INFLAMMATION & REPAIR CONTENTS INFLAMMATION DEFINITION SIGNS TYPES OF INFLAMMATION REPAIR WOUND HEALING FRACTURE HEALING REFERENCES INFLAMMATION DEFINITION Inflammation is defined as the local response of living mammalian tissues to injury due to any agent. It is a body defense reaction in order to eliminate or limit the spread of injurious agent, followed by removal of the necrosed cells and tissues. Inflammation: Beneficial or Harmful? Inflammation is usually a protective response, which is beneficial for human body. The purpose of inflammation is: To dilute, localize and destroy injurious agent. To limit tissue injury. To restore the tissue towards normality. However, inflammation may be harmful if left untreated or the inflammation due to hypersensitivity reactions.

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2. BY
T.ANANYA
I MDS
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3. CONTENTS
 INFLAMMATION
DEFINITION
SIGNS
TYPES OF INFLAMMATION
 REPAIR
 WOUND HEALING
 FRACTURE HEALING
 REFERENCES
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4. INFLAMMATION
DEFINITION
Inflammation is defined as the local response of living
mammalian tissues to injury due to any agent. It is a
body defense reaction in order to eliminate or limit the
spread of injurious agent, followed by removal of the
necrosed cells and tissues.
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5. Inflammation: Beneficial or Harmful?
 Inflammation is usually a protective response, which
is beneficial for human body. The purpose of
inflammation is:
 To dilute, localize and destroy injurious agent.
 To limit tissue injury.
 To restore the tissue towards normality.
 However, inflammation may be harmful if left
untreated or the inflammation due to hypersensitivity
reactions.
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6. CAUSATIVE AGENTS
The agents causing inflammation may be as under:
1. Infective agents.
2. Immunological agents.
3. Physical agents.
4. Chemical agents.
5. Inert materials such as foreign bodies.
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SIGNS
• 4 Cardinal signs (Celsus)
– Rubor (redness)
– Tumor (swelling)
– Calor (heat)
– Dolor (pain)
• 5th sign functio laesa (loss of function) - Virchow

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TYPES OF INFLAMMATION
• Mainly of 2 types i.e. acute and chronic.
• Acute Inflammation
– short duration
– represents the early body reaction- followed by healing.
• Chronic inflammation
– longer duration
– causative agent of acute inflammation persists for a long
time.
• Another variant, Chronic active inflammation :
stimulus is such that it induces chronic inflammation from
the beginning.

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Acute inflammation
• The main features of
Acute inflammation are:
– Accumulation of fluid
and plasma at the
affected site.
– Intravascular activation
of platelets.
– Polymorphonuclear
neutrophils as
inflammatory cells.

10. ACUTE INFLAMMATION
 Acute inflammatory response by the host to any agent is
a continuous process & it can be divided into following
two events:
I. Vascular events.
II. Cellular events.
I. VASCULAR EVENTS
 Alteration in the microvasculature (arterioles, capillaries
and venules) is the earliest response to tissue injury.
 These alterations include: haemodynamic changes and
changes in vascular permeability.
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11. Sequence of Hemodynamic Changes
Transient vasoconstriction of arterioles
Persistent progressive vasodilation of arterioles
Elevation of local hydrostatic pressure
Transudation of fluid into extracellular space
Slowing or stasis of microcirculation
Leucocytic margination
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12. Lewis experiment:
 Lewis induced the changes in the skin of inner aspect of
forearm by firm stroking with a blunt point  Triple response
or red line response :
i) Red line appears within a few seconds following stroking
& is due to local vasodilatation of capillaries & venules.
ii) Flare - flush surrounding the red line & results from
vasodilatation of the adjacent arterioles.
iii) Wheal - swelling or oedema of the surrounding skin due
to transudation of fluid into the extravascular space.
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13. ‘Triple response’ elicited by firm stroking of skin of forearm
with a pencil.
1) Red line 2) Flare 3) Wheal
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14. Changes in vascular permeability:
• Starling’s hypothesis.
• In normal circumstances, the fluid balance is maintained
by two opposing sets of forces:
i) Forces that cause outward movement of fluid from
microcirculation are intravascular hydrostatic pressure
& colloid osmotic pressure of interstitial fluid.
ii) Forces that cause inward movement of interstitial fluid
into circulation are intravascular colloid osmotic pressure
and hydrostatic pressure of interstitial fluid.
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MECHANISMS OF SED VASCULAR PERMEABILITY
1. Contraction of endothelial cells.
2. Retraction of endothelial cells.
3. Direct injury to endothelial cells.
4. Endothelial injury mediated by leucocytes.
5. Leakiness and neo-vascularisation.

