACTIONS
Free radical:O2÷,H2O2,OH•
Bacteria
Trauma
Fungi
Temperature extremes
Host
(Inherent)
Parasites
Atmospheric pressure
Radiation
Electric shock
Genetic defects
Chemicals/Poisons
Hormonal imbalance
+ Inappropriate Immune Response
Electrolyte imbalance
Drugs
Nutritional Imbalance
Hepatic & renal failure
Alcohol
Allergy/autoimmunity
Cell membrane integrity ↓
Oxidative phosphorylation ↓
Aerobic respiration ↓
ATP ↓→Ca++ ↑
ATP ↓
Enzymatic protein synthesis ↓
Phospholipid synthesis ↓
Structural protein synthesis ↓
Phospholipase+Protease+ATPase ↑
Glycolysis ↑ → pH↓ Glycogen↓
DNA integrity ↓
Endonuclease ↑
Protein synthesis ↓
Metabolic derangements ↑
Phospholipid degradation ↑
Na pump ↓→
Ca++
↑ ,H20
↑,K+
↓
Lipid deposition ↑
Phospholipid loss ↑
Lipid peroxidation ↑
LESIONS
(structural abnormalities)
DEGENERATION
(REVERSIBLE)
Histopathology
Membrane damage ↑
NECROSIS
(IRREVERSIBLE)
SIGNS
(functional abnormalities)
Water, fat & glycogen vacuoles
Histopathology
Cellular swelling
Cytoplasmic changes
Cytoplasmic deposition of substances
Nuclear changes
Membrane changes
+ DEATH
Ultrastructural changes
Ultrastructural changes
Cellular swelling
Mitochondrial swelling
Cytoskeletal changes
NECROSIS
Loss of microvilli
Nuclear changes → pyknosis,
Blebs
karyorrhexis, karyolysis
ER swelling
Lysosomes lysis
Myelin figures
INFLAMMATION
Membrane lysis
Nuclear chromatin clumping
Myelin figures
Ribosomal detachment
ER lysis
Intramembranous particle aggregatn
Mitochondrial swelling
Large densities in mitochondria
Autophagy by lysosomes
Chulan2003
‫اﷲ‬
Pathogenesis and Sequelae of Oedema
(a condition of excessive fluid accumulation in interstitial tissue space and body cavities due to pressure imbalance or increased permeability)
Hydrostatic pr
Arterial Pr
Venous Pr
Central Venous Pr
Blood Osmotic Pr
Starling Forces
Lymphatic Pr
IT Osmotic Pr
IT Pr
Blood Volume
Cardiac Output
Fluid Homeostasis
Blood/Fluid
(Pressure/Vol)
Interstitial Tissue
Interstitial Tissue Space
Tissues of Lower Extremities
Tissues with Thrombosis
Tissues with Venous Obstruction
Vital Organs
Capillary
Venules
Chemical Mediators
Histamine, Serotonin
Complement, Kinin
Vasodilation
Arteriolar Dilation
Endothelial Integrity
Vascular Permeability
Vessel
(Permeability)
Stimulus
(Infectious,physical,chemical)
Tissue
(Type)
Hypoxia/ Hypoglycaemia
Free radical:O2÷,H2O2,OH•
Trauma, Temperature extremes
Virus, Bacteria, Fungi, Parasites, Toxins,
Pressure Imbalance in Non-inflammatory oedema
Or
Increased Permeability in Inflammatory oedema
(PINO or IPIO)
HAEMODYNAMICS
Pressure Imbalance (PI)
4 mechanisms of PI based on inc. or dec. Pr:
1.Increased Hydrostatic Pr (IHP=IAP) due to:
Excessive parenteral fluid infusion → ↑PVol
Excessive salt intake in renal insufficiency →
↑PVol →IAP
Heart failure →3 compensatory mechanisms
(Sympathetic, RAA,ADH) → ↑renal retension
of Na+H2O → ↑PVol →IAP
BP
BOP
4. Lymphatic Obstruction= ↑LPr=ILP due to:
Inflammation, Neoplasia, Parasites, Postsurgical, Postradiation
VP
ITS
IT
2. Decreased Osmotic Pr (DOP) due to:
PLGlo=Protein-losing Glomerulopathies,
PLGas=Protein-losing Gastroentropathies
Protein Malnutrition, Hepatic Diseases
3. Increased Venous Pr (IVP) due to:
CHF=Congestive Heart Failure →Congestion
Thrombus, Embolus, Immobilization of limbs
Increased Permeability (IP)
capillary
AP
Poisons, Drugs, Allergens
Mediated by 11 mediators (Histamine, Serotonin,
Bradykinin, C3a, C5a, Prostaglandins,
Leukotrienes C4, D4, E4, Oxygen metabolites,
and PAF).
