Inflamation-Pathology lecture notes

Inflammation and Repair 381500270@qq.com
Inflammation and Repair
Inflammation & Repair
Dr. saroj Kumar Suwal
1

Introduction
 Injurious stimuli cause a protective
vascular connective tissue reaction
called “inflammation”
 Dilute
 Destroy
 Isolate
 Initiate repair
 Acute and chronic forms

Inflammation and Repair 381500270@qq.comInflammation and Repair 381500270@qq.com
Rubor = redness
Tumor = swelling
Calor = heat
Dolor = pain
Functio laesa = loss of
function
5 CARDINAL SIGNS OF (ACUTE)
INFLAMMATION

5 Cardinal signs
4
1. Rubor (redness) and calor
(heat)
 Due to histamine-mediated
vasodilation of arterioles
2. Tumor (swelling)
a. Due to a histamine-mediated
increase in venular permeability
b. Synonymous with edema, which
refers to increased fluid in the
interstitial space

Inflammation and Repair 381500270@qq.com 5
3. Dolor (pain)
 Prostaglandin E2 (PGE2) sensitizes
specialized nerve endings to the
effects of bradykinin and other pain
mediators.
4. Functio laesa (loss of function)

Types of Inflamation
6
 Acute Inflamation
 Short duration and early onset followed by
healing
 PMNs
 Chronic Inflamation
 Long duration
 Causative agent of inflamtion remain for long
time
 Lymphocyts and Macrophases
 Chronic Active Inflamation

Immunity
10
 Innate
 inborn cell immunity, cytokines, complements,
activatiton of adaptive
 Adaptive 
 acquired immune system specialized cell
immunity
 eliminate or prevent pathogen growth.
 Active and Passive immunity
 Two types
 Humoral (antibody,complement pr, peptides)blood
tfx

Acute inflammation
 Immediate and early response to tissue injury
(physical, chemical, microbiologic, etc.)
 Vasodilation
 Vascular leakage and edema
 Leukocyte emigration (mostly PMNs)
Characterized by fluid & protein PMN’s
Exudates

Patterns of Acute Inflamaitons
13
 Serous Inflamation
 Fibrinous Inflamation
 Purulent inflamation
 Ulcer
 Granulomatous inflamation

morphological patterns of acute inflammation can be found depending on the
cause and extend of injury and site of inflammation
Serous inflammation
Fibrinous inflammation
Purulent inflammation
Ulcer
14

MORPHOLOGICAL PATTERNS OF ACUTE
INFLAMMATION
SEROUS INFLAMMATION
Outpouring of thin fluid
Depends on secretion of mesothelial cells –
peritoneal pleural , pericardial cavities- effusions
Skin blister- viral ,burns- large accumulation of
serous fluid
FIBRINOUS INFLAMMATION
 Fibrin accumulation
 Either entirely removed or becomes fibrotic
Inflammation in the lining of body cavities –
meninges pericardium, pleura Scarring

SUPPURATIVE OR PURULENT INFLAMMATION
pus & purulent exudates- neutrophil, necrotic cells
& edema fluid ，Pyogenic bacteria,
staphylococcus
Abscess , acute appendicitis
ULCERS
 Local defect or excavation of surface organ or
tissue that is produced by sloughing (
shredding) of necrotic tissue.
 Mouth, gut, subcutaneous inflammation of lower
extremities in older person, peptic ulcers - -
chronic – lymphocytes, macrophages and
plasma cells .
 Trauma, toxins, vascular insufficiency
GRANULOMATOUS- granulomas ,TB, leprosy,

Stimuli for AI
17
1. Infections (e.g., bacterial or viral)
2. Immune reactions (e.g., reaction to a bee
sting)
3. Other stimuli include:
• Tissue necrosis (e.g., acute myocardial
infarction), trauma, radiation, burns, and
foreign bodies (e.g., glass, splinter

Acute Inflammatory response consist of
Vascular reaction-->vascular event
Cellular reaction
18

Acute inflammation Major Events
19
With five cardinal signs of
inflammation
Extravasations of PMN’s
Increase vascular permeability
Vasodilatation
Transient vasoconstriction

Vascular Events
20
1. Constrictions of Arterioles
2. Dilatation of Arterioles
3. Increase Permeability
4. Transudate
5. Tumor/Edema/Swelling
6. Decrease blood flow

Sequential vascular events in
AI
21
1. Vasoconstriction of arterioles
• Due to a neurogenic reflex that lasts only a few
seconds
2. Vasodilation of arterioles
a. Histamine and other vasodilators (e.g., nitric
oxide) relax vascular smooth muscle, causing
increased blood flow.
b

 Increased blood flow
due to vasodilation
of arterioles
increases
hydrostatic pressure
(HP) in venule
lumens.

3. Increased permeability
23
a. Histamine and other mediators contract endothelial
cells in venules, producing endothelial gaps
exposing bare basement membrane.
• Tight junctions are simpler in venules than in
arterioles.
 b. Transudate
 (fluid low in proteins and cells) moves through the intact
venular basementmembrane into interstitial tissue because
of the increased HP.

24

25

Vascular Leakage
5 Mechanisms
26
Gap due to Endothelial cell contraction
Direct endothelial cell injury
Leukocyte- dependent endothelial
injury
Increase transcytosis of fluid
Leakage from new vessels

1. Gap due to Endothelial cell contraction
 Histamines, bradykinins, leukotrienes
cause an early, brief (15 – 30 min.)
immediate transient response in the form
of endothelial cell contraction that widens
intercellular gaps of venules (not
arterioles, capillaries)
 Cytokine mediators (TNF, IL-1) induce
endothelial cell junction retraction through
cytoskeleton reorganization (4 – 6 hrs
post injury, lasting 24 hrs or more)

2. Immediate Transient Response
28
 Severe injuriesimmediate direct
endothelial cell damage (necrosis,
detachment) make leaky until they
are repaired (immediate sustained
response),
 Either immidiate or delayed(2-12
HRS)
 Immidiatebacterial infection
 Delayed Thermal or UV injury,

3. Leucocyte dependenet endotheial injury
29
 Marginating and endothelial cell-
adherent leukocytes may pile-up
 damage the endothelium through
activation and release of toxic oxygen
radicals and proteolytic enzymes
making the vessel leaky
 Some bacterial toxins (delayed
prolonged leakage)

4. Increase transcytosis of fluid
 Certain mediators (VEGF) may cause increased
transcytosis via intracellular vesicles which travel
from the luminal to basement membrane surface
of the endothelial cell
 All or any combination of these events may
occur in response to a given stimulus
 Vascular endothelial growth factor (VEGF)

5.Leakage from new vessels
31
 New blood vessels
leakage due to weak or
immature tight junction
of endothelial cells in
vessel
 Are under influence of
VEGF

Vascular event cont.…
4. Swelling of tissue (tumor,
edema)
32
 Net outflow of fluid
inscrease
 In venules surpasses of
lymphatics to remove
fluid
 swelling of tissue

5. Reduced blood flow
33
 • Reduced blood flow eventually
occurs because of outflow of fluid into
the interstitial tissue
 increased uptake of fluid by
lymphatics
 Reactive Lymphnodes

Cellular events
34
 Leucocytes exudation
 Phagocytosis
 Phagocytosis and degranulation
Leukocyte-induced tissue injury
Margination and Rolling
Adhesion and transmigration
Chemotaxis and Activation

35

Exudation of Leucocytes
36

Margination and Rolling
Normal flow
• RBCs and WBCs flow in the center of the
vessels.
When injury or changes
• flowing adjacent to endothelium
• Slow blood flow WBCs collect along the
endothelium
37

Margination
38
 Inscrease vascular
permeability, fluid leaves the
vessel causing leukocytes to
settle-out of the central flow
column and “marginate”
along the endothelial surface
 Endothelial cells and
leukocytes have
Endothelial complementary
surface adhesion
molecules which briefly stick
and release causing the
leukocyte to roll along the
endothelium
 Roll unitil it adhesion occurs
by different events
 pavementing

Rolling
39
 Peripherally marginated and
pavemented neutrophils slowly
roll over the endothelial cells
lining the vessel wall (rolling
phase).
 Transient bond between the
leucocytes and endothelial
cells becoming firmer
(adhesion phase).