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CONTRACTION OF ENDOTHELIAL CELLS
• Affects venules exclusively.
• Endothelial cells develop
temporary gaps.
• Contraction resulting in
vascular leakiness.
• Mediated by the release of
Histamine, Bradykinin and
other chemical mediators.
• Short duration (15-30
minutes) - immediately
after injury.

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RETRACTION OF ENDOTHELIAL CELLS
• Structural re-organisation of
the cytoskeleton of endothelial cells – Reversible
retraction at the intercellular
junctions.
• Mediated by cytokines such
as interleukin-1 (IL-1) and
tumour necrosis factor
(TNF)-α.

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DIRECT INJURY TO ENDOTHELIAL CELLS
• Causes cell necrosis and
appearance of physical gaps.
• Process of thrombosis is initiated
at the site of damaged endothelial
cells.
• Affects all levels of microvasculature.
• It either appear immediately after
Injury & last for several hrs or
days e.g; severe bacterial infections.
• Or delay of 2-12 hours and last for
hours or days - moderate thermal
injury and radiation injury.

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ENDOTHELIAL INJURY MEDIATED BY LEUCOCYTES
• Adherence of leucocytes to the endothelium at the site of
inflammation.
• Activation of leucocytes – by release of proteolytic
enzymes and toxic oxygen.
• Cause endothelial injury & increased vascular leakiness.
• Affects mostly venules and is a late response.

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LEAKINESS AND NEOVASCULARISATION
• Newly formed capillaries under the influence of vascular
endothelial growth factor (VEGF).
• During the process of repair and in tumours are
excessively leaky.

22. CHEMICAL MEDIATORS OF INFLAMMATION
• These are a large and increasing number of endogenous
compounds which can enhance vascular permeability.
• The substances acting as chemical mediators of
inflammation may be released from the cells, the plasma,
or damaged tissue itself. They are broadly classified into
2 groups:
i) Mediators released by cells.
ii) Mediators originating from plasma.
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24. INFLAMMATORY CELLS AND MEDIATORS
• Macrophages
• Lymphocytes,
• Plasma Cells,
• Eosinophils,
• Mast Cells
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25. MACROPHAGES
 “Big eater” cells
 Dominant cells of chronic inflammation
 Develop in the bone marrow as monocytes, which
circulates in the blood stream & settle down in other
body tissues.
 Macrophages present in skin – Langerhans cells
Liver - Kupffer cells.
Bone - osteoclasts.
Lymph nodes - sinus histiocytes
Central nervous system - Microglial cells
Lungs - alveolar macrophages
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26. LYMPHOCYTES
• The 2 main classes of lympocytes are
• T cells- attack foreign cells directly.
• B cells- multiply to become plasma cells.
• T and B lymphocytes migrate to inflammatory sites –
chemokines.
• Lymphocytes and macrophages interact in a
bidirectional way
•Plays an Important role in chronic inflammation.
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27. EOSINOPHILS
• Inflammatory sites around parasitic infections or as
part of immune reactions mediated by IgE
• Associated with allergies
• Induced by specific chemokines – Eotaxin
• Granules contain major basic highly charged cationic
protein
– toxic to parasites
– also causes epithelial cell necrosis
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28. MAST CELLS
• Sentinel (watch) cells widely distributed in
connective tissues throughout the body
• Seen in both acute and chronic inflammatory
responses.
• It elaborate cytokines such as TNF and chemokines
– Mast cells armed with IgE antibody
– As the environmental antigens enters it releases
histamines and Arachidonic Acid metabolites
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29. II. CELLULAR EVENTS
• Consists of 2 processes:
- Exudation of leucocytes
- Phagocytosis
• Exudation of Leucocytes
• The escape of leucocytes from the lumen of
microvasculature to the interstitial tissue is the most
important feature of inflammatory response.
• The changes leading to migration of leucocytes are:
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30. i) Changes in the formed elements of blood:
There is slowing or stasis of bloodstream. With stasis,
changes in the normal axial flow of blood in the
microcirculation takes place.The central stream of cells
widens & peripheral plasma zone becomes narrower
(margination) & the neutrophils of the central column come
close to the vessel wall (pavementing).
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31. ii) Rolling And Adhesion:
Peripherally marginated & pavemented neutrophils
slowly roll over the endothelial cells lining the vessel
wall (rolling phase), followed by the transient bond
between the leucocytes & endothelial cells becoming
firmer (adhesion phase).
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32. iii) Emigration:
After sticking of neutrophils to endothelium, they become
lodged between the endothelial cells & basement
membrane, cross it by damaging it locally with secreted
collagenases and escape out into the extravascular space
(emigration). Simultaneously escape of red cells through
gaps between the endothelial cells, (diapedesis) occurs.
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iv) Chemotaxis:
The chemotactic factor-mediated transmigration of
leucocytes after crossing several barriers to reach the
interstitial tissues is called chemotaxis. It is mediated by
cytokines ,leukotrienes, complement proteins etc..