5 Mechanisms of IP at endothelia:
1.Endothelial Contraction (EC) →widened intercell. jn
in venules only by Histamine, Bradykinin,,
Leukotrienes + others
2.Junctional Retraction (JR) →Cytoskeletal &
junctional reorganisation by IL-1,TNF,IFN
heart
lymphatics
3.Direct Injury (DI) involving Necrosos & Apoptosis →
endothelial detachment of venules, capillaries,
arterioles dt bact. Toxins
4.Leukocyte Mediated (LM) → release of free radicals
& proteolytic enzymes →endo. Detachment
AP=Arterial Pr
BP=Bld Pr
VP=Venous Pr
ITS=IT Space
5.Regenerating Endothelium (RE) in angiogenesis with
capillary sprouts which are leaky
BOP=Bld Osmotic Pr IT=Inter. Tiss.
LESIONS
Grossly organs appeared swollen and wet.
LESIONS
Grossly organs appeared swollen and wet.
Microscopically tissues and cavities filled with fluid
Microscopically tissues and cavities filled with fluid
SIGNS
SIGNS
Depends on the organs affected eg. Vital organs could result in organ
failure and death.
Depends on the organs affected eg. Vital organs could result in organ failure
and death.
SEQUELAE
SEQUELAE
Depends on organs affected -> death
Depends on organs affected
Prolonged oedema lead to fibrosis
Prolonged oedema lead to fibrosis
Chulan2005
‫ﺍﷲ‬
Pathogenesis of Cellular Regeneration
(Regeneration as hyperplasia (of same cell type) which occur after the cells in the G 0 stage is recruited into the cell growth cycle)
EpidermalGF
PlateletDerivedGF
FibroblastGF
Mediators
(Growth Factors)
TransformingGF
Insulin-likeGF
Extracellular Matrix
(Micro-environment)
Stimuli
(Infectious,chemical,physical)
Fibrous Structural Protein
Collagens(15 Types) + Elastin
VasoPermeabilityF
Interstitial Matrix(IM)
HepaticGF
Basement membrane (BM)
ColonyStimulatingF
Erythropoietin
Cell
(Types,Enzymes,genes)
Cytokines
IM composed of adhesive glycoproteins
(AG) embedded in a gel of proteoglycans
and glycosaminoglycans
AG= Fibronectin + Laminin
NerveGF
Growth Inhibitors
1.Labile cells (dividing) of skin,
oral cavity, vagina, cervix,
glandular ducts, GIT, uterus,
urinary tract, bone marrow,
haemopoeitic tissues of stem cells.
Continue to proliferate
throughout life.
2.Stable cells (quiescent)
parenchymal cells of liver, kidney,
pancreas, fibroblasts, smooth
muscle, mesenchymal cells,
connective tissues, endothelium.
Can be stimulated to go from
from G0 to G1 stage of cell
growth cycle. BM needed for
organised regeneration
3.Nondividing cells (permanent)
cannot undergo mitosis or
regeneration. Include nerve cells,
skeletal and cardiac muscles.
Skeletal muscles may regenerate
from transformation of satellite
cells in the endomysial sheaths.
Neurons replaced by glial cells.
Cardiac muscles replaced by
fibrous tissues.
1.Ligand-Receptor Binding at cell surface or inside
cells. Steroid receptors are intracellular in nuclei or
cytoplasm.
Infectious Agents
2.Growth Factor Receptor Activation
Physical agents
Most growth factor receptors have intrinsic protein
tyrosine kinase activity. Otherwise intracellular protein
kinases recruited to cell periphery.