Rolling and Adhesion
40
 Early rolling and adhesion
mediated by selectin
family:
 E-selectin ,P-selectin , L-
selectin
 They bind other surface
molecules (i.e.,CD34,
Sialyl-Lewis X-modified GP)
that are upregulated on
endothelium by cytokines
(TNF, IL-1) at injury sites
 Adhesion Mediated by
integrins ICAM-1 and
VCAM-1

4 Types of Adhesion and
migration Molecules
41
• Selectin(E,P& L selectin)
• Integrins (alpha and beta chains)
• Mucin(likee proteoglycan)
• Immunoglobulins(ICAM1,VCAM1)

Selectins
42
 E-selectin (on endothelium)
 P-selectin (on endothelium & platelets; is
preformed and stored in Weible Palade
bodies)
 L-selectin (leukocytes)
 Ligands for E-and P-Selectins are
sialylated glycoproteins (e.g Sialylated
Lewis X)
 Ligands for L-Selectin are Glycan-bearing
molecules such as GlyCam-1, CD34,

Integrins (a + b chain)
43
 Heterodimeric molecules
Integrin a
 von Willebrand factor (alpha)
 Binds to collagen
(e.g. integrins α1 β1, and α2 β1), OR
 act as cell-cell adhesion molecules (integrins of
the β2 family).

Integrin beta
44
 Expressed on leukocytes
 VLA-4 (b1 integrin) binds to VCAM-1
 LFA1 and MAC1 (CD11/CD18) = b2 integrin
bind to ICAM

Selectin
s
Integrins
45

Mucin-like glycoproteins
46
 Heparin sulfate (endothelium)
 Ligands for CD44 on leukocytes
 Bind chemokines

Immunoglobulin family
47
 ICAM-1 (intercellular adhesion molecule 1)
 VCAM-1 (vascular adhesion molecule 1)
 Are expressed on activated endothelium
 Ligands are integrins on leukocytes

Transmigration
48
 After sticking of
neutrophils to
endothelium,
 • Cross the basement
membrane by damaging
it locally called as
transmigration

Transmigration (diapedesis)
 Diapedesis –(cell crawling) escape of
red cells through gaps between the
endothelial cells
 Hemorragic inflamatory exudates
 Must then cross basement membrane
 Collagenases
 Integrins
 Platelet endothelial cell adhesion
molecule (PECAM-1)

Chemotaxis
51
 After extravasating from the blood,
Leukocytes migrate toward sites of infection
or injury along a chemical gradient by a
process called chemotaxis
 • They have to cross several barriers -
endothelium,
 basement membrane, perivascular
myofibroblasts and matrix.

Potent chemotactic substances or
chemokines for Neutrophils
52
– Leukotriene B4 (LT-B4) - arachidonic acid
metabolites.
– Components of complement system - C5a and
C3a in particular.
– Cytokines
– Interleukins, in particular IL-8
Chemotactic agents bind surface receptors
inducing calcium mobilization and assembly of
cytoskeletal contractile elements

There are three general modes of signaling-
Autocrine ,Paracrine, Endocrine
Autocrine: Cells respond to the molecule that they
themselves secrete
Paracrine: One cell type that contains an appropriate
receptor responds to the legand produced by the
adjacent cell.
Juxtacrine: the signaling molecule is anchored in a cell and
bind a receptor in the plasma membrane of another cell.
Endocrine: The signaling molecule, hormone, is
synthesized by cells of endocrine organs and acts on
target cells distant from there site of synthesis.
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54

Phagocytosis
55
process of engulfment of solid material by the cells.
2 main types of phagocytic cells
 Polymorphonuclear neutrophils (PMNs) : early in
acute inflammatory response, also known as
microphages
 Macrophages : Circulating monocytes and fixed
tissue mononuclear phagocytes
 They releases proteolytic enzymes-
 lysozyme, protease, collagenase, elastase, lipase,
proteinase, gelatinase and acid hydrolases

Phagocytosis and Degranulation
Involves three sequential steps
1. Recognition and attachment of the particle to be
ingested by leucocytes
2. Phagocytosis (engulf and destroys )
3. Killing/degranulation
56

Recognization and Attachment
57
 Phagocytosis is initiated by the expression of surface receptors
on macrophages.
 Its further enhanced when the microorganisms are coated with
specific proteins, opsonins.
 Establish a bond between bacteria and the cell membrane of
phagocytic cell.
 – Major opsonins are IgG opsonin ,C3b opsonin, Lectins

Engulfment
58
 Formation of cytoplasmic pseudopods around
the particle due to activation of actin filaments
around cell wall.
 • Eventually plasma membrane gets lysed and
fuses with nearby lysosomes –
phagolysosome

Killing and Degranulations
59
 Killing take place by Antibacterial substances
further degraded by hydrolytic enzymes
 Sometimes this process fails to kill and
degrade some bacteria like tubercle bacilli

Killing and degranulation
60
Intracellular mechanisms
1. Oxidative bactericidal mechanism
• oxygen free Radicals(oxidative brust)
• MPO-dependent, MPO-independent
• lysosomal granules
2. Non oxidative Mechanism
•Extracellular mechanisms
• – Granules
• – Immune mechanisms

Oxidative bactericidal mechanism by
oxygen free radicals.
62
 production of reactive oxygen metabolites (O’2
H2O2, OH’, HOCl, HOI, HOBr)
 activated phagocytic leucocytes requires the
essential presence of NADPH oxidase
 Reduction of oxygen to superoxide ion (O’2)

 superoxide reacts with NO--》peroxynitriteoxynitrite
 NO dilatates arterioles and venules
 Perioxidation of the protein and lipid

 Superoxide is subsequently converted into
H2O2 .
 Bactericidal activity is carried out either
via enzyme myeloperoxidase (MPO) or
MPO independent.
MPO dependent killings
 – MPO acts on H2O2 in the presence of
halides – form hypohalous acid (HOCl,
HOI, HOBr)
MPO independent killings
 Mature macrophages lack the enzyme
MPO.
 – bactericidal activity by producing OH–
ions and superoxide singlet oxygen (O’)
 – H2O2 in the presence of O’2 (Haber-
Weiss reaction) or in the presence of
Fe++ (Fenton reaction)

Deficiency of NADPH oxidase
 There will be no oxygen-dependent killing mechanism
(chronic granulomatous disease)
 Granulomatous inflammation occurs in tissue, because
the neutrophils, which can phagocytose bacteria but
not kill most of them, are eventually replaced by cells
associated with chronic inflammation, mainly
lymphocytes and macrophages.
 Macrophages fuse to form multinucleated giant cells,
which is a characteristic feature of granulomatous
inflammation

CGD
66
 Xlinked recessive
 Absence of NAPDH
Oxidase
 pneumonia
 abscesses of the skin,
tissues, and organs
 suppurative arthritis
 osteomyelitis
 bacteremia/fungemia

Myeloperoxidase (MPO)
deficiency
67
 Autosomal recessive
 Myeloperoxidase (MPO) deficiency differs from CGD
 in that both O2 •– and H2O2 are produced (normal respiratory
burst).
 However, the absence of MPO prevents synthesis of
HOCl•.

Tetrazolium Test
69

Lysosomal Granules killing
70
Oxidative bactericidal mechanism by lysosomal
granules
 – preformed granule-stored products of neutrophils and
macrophages.
 – secreted into the phagosome and the extracellular
environment.
Non-oxidative bactericidal mechanism
 Granules: cause lysis within phagolosome
 Lysosomal hydrolases, permeability increasing factors,
cationic proteins (defensins), lipases, ptoteases, DNAases.
 Nitric oxide : reactive free radicals similar to oxygen
free radicals
 – potent mechanism of microbial killing
 – produced by endothelial cells as well as by activated
macrophages

Extracellular Mechanism
71
 Granules
 Degranulation of macrophages and neutrophils
 Immune mechanisms
 – immune-mediated lysis of microbes
 – takes place outside the cells
 – by mechanisms of cytolysis, antibody-mediated
lysis and by cell-mediated cytotoxicity

 An 11-year-old child falls and cuts his hand. The
wound becomes infected. Bacteria extend into the
extracellular matrix around capillaries. In the
inflammatory response to this infection, which of
the following cells removes the bacteria?
 A B lymphocyte
 B Fibroblast
 C Macrophage
 D Mast cell
 E T lymphocyte

 A B lymphocyte
 B Fibroblast
 C Macrophage
 D Mast cell
 E T lymphocyte
Macrophages --phagocytic cells that
respond to a variety of stimuli,
The other cells listed are not phagocytes.
B cells secreting antibodies to neutralize
infectious agents.
Fibroblasts form collagen as part of a
healing response.
Mast cells can release a variety of
inflammatory mediators.
T cells are a key part of chronic
inflammatory processes in cell-mediated
immune responses.