34. Sequence of changes in the exudation of leucocytes. A, Normal axial flow
of blood with central column of cells and peripheral zone of cell-free
plasma. B, Margination and pavementing of neutrophils with narrow
plasmatic zone. C, Adhesion of neutrophils to endothelial cells with
pseudopods in the intercellular junctions. D, Emigration of neutrophils
and diapedesis with damaged basement membrane.
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35. PHAGOCYTOSIS:
• Phagocytosis is defined as the process of engulfment
of solid particulate material by the cells (cell-eating).There
are 2 main types of phagocytic cells:
• i) Polymorphonuclear neutrophils (PMNs) which appear
early in acute inflammatory response, sometimes called as
microphages.
• ii) Circulating monocytes and fixed tissue mononuclear
phagocytes, commonly called as macrophages.
• The microbe undergoes the process of phagocytosis by
polymorphs and macrophages and involves 3 steps
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36. 1. RECOGNITION AND ATTACHMENT
Phagocytosis is initiated by the expression of surface
receptors on macrophages.which recognise microorganisms
The process of phagocytosis is further enhanced when the
microorganisms are coated with specific proteins,(opsonins)
establish a bond between bacteria and the cell membrane of
phagocytic cell.
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2. ENGULFMENT
Formation of cytoplasmic pseudopods around the particle due
to activation of actin filaments beneath cell wall, enveloping it in
a phagocytic vacuole.
Eventually, the plasma membrane enclosing the particle
breaks from the cell surface so that membrane lined phagocytic
vacuole or phagosome lies internalised and free in the cell
cytoplasm. The phagosome fuses with one or more lysosomes
of the cell and form bigger vacuole called phagolysosome.

38. 3. KILLING AND DEGRADATION
• The microorganisms after being killed by
antibacterial substances are degraded by hydrolytic
enzymes.
• However, this mechanism fails to kill and degrade
some bacteria like tubercle bacilli.
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39. CHRONIC INFLAMMATION
• Chronic inflammation is defined as prolonged process in
which tissue destruction and inflammation occur at the
same time.
• CAUSES
- Following acute inflammation
- Recurrent attacks of acute inflammation
- Chronic inflammation starting from the begining
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40. GENERAL FEATURES
• 1. MONONUCLEAR CELL INFILTRATION: Chronic
inflammatory lesions are infiltrated by mononuclear
inflammatory cells like phagocytes and lymphoid cells.
• The macrophages comprise the most important cells in
chronic inflammation.
• These may appear at the site of chronic inflammation from:
i) chemotactic factors and adhesion molecules for continued
infiltration of macrophages;
ii) local proliferation of macrophages; and
iii)longer survival of macrophages at the site of inflammation.
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2. TISSUE DESTRUCTION OR NECROSIS:
• This is brought about by activated macrophages
which release a variety of biologically active
substances e.g. protease, elastase, collagenase etc..
3. PROLIFERATIVE CHANGES:
• As a result of necrosis, proliferation of small blood
vessels and fibroblasts is stimulated resulting in
formation of inflammatory granulation tissue.