Can activate the immediate early response
genes including the proto-oncogenes
Tyrosine kinase activity activitated after ligand binding
Dimerization of receptors
Phosphorylation of kinase
Activation of protein phosphorylation cascade
Quiescent cells enter growth cycle (G0 → G1)
3.Signal Transduction and Second Messengers
Activation of signalling proteins:
Phospholipase C-γ convert PIP2 → IP3 → Ca2+ + DAG
release → PKC activated
GTP-binding proteins: G proteins + ras family of
proteins for coupling the extracellular signals to cellular
effectors (phospholipase). Conversion of GDP →GTP
controlled by GAP. Activated ras phosphorylates MAPKs
→ activation of transcription factors
Raf-1 aactivated by ras activates MAPK
Cellular phosphotases act as growth inhibitors
4.Transcription Factors
Cascade of MAP kinases
Growth signals transmitted to nucleus
Induction of cellular genes
Early growth-regulated genes: c-fos, c-jun, c-myc
Late growth-regulated genes: myc, fos, jun
Regulation of mRNA and DNA sysnthesis
5.Cell Cycle and Cyclin: G1 and G2 cyclins controls
DNA replication with bcl1, Rb and p53 genes. G2 cyclins
degraded after mitosis. Daughter cells start new cell cycle
again.
Chulan2005
Mitosis → Proliferation → Hyperplasia → Regeneration
Chemical agents
‫ﺍﷲ‬
Mechanisms of Wound Healing
(Wound healing as a complex process involving inflammation, regeneration, remodelling and collagenization)
EpidermalGF
PlateletDerivedGF
FibroblastGF
Mediators
(Growth Factors)
TransformingGF
Insulin-likeGF
Extracellular Matrix
(Micro-environment)
Stimuli
(Infectious,chemical,physical)
Fibrous Structural Protein
Collagens(15 Types) + Elastin
VasoPermeabilityF
Interstitial Matrix(IM)
HepaticGF
Basement membrane (BM)
ColonyStimulatingF
Erythropoietin
Cell
(Types,Enzymes,genes)
Cytokines
IM composed of adhesive glycoproteins
(AG) embedded in a gel of proteoglycans
and glycosaminoglycans
AG= Fibronectin + Laminin
NerveGF
Growth Inhibitors
1.Labile cells (dividing) of skin,
oral cavity, vagina, cervix,
glandular ducts, GIT, uterus,
urinary tract, bone marrow,
haemopoeitic tissues of stem cells.
Continue to proliferate
throughout life.
2.Stable cells (quiescent)
parenchymal cells of liver, kidney,
pancreas, fibroblasts, smooth
muscle, mesenchymal cells,
connective tissues, endothelium.
Can be stimulated to go from
from G0 to G1 stage of cell
growth cycle. BM needed for
organised regeneration
3.Nondividing cells(permanent)
cannot undergo mitosis or
regeneration. Include nerve cells,
skeletal and cardiac muscles.
Skeletal muscles may regenerate
from transformation of satellite
cells in the endomysial sheaths.
Neurons replaced by glial cells.
Cardiac muscles replaced by
fibrous tissues.
1.Healing by first intention.
Infectious Agents
In uninfected surgical incision. Minimal necrosis of
epithelial and connective tissues. Blood clot with fibrin +
RBC form scab.
Chemical agents
Within 24 h neutrophil appear + basal cell hyperplasia.
Epithelial cells migrate and grow along cut margin, and
fused in the midline beneath the surface sacb.
Can activate the immediate early response
genes including the proto-oncogenes
By day 3, macrophages replaced neurophil, and
granulation tissue invades incision space. Collagen
fibres present. Epithelial cell profileration.
By day 5, incision space filled with granulation tissue.
Neo vascularization maximal. Collagen abundant.
Mature epidermal structure with keratinization.
2nd week – collagen and fibroblast increase. Exudate,
oedema, and increase vascularity disappeared.
1st month – scar formation covered by intact epidermis
and no inflammatory cells. Dermal appendages
permanently lost.
2. Healing by second intention.
More extensive loss of cells and tissues as occurs in
infarction, inflammatory ulcerations, abscess formation
and skin wounds with large defects. Regeneration of
parenchymal cells cannot completely reconstitute the
original architecture. Abundant granulation tissue grows
in from the margin to complete the repair.
Wound contractions occurs in large surface wound by
myofibroblasts.
Collagen Synthesis and Degradation and W.Strength
See Fig. 3-43
Cross linkages between alpha chains of adjacent
molecules is basis for structural stability of collagen.
Cross-linking contributes to tensile strength of collagen.
Nett collagen accumulation depends on synthesis and
degradation.
Degradation of collagen by metalloproteinases dependent
on Zn ions.
Chulan2005
Fibrosis → Fibroplasia → Repair
Physical agents