 A 53-year-old woman has had a high fever and cough
productive of yellowish sputum for the past 2 days. Her vital
signs include temperature of 37.8° C, pulse 103/min,
respirations 25/min, and blood pressure 100/60 mm Hg. On
auscultation of the chest, crackles are audible in both lung
bases. A chest radiograph shows bilateral patchy pulmonary
infiltrates. Which of the following inflammatory cell types is
most likely to be seen in greatly increased numbers in her
sputum specimen?
 A Langhans giant cells
 B Macrophages
 C Mast cells
 D Neutrophils
 E T lymphocytes

 A Langhans giant
cells
 B Macrophages
 C Mast cells
 D Neutrophils
 E T lymphocytes
suggest acute bacterial pneumonia. Acute
infections induce an acute inflammation
dominated by neutrophils that fill alveoli,
and are coughed up, which gives the sputum
its yellowish, purulent appearance.
Langhans giant cells are seen in
granulomatous inflammatory responses.
Macrophages become more after initiation of
acute events, cleaning up tissue and bacterial
debris through phagocytosis.
Mast cells are better known as participants in
allergic and anaphylactic responses.
Lymphocytes are a feature of chronic
inflammation

 A 4-year-old child has had a high-volume diarrhea for the
past 2 days. On examination she is dehydrated. A stool
sample examined by serologic assay is positive for rotavirus.
She is treated with intravenous fluids and recovers. Which of
the following components is found on intestinal cells and
recognizes double-stranded RNA of this virus to signal
transcription factors that upregulate interferon production for
viral elimination?
 A Caspase-1
 B Complement receptor
 C Lectin
 D T cell receptor
 E Toll-like receptor

 A Caspase-1
 B Complement receptor
 C Lectin
 D T cell receptor
 E Toll-like receptor
double-stranded RNA of viruses,
bacterial DNA, and bacterial
endotoxin, can be recognized by Toll-
like receptors (TLRs) on human cells
as part of an innate defense
mechanism against infection.
Caspase-1 is activated by an
inflammasome complex of proteins
and produce active interleukin-1 (IL-
1).
Complement receptors on
inflammatory cells recognize
complement components that aid in
triggering immune responses through
co-stimulatory signals.
Lectins found on cell surfaces can
bind a variety of substances, such as
fungal polysaccharides, that trigger
cellular defenses.

 A woman who is allergic to cats visits a neighbor
who has several cats. During the visit, she inhales
cat dander, and within minutes, she develops
nasal congestion with abundant nasal secretions.
Which of the following substances is most likely to
produce these findings?
 A Bradykinin
 B Complement C5a
 C Histamine
 D Interleukin-1 (IL-1)
 E Phospholipase C
 F Tumor necrosis factor (TNF)

 A Bradykinin
 B Complement C5a
 C Histamine
 D Interleukin-1 (IL-
1)
 E Phospholipase C
 F Tumor necrosis
factor (TNF)
Histamine is found in abundance in mast cells,
which are normally present in connective
tissues next to blood vessels beneath mucosal
surfaces in airways.
Binding of an antigen (allergen) to IgE
antibodies that have previously attached to the
mast cells by the Fc receptor triggers mast cell
degranulation, with release of histamine. This
response causes increased vascular
permeability and mucous secretions.
Bradykinin, generated from the kinin system on
surface contact of Hageman factor with
collagen and basement membrane from
vascular injury, promotes vascular
permeability, smooth muscle contraction, and
pain.
Complement C5a is a potent chemotactic
factor for neutrophils.
Interleukin-1 (IL-1) and tumor necrosis factor
(TNF), both produced by activated
macrophages, mediate many systemic effects,
including fever, metabolic wasting, and

A 92-year-old woman is diagnosed with
Staphylococcus aureus pneumonia and receives a
course of antibiotic therapy. Two weeks later, she
no longer has a productive cough, but she still has
a temperature of 38.1° C. A chest radiograph shows
the findings in the figure. Which of the following
terms best describes the outcome of the patient’s
pneumonia?
A Abscess formation
B Complete resolution
C Fibrous scarring
D Chronic inflammation
E Tissue regeneration

A Abscess
formation
B Complete
resolution
C Fibrous scarring
D Chronic
inflammation
The rounded density in the right lower lobe of the
lung has liquefied contents that form a central air-
fluid level. There are surrounding infiltrates. The
formation of a fluid-filled cavity after infection with
Staphylococcus aureus suggests that liquefactive
necrosis The cavity is filled with tissue debris and
viable and dead neutrophils (pus). Localized, pus-
filled cavities are called abscesses.
Some bacterial organisms, such as S. aureus, are
more likely to be pyogenic, or pus-forming. With
complete resolution, the structure of the lung
remains almost unaltered.
Scarring or fibrosis may follow acute inflammation as
the damaged tissue is replaced by fibrous
connective tissue.
Most bacterial pneumonias resolve, and progression
to continued chronic inflammation is uncommon.
Lung tissue, in contrast to liver, is incapable of
regeneration, except for epithelium and endothelium.

A 9-year-old boy has had a chronic cough and fever for the past
month. A chest radiograph shows enlargement of hilar lymph
nodes and bilateral pulmonary nodular interstitial infiltrates. A
sputum sample contains acid-fast bacilli. A transbronchial biopsy
specimen shows granulomatous inflammation with epithelioid
macrophages and Langhans giant cells. Which of the following
mediators is most likely to contribute to giant cell formation?
A Complement C3b
B Interferon-γ
C Interleukin-1 (IL-1)
D Leukotriene B4
E Tumor necrosis factor (TNF)

A Complement C3b
B Interferon-γ
C Interleukin-1 (IL-1)
D Leukotriene B4
E Tumor necrosis factor
(TNF)
B Interferon-γ is secreted by activated T cells
and is an important mediator of granulomatous
inflammation. It causes activation of
macrophages and their transformation into
epithelioid cells and then giant cells.
Complement C3b acts as an opsonin in acute
inflammatory reactions.
Interleukin-1 (IL-1) can be secreted by
macrophages to produce various effects,
including fever, leukocyte adherence, fibroblast
proliferation, and cytokine secretion.
Leukotriene B4 induces chemotaxis in acute
inflammatory processes.
Tumor necrosis factor (TNF) can be secreted
by activated macrophages and induces
activation of lymphocytes and proliferation of
fibroblasts, which are other elements of a
granuloma.

