Inflammation and tissue Repair

1. Inflammation & Repair
Dr Sarita Sharma
Associate professor
MMCP, MMDU

2. Chapter 8
• Basic Mechanisms involved in the
process of Inflammation & Repair
1) Alteration in vascular permeability & blood flow
2) Migration of WBC
3) Acute & chronic inflammation
4) Brief outline of the process of Repair

3. Innate immunity or Non-specific defense mechanisms:
• It refers to defenses that are present at birth.
• Innate immunity does not involve specific recognition of a
microbe and acts against all microbes in the same way.
• These protect against any of an enormous range of possible
dangers.
• Among the components of innate immunity are the;
a) first line of defense: The physical and chemical barriers of
the skin and mucous membranes) and
b) Second line of defense: Antimicrobial substances, natural
killer cells, phagocytes, Inflammation, and fever.

4. Inflammation:
It is one of the body’s nonspecific defense mechanisms.
Inflammation is a physiological, nonspecific, defensive response
of the body to tissue damage.
Example: Inflammatory conditions are recognized by their Latin
suffix '-itis'; for example, appendicitis is inflammation of the
appendix and laryngitis is inflammation of the larynx.

5. Causes of inflammation:
a) microbes, e.g. bacteria, viruses, protozoa, fungi
b) physical agents, e.g. heat, extreme temperatures,
cold, mechanical injury, ultraviolet and ionising
radiation
c) chemical agents
a) organic, e.g. microbial toxins and organic poisons,
such as weedkillers
b) inorganic, e.g. acids, alkalis
d) antigens that stimulate immunological responses
e) disturbances of cells

6. • Signs and symptoms of inflammation:
a) redness,
b) pain,
c) heat, and
d) swelling
 Inflammation can also cause a loss of function in the
injured area, depending on the site and extent of the
injury.

7. TYPES OF INFLAMMATION
• Depending upon the defense capacity of the host and duration
of response,
– Classified as acute and chronic.
A. Acute inflammation
– Of short duration (lasting less than 2 weeks) and
– Represents the early body reaction,
– Resolves quickly and is usually followed by healing.
• The main features of acute inflammation are:
1. Accumulation of fluid and plasma at the affected site;
2. Intravascular activation of platelets; and
3. Polymorphonuclear neutrophils as inflammatory cells.
• Sometimes, the acute inflammatory response may be
quite severe
– Termed as fulminant acute inflammation.

8. B. CHRONIC INFLAMMATION
• Of longer duration
– Occurs either after the causative agent of acute
inflammation persists for a long time, or
– The stimulus is such that it induces chronic inflammation
from the beginning.
• The characteristic feature of chronic inflammation is
– Presence of chronic inflammatory cells such as
• Lymphocytes, plasma cells and macrophages, granulation tissue
formation, and in specific situations as granulomatous inflammation.
• The term subacute inflammation is used
– For the state of inflammation between acute and chronic.

9. ACUTE INFLAMMATION
• Episodes of acute inflammation
are usually of short duration, e.g.
days to a few weeks, and may
range from mild to very severe.
• The Acute inflammatory
response has three basic stages:
•
1. Alteration in vascular
permeability & blood flow
2. Migration (movement) of
phagocytes from the blood
into interstitial fluid, and
ultimately,
3. Tissue repair

11. ACUTE INFLAMMATION
• Autce inflammatory response is a continuous process
divided into following two events:
I. Vascular events.
II. Cellular events.
• Intimately linked to these two processes is
– The release of mediators of acute inflammation

12. I. VASCULAR EVENTS
• Alteration in the microvasculature (arterioles, capillaries
and venules)
– The earliest response to tissue injury.
• These alterations include:
– Haemodynamic changes
– Changes in vascular permeability.
• Haemodynamic Changes
– The earliest features of inflammatory response result
from
• Changes in the vascular flow and Calibre of small blood
vessels in the injured tissue.

13. The sequence of these changes is as under:
1. Irrespective of the type of injury,
– Immediate vascular response is
• Transient vasoconstriction of arterioles.
• With mild form of injury,
– The blood flow may be re-established in 3-5 seconds
– With more severe injury the vasoconstriction may last for about
5 minutes.
2. Next follows persistent progressive vasodilatation
– Involves mainly the arterioles, venules and capillaries.
– This change is obvious within half an hour of injury.
– Vasodilatation results in
– Increased blood volume in microvascular bed of the area,
• Which is responsible for redness and warmth at the site of acute
inflammation.

14. 3. Progressive vasodilatation, in turn,
– May elevate the local hydrostatic pressure
– Resulting in transudation of fluid into the extracellular space.
– This is responsible for swelling at the local site of acute
inflammation.
4. Slowing or stasis of microcirculation follows
– Causes increased concentration of red cells, and thus, raised blood
viscosity.
5. Stasis or slowing is followed by
– Leucocytic margination or peripheral orientation of leucocytes
(mainly neutrophils) along the vascular endothelium.
– The leucocytes stick to the vascular endothelium briefly, and then
move and migrate through the gaps between the endothelial cells
into the extravascular space.
– This process is known as emigration.