42. • TYPES OF CHRONIC INFLAMMATION
I) Conventionally Non-specific
Specific
II) Histological Chronic non-specific
Chronic granulomatous
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43. GRANULOMATOUS INFLAMMATION
• Granuloma is defined as a circumscribed, tiny lesion,
about 1 mm in diameter, composed predominantly of
collection of modified macrophages called epithelioid cells,
and rimmed at the periphery by lymphoid cells.
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MECHANISM OF GRANULOMA FORMATION

45. REGULATION OF INFLAMMATION
i)Acute phase reactants: A variety of (APR) proteins are
released in plasma in response to tissue trauma and
infection. APRs include the following:
i) Certain cellular protection factors (e.g. α1-antitrypsin,α1
chymotrypsin, α2- antiplasmin, plasminogen activator
ii) Some coagulation proteins (e.g. fibrinogen,
plasminogen, vonWillebrand factor, factor VIII)
iii) Transport proteins (e.g. ceruloplasmin, haptoglobin)
iv) Immune agents (e.g. serum amyloid A & P component,
C reactive protein).
v) Stress proteins (e.g. heat shock proteins,ubiquitin)
vi) Antioxidants (e.g. ceruloplasmin are active in elimination
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46. ii) Glucosteroids: The endogenous glucocorticoids
act as anti-inflammatory agents. Their levels are
raised in infection and trauma by self-regulating
mechanism.
iii) Free cytokine receptors: The presence of
freely circulating soluble receptors for cytokines
in the serum correlates directly with disease
activity.
iv) Anti-inflammatory chemical mediators:
PGE2 or prostacyclin have both pro-
inflammatory as well as anti-inflammatory
actions.
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47. REPAIR
• Repair is the replacement of injured tissue by fibrous
tissue.
• Includes 2 processes:
1. Granulation tissue formation.
2. Contraction of wounds.
• Repair response takes place by participation of
mesenchymal cells (consisting of connective tissue
stem cells, fibrocytes and histiocytes), endothelial
cells, macrophages, platelets, and the parenchymal
cells of the injured organ.
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48. 1. Granulation tissue formation:
involves 3 phases
i) Phase of inflammation: Following trauma,
blood clots at the site of injury. There is acute
inflammatory response with exudation of plasma,
neutrophils and some monocytes within 24 hours.
• ii) Phase of clearance: Combination of proteolytic
enzymes liberated from neutrophils, autolytic enzymes
from dead tissues cells, and phagocytic activity of
macrophages clear off the necrotic tissue, debris & RBC.
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49. • iii) Phase of Ingrowth of granulation tissue:
• This phase consists of 2 main processes: angiogenesis or
neovascularisation, and fibrogenesis.
• a) Angiogenesis (neovascularisation): Formation of new
blood vessels at the site of injury takes place by
proliferation of endothelial cells from the margins of
severed blood vessels.
• Angiogenesis takes place under the influence of Vascular
endothelial growth factor (VEGF), Platelet-derived growth
factor (PDGF), transforming growth factor-β (TGF-β),
basic fibroblast growth factor.
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50. • b) Fibrogenesis: The new fibroblasts originate from
fibrocytes as well as by mitotic division of
fibroblasts.
• Collagen fibrils begin to appear by about 6th day.
• As maturation proceeds, more and more of collagen
is formed while the number of active fibroblasts and
new blood vessels decreases.
• 2) Contraction of wounds:
• The wound starts contracting after 2-3 days and the
process is completed by the 14th day.
• Contracted wound results in rapid healing since
lesser surface area of the injured tissue has to be
replaced.
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51. WOUND HEALING
• Healing of skin wounds provides a classical example
of combination of regeneration and repair.
• Wound healing can be accomplished in one of the
following two ways:
1. Healing by first intention (primary union)
2. Healing by second intention (secondary union).
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52.  Healing by First Intention (Primary Union)
• This is defined as healing of a wound which has the
following characteristics:
i) clean and uninfected;
ii) surgically incised;
iii) without much loss of cells and tissue; and
iv) edges of wound are approximated by surgical
sutures.
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53. • Sequence of events
• 1. Initial haemorrhage: Immediately after injury, incised
wound is filled with blood which then clots and seals it.
• 2. Acute inflammatory response:
PMNS- appear within 24 hours
By 3rd day- they are replaced by macrophages
• 3. Epithelial changes: The basal cells of epidermis from
both the cut margins start proliferating and migrating
towards incisional space .
• 4. Organisation: By 3rd day, fibroblasts also invade the
wound area. By 5th day, new collagen fibrils start forming.
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54. Primary union of skin wounds. A, The incised wound as well as suture
track on either side are filled with blood clot and there is inflammatory
response from the margins. B, Spurs of epidermal cells migrate along
the incised margin on either side as well as around the suture track.
Formation of granulation tissue also begins from below. C, Removal of
suture at around 7th day results in scar tissue at the sites of incision
and suture track.
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55. • Healing by Second Intention (Secondary Union)
• This is defined as healing of a wound having the following
characteristics:
• i) open with a large tissue defect, at times infected;
• ii) having extensive loss of cells and tissues; and
• iii) the wound is not approximated by surgical sutures but
is left open.
• The healing by second intention is slow and results in a
large, at times ugly, scar as compared to rapid healing and
neat scar of primary union.
• Sequence of events in healing is similar to that of primary
except for that the main bulk of it is formed by granulation
tissue
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56. Secondary union of skin wounds. A, The open wound is filled with blood
clot and there is inflammatory response at the junction of viable tissue.
B, Epithelial spurs from the margins of wound meet in the middle to
cover the gap and separate the underlying viable tissue from necrotic
tissue at the surface forming scab. C, After contraction of the wound, a
scar smaller than the original wound is left.
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57. COMPLICATIONS
1) Infection of wound
2) Implantation cyst
3) Pigmentation
4) Keloid formation
5) Deficient scar formation
6) Excessive contraction
7) Neoplasia.
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58. LOCAL FACTORS
 Infection
 Poor blood supply
 Radiation exposure
 Location ,size & type
SYSTEMIC FACTORS
 Age, nutrition
 Uncontrolled DM
 Systemic infections
 Hematologic abnormalities
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FACTORS INFLUENCING HEALING