Leukocyte express several receptors that
recognize external stimuli and deliver activating
signals
• Mannose Receptor
• Receptors for microbial products-toll like
receptors(TLRs)
• G protein-coupled receptors
• Receptors for opsonins
• Receptors for cytokines
85

86

87

88

Inflammatory Cells
The circulating cells includes-
 Neutrophils ,Monocytes
 Eosinophils,Lymphocytes
 Basophils ,Platelets
The connective tissue cells are-
 Mast cells
 Fibroblast
 Macrophages
 Lymphocytes
89

Inflammatory Cells
90

Vasodilatation:
• Histamine
• Prostaglandins
• Nitric oxide
Increased vascular permeability:
• Histamine
• Anaphylatoxins C3a and C5a
• Kinins
• Leukotrienes C, D, and E
• PAF
• Substance P
Chemotaxis:
• Complement fragment C5a
• Lipoxygenase products, lipoxins
& leukotrines (LTB4)
• Chemokines
Tissue Damage
• Lysosomal products
• Oxygen-derived radicals
• Nitric Oxyde
Events in Acute Inflammation(summary)

Chemical mediators
 Plasma-derived:
 Complement, kinins, coagulation factors
 Cell-derived:
 Preformed, sequestered and released (mast cell
histamine)
 Synthesized as needed (prostaglandin)

Chemical mediators
 May or may not utilize a specific cell surface
receptor for activity
 May also signal target cells to release other
effector molecules that either amplify or inhibit
initial response (regulation)
 Are tightly regulated:
 Quickly decay (AA metabolites), are inactivated
enzymatically (kininase), or are scavenged
(antioxidants)

Chemical mediators in inflammation
Cell mediators
 Preformed Mediator (secretory
granules)
 Newly formed
Plamsma Mediators
 Factor 12
 complement activation
94

Cellular Mediators
95
 Prefound mediators
 Histamines
 Serotonin
 Lysosomal enzymes
 New Mediators
 Prostaglandins
 Leucotrines
 Platelet activating factors
 Active oxygen specis
 Nitric oxide
 Cytokines

CHEMICAL MEDIATORS

Cell derived mediators-Vasoactive amines
Histamine –
1. Found in mast cells , basophils and platelets
2. Release in response to stimuli(trauma, infection)
3. Promotes arterioles dilation and venules endothelial
contraction
4. Results in widening of inter-endothelial cell junction
with increase in vascular permeability
5. anaphylatoxins (C3a, C5a fragments)
6. immune reactions (IgE-mast cell FcR),,
7. Neuropeptide substance p
8. Itching and pain
9. Neutralize by histaminase
97

Serotonin/5 hydroxytryptamine-
1. Vaso-active effects similar to histamine but less potent
2. Found in
1. chromaffin cells of GIT, spleen,
nervous system, mast cells and
platelets
3. Release when platelet aggregation
Medical uses
Antidepressant(SSRI), antipsychotic, antiemetics,
antimigrane
98

Arachodonic acid/eicosanoids
• AA is component of cell membrane
phospholipids
• Metabolites of AA –short range hormone
• Acts locally at the site of generation
• Rapidly decay or destroys
• activated by some stimuli or mediators like C5a so as to
form AA metabolites
• cause vasodilation and prolong edema; but also
protective (gastric mucosa);
• Derived from : Leukocytes, mast cells, endothelial cells, and platelets
• Dietary linoleic acid
99

lypoxygenase and cycloxygenase
Pathways
Cycloxygense
• synthesize-prostaglandin, thromboxane
,resolvins
Lypoxygenase
synthesize- leucotrines and lipoxins
100
AA metabolites occurs by two major pathways

Cycloxygense pathway
Prostaglandin-Increase vascular permeability,
vasodilatation, inhibit inflammatory cell function. PGD2,
PGE2 and PGF2-α)
Prostacyclin(PGI2)- Vasodilatation and inhibits platelet
aggregation
Thromboxane A2-Vasoconstriction,broncoconstriction,
enhances inflammatory cell function Promotes platelet
aggregation
Resolvins
101
a fatty acid enzyme present as COX-1 and COX-2,
Cycloxygense act on activated AA  form prostaglandin which further
activated by enzyme to form metabolites-
Major anti-inflammatory drugs act by inhibiting activity of the enzyme COX – NSAIDs &
COX-2
inhibitors

102

Lipoxygenase pathway
Leucotrines
Lipoxins
Causes Vasoconstriction, Bronchospasm, Increase
vascular permeability
103
lypoxygenase  Acts on AA
-form 5-HETE
(hydroperoxy eico-
astetraeonic acid) further
perioxidation forms 2
metabolites

104

105

106

Lysosomal components
107
 Inflammatory cells like neutrophils and monocytes – lysosomal
granules. Its of 2 types :
Granules of neutrophils
 – Primary or azurophil : myeloperoxidase, acid hydrolases, acid
phosphatase, lysozyme, defensin (cationic protein),
phospholipase, cathepsin G, elastase, and protease
 – Secondary or specific: alkaline phosphatase, lactoferrin,
gelatinase, collagenase, lysozyme, vitamin-B12 binding proteins,
plasminogen activator
 – Tertiary: gelatinase and acid hydrolases
Granules of monocytes and tissue macrophages
 – acid proteases, collagenase, elastase and plasminogen activator
 – more active in chronic inflammation

Platelet activating factor
Another phospholipids derived mediator release by
phospholipase Induces
Aggregation of platelets
Vasoconstriction induce vasodilation,
Inscrease vascular permeability
Broncho-constriction
• 100-1000 times more potent then histamine in inducing
vasodilatation and vascular permeability
• Enhances leukocyte adhesion, chemotaxis,
degranulation and oxydative burst
108

Cytokines
 polypeptide substances produced by activated lymphocytes
(lymphokines) and activated monocytes
(monokines).chemokines,Interleukins
Major cytokines in acute inflammation
– TNF and IL-1
Chemokines –
a group of chemoattractant cytokines
 Chronic inflammation :
 interferon-γ (IFN-γ) and IL-12

IL-1 /TNF
Acute phase reaction- Acute phase protein
hemodynamic effects , Decreases appetite
• Inscrease can damage BBB
• IL1 given after kidney tranplant for improve
engraftment
• IL beta 1given for the autoimmune disease or
lymphoma,RA
Prinical Role endothelial activation
Endothelial effects-
• Increases Leukocyte adhesion, PG synthesis, pro-
coagulants
111

IL1 and TNF
112
 May enter the circulation - systemic acute-
phase
reaction
 – Fever & lethargy
 – hepatic synthesis of various acute-phase
proteins,
 – metabolic wasting (cachexia),
 – neutrophil release into the circulation,
 – release of adrenocorticotropic hormone
(inducing corticosteroid synthesis and release).

114

Chemokines
115
 act primarily as chemoattractants for different
subsets of leukocytes
 Also activate leukocytes
 Chemokines are classified into four groups out
of which 2 are the major group
 CXC chemokines: IL-8
 CC chemokines : MCP-1
 C chemokines
 CX3 chemokines

Reactive Oxygen Species
116
 synthesized via the NADPH oxidase – from
neutrophils and macrophages
 by microbes, immune complexes, cytokines, and
a variety of other inflammatory stimuli
 Within lysosomes - destroy phagocytosed
microbes and necrotic cells
Levels o ROS
 Low level
 High Level

low levels-ROS
117
 – increase chemokine, cytokine, and adhesion
molecule expression
 – amplifying the cascade of inflammatory
mediators

High levels -ROS
118
tissue injury by several mechanisms
1. endothelial damage, with thrombosis and increased
permeability;
2. protease activation and antiprotease inactivation,
with a net increase in breakdown of the ECM;
3. direct injury to other cell types
• Various antioxidant - protective mechanisms
against this ROS
– catalase, superoxide dismutase, and glutathione

Neuropeptides
• Secreted by sensory nerves and various leucocytes
• Role in initiation and propagation of inflammatory
response
• Substance P and neurokinnin A are neuropeptides
• Has many biological function like transmission of
pain signals, regulation of B.P., increasing vascular
permeability
• • prominent in the lung and gastrointestinal tract
119

Nitric Oxide
 short-acting soluble free-
radical gas with many
functions
 Produced by endothelial
cells, macrophages,
 causes:
 Vascular smooth muscle
relaxation and vasodilation
 Kills microbes in activated
macrophages
 Counteracts platelet
adhesion, aggregation, and
degranulation

 Three isoforms of NOS
– Type I (nNOS) – neuronal,
– Type II (iNOS) – induced by chemical mediators,
macrophages and endothelial cells
– Type III (eNOS) - primarily (but not exclusively)
within endothelium

Plasma Mediators
122
 Factor 12 (Hageman factor )Activation
 KININ(Bradykinin)
 Coagulation and Fibrinolysis system
 Complement activation
 C3a,c5a(Anaphylatoxin)
 ,c3b,c5b-9(Membrane attach complex-MAC)

Hageman factor (factor XII)
123
• protein synthesized by the liver.
• initiates four systems involved in the
inflammatory response
– Kinin system - vasoactive kinins;
– Clotting system - inducing the activation of
thrombin,
fibrinopeptides, and factor X,
– Fibrinolytic system - plasmin and inactivating
thrombin;
– Complement system - anaphylatoxins C3a and
C5a

Kinin system
 Leads to formation of bradykinin from cleavage of
precursor (HMWK) High-molecular-weight
kininogen
 Vascular permeability
 Arteriolar dilation
 Non-vascular smooth muscle contraction (e.g.,
bronchial smooth muscle)
 Causes pain

Clotting system
125
 factor XIIa-driven proteolytic
cascade leads to activation of
thrombin.
Functions of thrombin
 – cleaves circulating soluble
fibrinogen to generate an
insoluble fibrin clot and
Fibrinopeptides –
Fibrinopeptides –
 increase vascular
permeability & chemotactic for
leukocytes.

Coagulation pathways
126
 Intrinsic Pathway
 Extrinsic pathway
 Common pathway

COMPLEMENT PATHWAY
 Components C1-C9 present in inactive form
 Activated via
 classic (C1) or alternative (C3) pathways to generate
MAC (C5 – C9) that punch holes in microbe
membranes
 In acute inflammation
 Vasodilation, vascular permeability, mast cell degranulation
(C3a, C5a)
 Leukocyte chemotaxin, increases integrin avidity (C5a)
 As an opsonin, increases phagocytosis (C3b, C3bi)

activation of active complement products is the activation of the
third component, C3 – C3a. • This occurs in 3 steps :
1. Classical Pathway : antigen-antibody
complexes
2. Alternative pathway : triggered by bacterial
polysaccharides - microbial cell-wall
components
3. Lectin pathway : plasma lectin binds to
mannose
residues on microbes – activates early
component of
the classical pathway
•As C3 activated – further activation of other complement

Complement system
)

The actions of activated complement system in
inflammation are as under:
– C3a, C5a, C4a (anaphylatoxins) - activate mast
cells and basophils to release of histamine
– C3b - an opsonin.
– C5a - chemotactic for leucocytes.
– Membrane attack complex (MAC) (C5b-C9) - a
lipid
dissolving agent and causes holes in the
phospholipid membrane of the cell

Outcomes of acute inflammation
1. Complete Resolution
2. Scarring or Fibrosis
3. Abscess formation
4. Progression to chronic inflammation
133

Possible outcomes of acute
inflammation
 Complete resolution
 Little tissue damage
 Capable of regeneration &restoration of
injury cell to normal

Resolution involves
135
 neutralization,
 spontaneous decay of chemical mediators ,
 subsequent return of normal vascular
permeability ,
 cessation of leukocyte infiltration ,
 death by apoptosis removes edema ,protein,
foreign substance & necrotic debris .

Scarring (fibrosis)
136
 In tissues unable to
regenerate
 Excessive fibrin
deposition organized
into fibrous tissue
 in many pyogenic
infection – intense
neutrophil infiltration
&liquefaction of tissue
– pus formation-
fibrosis.
Abscess
formation
 occurs with some
bacterial or fungal
infections
 Pneumonia, chronic
lung abscess, peptic
ulcer of duodenum or
stomach
Progression
to
chronic
inflammation

137

CHRONIC INFLAMMATION
• inflammation of prolonged duration(weeks
or months)
• The inflammation, tissue injury, are
attempts at repair
When acute phase cannot be resolved
Persistent injury or infection (ulcer, TB)
Prolonged toxic agent exposure (silica)
Autoimmune disease states (RA, SLE)
138

Events in Chronic Inflamation
139
– Angiogenesis
– Mononuclear cell infiltrate -
macrophages, lymphocytes, and plasma
cells
– Fibrosis - Scar

Causes of chronic inflammation
 Persistent infection-that are difficult
to eradicate
 Immune mediated inflammatory
disease
 Prolonged exposure to potentially
toxic agents, either exogenous or
endogenous
140

Morphological features of chronic
inflammation
1. Infiltration with mononuclear cell-macrophages,
lymphocytes, plasma cell
2. Tissue destruction-induced by persistent
offending agents or by inflammatory cells
3. Attempts at healing, replacement of damaged
tissue
4. (angiogenesis, fibrosis)
141

Chronic Inflammatory Cells and Mediators
142
 • Macrophages
 • Lymphocytes,
 • Plasma Cells,
 • Eosinophils,
 • Mast Cells

Role of Macrophages
Dominant cells of chronic inflammation
Macrophages in different cells
• liver - Kupffer cells
• lymph nodes - sinus histiocytes
• CNS-microglial cells
• lungs - alveolar macrophages
• Bone-osteoclast
• Skin and mucosaLangerhans cells
• Blood and bone marrowMonocytes(M1,M2)
• Kidney  Intraglomerular mesangial cells
• GranulomaEpithelioid cells
• Spleen  Red pulp macrophages (Sinusoidal lining
cells
• Peritoneal Cavity Peritoneal Macrophages
143

Lymphocytes-
• important role in chronic inflammation
• Uses same adherent molecule (selectin,
integrin, ligands) and chemokines to
migrate into inflammatory sites
Type of Lymphocytes
• B cells
• Humoral , antibody derived adaptive
immunity
• T cells
• Cell Mediated Adaptive immunity
• cell mediated and antibody mediated
immune reaction T and B cells
• Nature Killer Cells
• Cell mediated cytoxic innate
immunity
144

Plasma cells-
• Develops from activated B lymphocytes
• Produce antibodies against foreign bodies
• Present in germinal center of lymph nodes
B1 cells
B2 cells
Plasmablast
Eosinophils-
• Are abundant in immune reaction mediated by IgE and
in parasitic infection
Chemokine toxin
• is important for eosinophilic recruitment
• contribute to tissue damage in immune reactions such
as allergies
145

146

147
T-Lymphocytes
• T helper cells (CD4+ T cells)
• Produce cytokines
• Present with MHC class II molecules
• Cytotoxic T cells (CD8+ T cells)
• Destroy virus infected and tumor cells by toxic
granules
• With MHC I molecule
• Memory T cells(central, effector and resident memory
T cells)
• Present long time after resloving infection,CD4+
and CD8+
• Supressor T cells
• For immunological tolerance maintainance
• Natural Killer T cells
• Eliminate Tumore cells and Herpese infected cells

148

Mast cells-
• Widely distributed in connective tissue
• Contribute in acute and chronic inflammation
• Releases mediators such as histamine and
prostaglandin
• Responses occurs
• in allergic reaction to food, insect venom, or drugs,
anaphylaxis
• Mast cells also take part in chronic inflammation
• secrete a plethora of cytokine promote and limit
inflammatory reaction
149

Acute Phase Protein and Reaction
Acute Phase Reaction
• is positive or negative acute phase reaction in response
to inflammation
Acute phase proteins are protein that
• increase in plasma  Positive acute phase reaction
• Decrease in plasma  Negative acute phase reaction
150

Acute Phase reaction
151
Injury
inflammatory cells
neutrophil granulocytes and
macrophages) secrets
interleukins IL1, IL6 and
IL8, and
TNFα.(CYTOKINES)
liver produce
More acute-
phase proteins
Proteien
production of
proteins is
reduced;
reactants.
negative" acute-
phase reactants
Increased
acute phase
proteins MAY
promote
sepsis
At the same time

 Positive Acute phase Reactants
/Protients
 C reactive protein, amyloid protein, complement
factor, mannose binding protien, hepatoglobulin,
feritinin, fibrinogen are acute phase proteins
increase in infection
 Inhibit growth of microbes, negative feedback for
coagulation,chemotaxis, phagocytic effects
 Negative Acute phase
Reactants/proteins
 Decreases inflamation
 If decrease marker of inflamation
 Eg. Albumin, transferin, antithrombin decrease in

CRP and ESR
153
C-Reactive Protein
 rises rapidly , Increase in chronic infection, IL6 stimulate secrection from
macrophase
 CRP rises within two hours of the onset of inflammation,
 Higher levels are found in aging, late pregnant women, mild inflammation
and viral infections (10–40 mg/L), active inflammation, bacterial infection
(40–200 mg/L), severe bacterial infections and burns (>200 mg/L).
 Co-relates with ESR not always directly because of it is dependent
fibrinogen elevation
 can quickly return to within the normal range if treatment is employed. (in
active systemic lupus erythematosus, one may find a raised ESR but
normal C-reactive protein)
 Also indicate liver failure, marker for Obstructive Sleep Apnea (markedly
inscrease of CRP and ESR)
 Interferon alpha inhibits CRP production so decrease duing viral
infection
 Normal 5 and 10 mg/L

ESR
154
 half-life of approximately one week.
 remain higher for longer despite removal of the inflammatory stimuli.
elevated in
 MM, Lymphoma, Pregnency, Temporal ateritis,autoimmunine sle,
RA,subacute thyroiditis
 Chornoinc infection Tuberculosis, infective endocarditis
 For differentiating Kawasaki's disease from Takayasu's
arteritis(markedly high)
Decrease in
 polycythemia, hyperviscosity, sickle cell anemia, leukemia, low
plasma protein (due to liver or kidney disease) and congestive heart
failure.