59. FRACTURE HEALING
 Primary union of fractures occurs in a few special
situations when the fracture ends approximated as done by
application of compression clamps. In these cases, bony
union takes place with formation of medullary callus
without periosteal callus formation.
 Secondary union is the more common process of fracture
healing. Involves 3 steps
 i) Procallus formation
 ii) Osseous callus formation
 iii) Remodelling
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60. I ) Procallus formation: Steps involved
Hematoma formation.
Local inflammatory response.
Ingrowth of granulation tissue.
Callus composed of woven bone & cartilage.
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61. ii) Osseous callus formation: The Procallus acts as
scaffolding on which osseous callus composed of
lamellar bone is formed.
iii) Remodelling: During the formation of lamellar bone,
osteoblastic laying and osteoclastic removal are taking
place remodelling the united bone ends, which after
sometime, is indistinguishable from normal bone.
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62. Fracture healing. A, Haematoma formation & local inflammatory response at
the fracture site. B, Ingrowth of granulation tissue with formation of soft
tissue callus. C, Formation of Procallus composed of woven bone & cartilage
with its characteristic fusiform appearance & having 3 arbitrary components
—external, intermediate & internal callus. D, Formation of osseous callus
composed of lamellar bone following clearance of woven bone & cartilage. E,
Remodelled bone ends; the external callus cleared away. Intermediate callus
converted into lamellar bone & internal callus developing bone marrow cavity.
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63. • COMPLICATIONS OF FRACTURE HEALING.
These are as under:
1. Fibrous union may result instead of osseous union if
the immobilisation of fractured bone is not done.
Occasionally, a false joint may develop at the fracture
site(pseudo arthrosis).
2. Non-union may result if some soft tissue is interposed
between the fractured ends.
3. Delayed union may occur from causes of delayed
wound healing in general such as infection, inadequate
blood supply, poor nutrition, movement and old age.
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64. REFERENCES
• Textbook of pathology- Harsh Mohan 6th edition.
• Inflammation & Repair General Pathology (VPM
152), Winter 2013 .
• Robbinson's basic pathology 8 edition.
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