Serum Protein Electrophorosis in
Inflamation
155
 Albumin is decreased because of increased
synthesis of acute phase reactants in the
liver.

The primary difference
between acute versus
chronic inflammation is the
marked increase in IgG
antibody production in
chronic inflammation
producing a diffusely
enlarged γ-globulin peak
(polyclonal
gammopathy).

SYSTEMIC EFFECTS OF CHRONIC INFLAMMATION
156
 Fever : infectious form of inflammation
 Anaemia : accompanied by anaemia of
varying degree
 Leucocytosis : leucocytosis but generally
there
 is relative lymphocytosis in these cases.
 ESR : elevated
 Amyloidosis : develop secondary systemic
amyloidosis.

Fever
157
Especially when inflammation is caused by infection
Pyrogens - Prostaglandin (PG) synthesis in the
vascular and perivascular cells of the
hypothalamus – NEUROTRANSMITTER- temp.
reset.
• Lipopolysaccharide (LPS) from bacterial cell wall
(Exogenous Pyrogens) – Leukocytes – cytokines
like IL1 & TNF (Endogenous Pyrogens) – COX )

Leukocyte count -
Usually climbs to 15,000 to 20,000
Bone marrow output is increased
Other systemic effects are –
• Increase pulse
• Increase blood pressure
• Shivering, chills
• Anorexia
• Malaise sometimes in severe bacterial infection
=sepsis
158

Tissue Repair
159

Repair of tissue two processes:
• growth of cells and tissue to replace lost
structures.
REGENERATION
• tissue response,
• to a wound
• to inflammatory processes
• to cell necrosis
• in an organ incapable of regeneration
• consist of variable proportion of two distinct
processes – regeneration and laying down of
fibrous tissue, or scar formation.
HEALING
160

Growth factors & cytokines in regeneration &
wound healing
Epidermal growth factor (EGF) Mitogenic; stimulate keratinocytes migration and
granulation tissue formation.
Transforming growth factor alpha (TGF-α) Similar to EGF; replication of hepatocytes.
Hepatocytes growth factor / Scatter factor (HGF) Proliferation of hepatocytes & epithelial / endothelial
cells
Vascular endothelial cell growth factor (A,B,C,D) Increased vascular permeability; mitogenic for
endothelial cells
Platelet deived growth factor (PDGF-A,B,C,D) Chemotaxis and activation of PMNs, macrophages &
fibroblast; Mitogenic for fibroblast endothelial cells;
stimulates angiogenesis and wound contracture.
Fibroblast growth factor 1,2 and family (FGF-1,2..) Chemotactic and mitogenic for fibroblast.
Angiogenesis, wound contraction & matrix deposition
Transforming growth factor-beta (TGF-β) Keratinocyte migration; Angiogenesis & fibroplasia;
regulates integrin expression.
Keratinocyte growth factor (KGF) also called FGF-7 Keratinocyte migration, proliferation & differentiation.
Insulin like growth factor (IGF-1) Synthesis of sulfated protioglycan, collagen.
Tumour necrosis factor (TNF) Activates macrophages, regulate other cytokines.
Interleukins (IL-1 etc.) Synthesis of IL-1 ; Angiogenesis ( IL-8).
Interferon (IFN-α etc.) Inhibit fibroblast proliferation & synthesis of MMPs.
161

Extracellular Matrix & Cell Matrix
Interactions
Constituent of ECM-
• Fibrous structural proteins e.g.
collagen & elastin.
• Adhesive glycoproteins.
• Proteoglycans and hyaluronic acid.
162
Synthesis & degradation of ECM
• involved in morphogenesis, wound healing,
chronic fibrotic processes & also in tumors
invasion and metastasis

 These
macromolecules in
ECM assemble into
two forms
 Interstitial matrix and
 Basement membrane

Interstitial matrix
Fibrillar & non-fibrillar
collagen
Elastin
Fibronectin
Proteoglycan
Hyaluronate
Other components
164
"HELP Form College":
Hyaluronic acid, Elastin, Laminin, Proteoglycan
Fibronectin,Collagen

BM consists of:-
165
Amorphous nonfibrillar collagen
(type-4)
Laminin
Heparin sulphate
Proteoglycan
Other glycoproteins

Repair by Healing, Scar Formation, and
Fibrosis
166
• Fibro-proliferative response that “patches” rather
than restores a tissue.
Process Involved
1. Induction of an inflammatory process
2. removal of damaged and dead tissue.
3. Proliferation and migration of parenchymal deposition.
4. Formation of new blood vessels (angiogenesis) and granulation
tissue.
5. . Synthesis of ECM proteins and collagen deposition.
6. Tissue remodeling
7. Wound contraction

• Inflammatory reaction contain the
damage, eliminates the
damaging stimulus, removes
injured tissue, initiates the
deposition of ECM components
• For tissue that are incapable of
regeneration repair is
accomplished by connective
tissue deposition , producing a
scar.
• If damages persists, inflammation
becomes chronic, tissue
damages and repair may occur
concurrently-FIBROSIS.
167

GRANULATION TISSUE
As early as 24 hours
fibroblasts and vascular
endothelial cell begin
proliferating to form a
specialized type of tissue that
is the hallmarks of healing,
called granulation tissue.
Characteristic:
• the formation of new small
blood vessels
(angiogenesis) and
• the proliferation of
fibroblasts .
168

Angiogenesis
Blood vessels are assembled during embryonic
development by vasculogenesis.
Angiogenesis/Neo-vascularization
• Process of blood vessel formation
• Fromed by
• EPCs (endothelial progenitor cells(bone
marrow)
• Banching
169

Angiogenesis from Endothelial
Precursor Cells
EPCsAngio-blasts
proliferate migrate to
peripheral
sitesdifferentiate into
endothelial cells that
form arteries, veins,
lymphatics .
Also can generate
pericytes and smooth
muscle cells of vessel
wall (periendothelial
cells)
170

Pericytes(
Rouget cells or
mural cells,)
171
 contractile cells that wrap around the endothelial cells of capillaries
and venules throughout the body.
 pericytes are embedded in basement membrane where they
communicate with endothelial cells of the body's smallest blood
vessels by means of both direct physical contact and paracrine
signaling
 help to sustain the blood–brain barrier as well as several other
homeostatic and hemostatic functions of the brain
 Pericytes regulate capillary blood flow, the clearance and
phagocytosis of cellular debris, and the permeability of the blood–
brain barrier.
 Deficienty cause damage to BBB

Angiogenesis from Pre-Existing
Vessels
Major steps:
• Vasodilatation increased permeability
• Proteolytic degradation of the BM of the parent vessel ( by metalopoteinase)
and disruption of cell-to-cell contact between endothelial cell of vessel (by
plasminogen activator).
• Migration of endothelial cells
• Proliferation of endothelial cells
• Maturation of endothelial cells & remodeling into capillary tube.
• Recruitment of periendothelial cells & formation of mature vessel.
172

ANGIOGENESIS FROM PRE-
EXISTING VESSELS
173

Scar formation
Scar formation can be divided in three processes-
• Emigration and proliferation of fibroblasts
• Deposition of ECM
• Tissue remodeling
• Degradation is achieved by
matrixmetaloproteinases
174

CUTANEOUS WOUND HEALING
It is divided into three phases-
• Inflammation
• Granulation tissue formation and re-
epithelization
• Wound contraction, ECM deposition and
remodeling
175

Wound healing types
176
According to nature of wound rather
than healing
 primary healing or healing by First
Intension
 Seondary healing or Healing by Second
Intension
 Tertirary Healing

HEALING BY PRIMARY INTENTION
Healing of clean wound, uninfected surgical incision
approximated by surgical suture
phases of healing are –
• Immidiate Phase
• Inflamatory Phase
• Poliferative Phase(epithelial cell)
• Granulization
• Fibrous tissue formation
• Remodelling
177

Immediately- 1st Day
178
capillaries of either side of
wound are thrombosed
 Gap is filled with blood
 Coagulation and sealing of
defect
 If clot reaches the surface, it
dries to form a crust or scab

Inflammatory phase( 2nd Day)
179
Neutrophils appear at margins
of incision
 Acute inflammatory
response on either side of
narrow incision space
 Swelling, redness, pain at
the wound site
 Epithelial cells at edge of
wound undergo mitosis and
begin to migrate across the
wound
2nd day-

Proliferative phase
Cellular proliferation involves three processes
1. Angiogenesis-the wound surface or edge is
relatively ischemic and healing cannot effectively
proceed until sufficient flow is restored Also called
as neo-vascularisation
2. formation of new blood vessels by proliferation
and
3. migration of endothelial cells from preexisting
blood vessels
180

Epithelial cell proliferation
The epidermis at the cut ends thickens (mitotic
division of basal cells)
Within 48 to 72 hrs ,epithelial cells from both the
margins grows towards the cut end depositing the
basement membrane as they moves
They fuses in the midline, beneath the scab, thus
producing a continuous but thin epithelial layer
181

• The neutrophils are largely replaced by macrophages.
•
• Granulation tissue progressively invades the incision
space.
• Collagen at first are vertically oriented, not bridging the
incision site
• Epithelial cells proliferation thickens
• The thickening of epidermal covering layer yields mature
epidermal architecture with surface keratinisation
By day 3:-
182

By day 5:-
• Incisional space is filled with granulation tissue.
• Neo-vascularization is maximal.
• Collagen begin to bridge the incision.
• Epidermis recovers its normal thickness.
• Surface keratinization starts
Day 7- interstitial matrix production
183

Day 10th
Fibrous Union phase begins on about 10th day184

Remodeling
Day 30
Scar is largely devoid of inflammatory cells and
covered by an essentially normal epidermis
Serine proteinases is important factor for
remodelling
3 Months
Devascularisation of tissue, remodeling of collagen by
enzyme action , scar is now minimum and merges
with surrounding tissues
185

Healing by second intention
• Edges are separated.
• More extensive loss of cells and tissue.
• Prone for infection
• Regeneration of parenchymal cells can not
completely restore the original architecture, and
• Hence, abundant granulation tissue grows is
referred to as secondary union.
• Cannot be brought together by sutures
186

Early phase
• Edges cannot be brought together
and defect remains
• Base of wound may covered with
plasma
• Plasma oozes out from the base of
the wound
• Wound are filled with the blood from
the cut ends of capillaries, fibrin
threads and platelets
187

One week approximately-
• Fibrovascular granulation tissue
gradually fills the wound space and
epithelium grows over its surface
• The exudative inflammatory changes
and migration of neutrophills subsides
• Formation of loose connective tissue
by fibroblast
• Macrophages come to clear the debris
• Granulation tissue grows into the
wound from the base
188

Second week-
• During the second week continuous accumulation of
collagen and proliferation of fibroblast
• Leukocyte infiltration, edema, increased vascularity is
greatly reduced
• Increased collagen deposition within the incision scar
and disappearance of vascular channels
Months
• Contraction of wound by myofibroblast present in
granulation tissue
• Wound contraction occur in case of shrinkage of
granulation tissue that pulls the edges together
189

190

Wound strength
First week:- 10 % of unwounded
Next 4 weeks:- rapid increase
3rd month:- rate slows down & reaches a plateau at
about 70 % to 80 % of tensile strength.
191

Local & Systemic factors that
influence Wound Healing
Systemic factors:-
– Nutrition: Vit-c def. retards healing
– Metabolic state: Diabetes retards healing.
– Circulatory status: atherosclerosis and
venous diseases retards healing
– Hormones: glucocorticoids have anti-
inflammatory effects & inhibits collagen
synthesis.
192

• Local factors:-
– Infection (most imp.) retards healing
– Mechanical factors:- early motion retards
healing
– Foreign bodies: inhibits healing
– Size location & type of wound: richly
vascularised sites heal quickly

Complications In Cutaneous Wound Healing
Deficient scar formation
Excessive formation of the repair components
The accumulation of excessive amounts
of collagen may give to a raised scar
known as a hypertrophic scar
If scar tissue grows beyond the
boundaries of the original wound and
does not regress, it is called a keloid
194
Normal scars have collagen bundles that
are randomly arrayed (not all in the same
direction), whereas keloids and
hypertrophic scars have stretched
collagen bundles
arranged in the same plane as the
epidermis.

 Exuberant proliferation –
 Desmoids, or aggressive
fibromatoses (interface
between benign proliferations
and malignant tumors)
 Formation of contractures:
Serious burns.

Repair in other tissue
196
Liver
 Mild injury (e.g., hepatitis
A)
 Regeneration of hepatocytes
with restoration
Severe or persistent injury
(e.g., hepatitis C)
 Regenerative nodules develop
that show twinning of liver
cell plates (two cells thick);
 a double line of hepatocytes is
present, and nuclei seem to
run in parallel cirrhosis

Lungs
197
 Type II pneumocytes are the key repair cells
of the lung.
 b. Replace damaged type I and type II
pneumocytes and synthesize surfactant.

Brain
 Gliosis  Astrocytes proliferate in response to an
injury (e.g., brain infarction).
 Microglial cells (macrophages) are scavenger
cells that remove debris (e.g., myelin).
 Peripheral nerve transection
 If muscle not innervatedatrophy in 15 days
 Wallerian degeneration distal degeneration of
the axon and myelin sheath and proximal
axonal degeneration up to the next node of
Ranvier.
 axon grows 2 to 3 mm/day.

Heart
a. Cardiac muscle is permanent tissue.
b. Damaged muscle is replaced by noncontractile
scar tissue.
6. Skeletal muscle postexercise
a. After exercise, there is damage to the
sarcomeres in skeletal muscle.
b. Satellite cells are stem cells that repair and
form new myofibers in sarcomeres that have
been damaged by mechanical strain.

Tertiary Healing or Delayed
Primary closure
200
 Healing by debridement
 Antibiotics
 Flaps, grafts

201

 A 65-year-old man develops worsening congestive heart
failure 2 weeks after an acute myocardial infarction. An
echocardiogram shows a markedly decreased ejection
fraction. Now, capillaries, fibroblasts, collagen, and
inflammatory cells have largely replaced the infarcted
myocardium. Which of the following inflammatory cell types in
this lesion plays the most important role in the healing
process?
 A Eosinophils
 B Epithelioid cells
 C Macrophages
 D Neutrophils
 E Plasma cells

 A Eosinophils
 C Macrophages
 D Neutrophils
 E Plasma cells
Macrophages, present in such lesions, play a
prominent role in the healing process. Activated
macrophages can secrete various cytokines that
promote angiogenesis and fibrosis, including
platelet-derived growth factor, fibroblast growth
factor, interleukin-1 (IL-1), and tumor necrosis
factor (TNF).
Eosinophils are most prominent in allergic
inflammations and in parasitic infections.
Epithelioid cells, which are aggregations of
activated macrophages, are typically seen with
granulomatous inflammation, and the healing of
acute inflammatory processes does not involve
granulomatous inflammation.
Neutrophils are most numerous within the initial
48 hours after infarction, but are not numerous
after the first week.
Plasma cells can secrete immunoglobulins and
are not instrumental to healing of an area of
tissue injury

 A 77-year-old woman experiences a sudden loss
of consciousness, with loss of movement on the
right side of the body. Cerebral angiography
shows an occlusion of the left middle cerebral
artery. Elaboration of which of the following
mediators will be most beneficial in preventing
further ischemic injury to her cerebral cortex?
 A Bradykinin
 B Leukotriene E4
 C Nitric oxide
 D Platelet-activating factor
 Thromboxane A2

A Bradykinin
B Leukotriene E4
C Nitric oxide
D Platelet-activating factor
Thromboxane A2
Endothelial cells can release
nitric oxide to promote
vasodilation in areas of ischemic
injury.
Bradykinin mainly increases
vascular
permeability and produces pain.
Leukotriene E4, platelet-
activating factor, and
thromboxane A2 have
vasoconstrictive properties.

 35-year-old woman takes acetylsalicylic acid
(aspirin) for arthritis. Although her joint pain is
reduced with this therapy, the inflammatory
process continues. The aspirin therapy alleviates
her pain mainly through reduction in the
synthesis of which of the following mediators?
 A Complement C1q
 B Histamine
 C Leukotriene E4
 D Nitric oxide
 E Prostaglandins

A Complement C1q
B Histamine
C Leukotriene E4
D Nitric oxide
E Prostaglandins
E Prostaglandins are produced through the
cyclooxygenase pathway of arachidonic acid
metabolism.
Aspirin and other nonsteroidal anti-
inflammatory drugs block the synthesis of
prostaglandins, which can produce pain.
Complement
C1q is generated in the initial stage of
complement activation, which can eventually
result in cell lysis.
Histamine is mainly a vasodilator.
Leukotrienes are generated by the
lipoxygenase pathway, which is not blocked
by aspirin.
Nitric oxide released from endothelium is a

 A 54-year-old man undergoes laparoscopic hernia
repair. In spite of the small size of the incisions, he
has poor wound healing. Further history reveals
that his usual diet has poor nutritional value and is
deficient in vitamin C. Synthesis of which of the
following extracellular matrix components is most
affected by this deficiency?
 A Collagen
 B Elastin
 C Fibronectin
 D Integrin
 E Laminin

 A 54-year-old man undergoes
laparoscopic hernia repair. In spite
of the small size of the incisions, he
has poor wound healing. Further
history reveals that his usual diet
has poor nutritional value and is
deficient in vitamin C. Synthesis of
which of the following extracellular
matrix components is most affected
by this deficiency?
 A Collagen
 B Elastin
 C Fibronectin
 D Integrin
 E Laminin
A Vitamin C deficiency leads to scurvy,
with reduced lysyl oxidase enzyme
activity that helps cross-link fibrillar
collagens to provide tensile strength.
Though elastin is a fibrillar protein, it
tends to regenerate poorly in scar
tissue, even with the best of nutrition,
explaining why a scar does not stretch
like the skin around it.
The other listed choices are
glycoproteins that have an adhesive
quality and are not vitamin C
dependent.

 A 37-year-old man has had midepigastric pain for the past 3
months. An upper gastrointestinal endoscopy shows a 2-cm,
sharply demarcated, shallow ulceration of the gastric antrum.
Microscopic examination of a biopsy from the ulcer base
shows angiogenesis, fibrosis, and mononuclear cell infiltrates
with lymphocytes, macrophages, and plasma cells. Which of
the following terms best describes this pathologic process?
 A Acute inflammation
 B Chronic inflammation
 C Fibrinous inflammation
 D Granulomatous inflammation
 E Serous inflammation

 A Acute
inflammation
 B Chronic
inflammation
 C Fibrinous
inflammation
 D Granulomatous
inflammation
 E Serous
inflammation
B One outcome of acute inflammation with
ulceration is chronic inflammation. This is
particularly true when the inflammatory process
continues for weeks to months. Chronic
inflammation is characterized by tissue
destruction, mononuclear cell infiltration, and
repair.
In acute inflammation, the healing process of
fibrosis and angiogenesis has not begun.
In fibrinous inflammation, typically involving a
mesothelial surface, there is an outpouring of
protein-rich fluid that results in precipitation of
fibrin.
Granulomatous inflammation is a form of chronic
inflammation in which epithelioid macrophages
form aggregates.
Serous inflammation is an inflammatory process
involving a mesothelial surface (e.g., lining of the

 A 65-year-old man develops worsening congestive heart
failure 2 weeks after an acute myocardial infarction. An
echocardiogram shows a markedly decreased ejection
fraction. Now, capillaries, fibroblasts, collagen, and
inflammatory cells have largely replaced the infarcted
myocardium. Which of the following inflammatory cell types in
this lesion plays the most important role in the healing
process?
 A Eosinophils
 C Macrophages
 D Neutrophils
 E Plasma cells

A Eosinophils
B Epithelioid cells
C Macrophages
D Neutrophils
E Plasma cells
Macrophages, present in such lesions, play a
prominent role in the healing process. Activated
macrophages can secrete various cytokines that
promote angiogenesis and fibrosis, including
platelet-derived growth factor, fibroblast growth
factor, interleukin-1 (IL-1), and tumor necrosis
factor (TNF).
Eosinophils are most prominent in allergic
inflammations and in parasitic infections.
Epithelioid cells, which are aggregations of
activated macrophages, are typically seen with
granulomatous inflammation, and the healing of
acute inflammatory processes does not involve
granulomatous inflammation.
Neutrophils are most numerous within the
initial 48 hours after infarction, but are not
numerous after the first week.
Plasma cells can secrete immunoglobulins and
are not instrumental to healing of an area of

 One month after an appendectomy, a 25-year-old woman
palpates a small nodule beneath the skin at the site of the
healed right lower quadrant sutured incision. The nodule is
excised, and microscopic examination shows macrophages,
collagen deposition, small lymphocytes, and multinucleated
giant cells. Polarizable, refractile material is seen in the
nodule. Which of the following complications of the surgery
best accounts for these findings?
 A Abscess formation
 B Chronic inflammation
 C Exuberant granulation tissue
 D Granuloma formation
 E Healing by second intention

 A Abscess formation
 B Chronic
inflammation
 C Exuberant
granulation tissue
 D Granuloma
formation
 E Healing by second
intention
The polarizable material is the suture,
and a multinucleated giant cell reaction,
typically with foreign body giant cells, is
characteristic of a granulomatous
reaction to foreign material.
Granulation tissue may form a nodular
appearance, and begins to appear 3 to
5 days following injury, but is unlikely to
persist for a month.
Chronic inflammation alone is unlikely to
produce a localized nodule with giant
cells.
Edema refers to accumulation of fluid in
the interstitial space. It does not
produce a cellular nodule.
If a large, gaping wound is not closed
by sutures, it can granulate it and

 A 24-year-old man with acute appendicitis
undergoes surgical removal of the inflamed
appendix. The incision site is sutured. A trichrome-
stained section representative of the site with blue
appearing collagen is shown in the figure. How
long after the surgery would this appearance most
likely be seen?
 A 1 day
 B 2 to 3 days
 C 4 to 5 days
 D 2 weeks
 E 1 month

 A 1 day
 B 2 to 3 days
 C 4 to 5 days
 D 2 weeks
 E 1 month
The figure shows dense collagen with
some remaining dilated blood vessels,
typical of the final phase of wound
healing, which is extensive by the end of
the first month.
On day 1, filled only with fibrin and
inflammatory cells.
2-3 days Macrophages and granulation
tissue are seen
4 and 5 days. Neovascularization is most
prominent
week 2, collagen is prominent, and fewer
vessels and inflammatory cells are seen.

 A 23-year-old woman receiving corticosteroid
therapy for an autoimmune disease has an
abscess on her upper outer right arm. She
undergoes minor surgery to incise and drain the
abscess, but the wound heals poorly over the next
month. Which of the following aspects of wound
healing is most likely to be deficient in this
patient? A Collagen deposition
 B Elaboration of VEGF
 C Neutrophil infiltration
 D Reepithelialization
 E Serine proteinase production

 B Elaboration of
VEGF
 C Neutrophil
infiltration
 D Reepithelialization
 E Serine proteinase
production
A Glucocorticoids inhibit wound healing
by impairing collagen synthesis. This is
a desirable side effect if the amount of
scarring is to be reduced, but it results
in the delayed healing of surgical
wounds.
Angiogenesis driven by vascular
endothelial growth factor (VEGF) is not
significantly affected by corticosteroids.
Neutrophil infiltration is not prevented
by glucocorticoids.
Reepithelialization, in part driven by
epidermal growth factor, is not affected
by corticosteroid therapy.
Serine proteinases are important in
wound remodeling.

Thankyou
220

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