15. FEATURES OF HAEMODYNAMIC CHANGES
• The reaction so elicited is known as triple response or red line
response consisting of the following :
i) Red line appears within a few seconds following stroking
– Due to local vasodilatation of capillaries and venules.
ii) Flare is the bright reddish appearance or flush surrounding the
red line
– Results from vasodilatation of the adjacent arterioles.
iii) Wheal is the swelling or oedema of the surrounding skin
– Occurring due to transudation of fluid into the extravascular
space.
• These features, thus, elicit the classical signs of inflammation—
Redness, heat, swelling and pain.

17. Substances that contribute to Vasodilation, increased permeability, and other aspects
of the inflammatory response are the following: They are known as Inflammatory
mediators;
i). Histamine:
 In response to injury, mast cells in connective tissue, basophils and platelets in
blood, release histamine.
 Neutrophils and macrophages attracted to the site of injury also stimulate the
release of histamine, which causes vasodilation and increased permeability of
blood vessels.
ii). Kinins:
 These are the polypeptides, formed in the blood from inactive precursors called
kininogens, which induce vasodilation and increased permeability. Example:
bradykinin.

18. iv). Leukotrienes (LTs):
 Produced by basophils and mast cells, LTs cause increased
permeability; they also function in adherence of
phagocytes to pathogens and as chemotactic agents to
attract phagocytes.
v). Complement:
 Different components of the complement system
stimulate histamine release, attract neutrophils by
chemotaxis, and promote phagocytosis; some
components can also destroy bacteria.

19. ALTERED VASCULAR PERMEABILITY
• In and around the inflamed tissue,
– There is accumulation of edema fluid in the interstitial
compartment
– Which comes from blood plasma by its escape through the
endothelial wall of peripheral vascular bed.
• In the initial stage,
– The escape of fluid is due to vasodilatation
– Consequent elevation in hydrostatic pressure.
• This is transudate in nature.
• But subsequently,
– The characteristic inflammatory oedema, exudate, appears
– By increased vascular permeability of microcirculation.

20. • Normally
– Whatever little fluid is left in the interstitial
compartment is drained away by lymphatics
– Thus, no oedema.
• In inflamed tissues
– The endothelial lining of microvasculature becomes
more leaky.

21. MECHANISMS OF INCREASED VASCULAR
PERMEABILITY
i) CONTRACTION OF ENDOTHELIAL CELLS.
– This is the most common mechanism
– That affects mostly venules.
– The endothelial cells develop temporary gaps between
them due to their contraction resulting in vascular
leakiness.
– It is mediated by the release of histamine, bradykinin
and other chemical mediators.
– The response begins immediately after injury, is usually
reversible, and is for short duration (15-30 minutes).

23. ii) Retraction of endothelial cells.
– There is structural re-organisation of the cytoskeleton
of endothelial cells
• That causes reversible retraction at the intercellular
junctions.
– Mediated by cytokines such as
• Interleukin-1 (IL-1) and tumour necrosis factor (TNF)-α.
– The onset of response takes 4-6 hours after injury and
lasts for 2-4 hours or more.

24. iii) Direct injury to endothelial cells.
– Direct injury to the endothelium causes cell necrosis.
– Appearance of physical gaps at the sites of detached
endothelial cells.
– Process of thrombosis is initiated at the site of damaged
endothelial cells.
– The change affects all levels of microvasculature (venules,
capillaries and arterioles).
– The increased permeability
• May either appear immediately after injury and last for several hours
or days (immediate sustained leakage), or
• May occur after a delay of 2-12 hours and last for hours or days
(delayed prolonged leakage).

25. – The examples of
• Immediate sustained leakage are severe bacterial
infections
• Delayed prolonged leakage may occur following
moderate thermal injury and radiation injury.

26. iv) Endothelial injury mediated by leucocytes.
– Adherence of leucocytes to the endothelium
• At the site of inflammation
• May result in activation of leucocytes.
– The activated leucocytes
• Release proteolytic enzymes and toxic oxygen species
• May cause endothelial injury and increased vascular leakiness.
– The examples
• Seen in sites where leucocytes adhere to the vascular
endothelium
– Eg: in pulmonary venules and capillaries.

27. v) Leakiness in neovascularisation.
– In addition, the newly formed capillaries
• Under the influence of vascular endothelial growth factor
(VEGF)
– This process takes place During the process of repair
and in tumours formation.
– Are excessively leaky.

29. II. CELLULAR EVENTS
• The cellular phase of inflammation consists of 2
processes:
1. Exudation of leucocytes
2. Phagocytosis.

30. EXUDATION OF LEUCOCYTES
• The most important feature of inflammatory response.
– The escape of leucocytes from the lumen of
microvasculature to the interstitial tissue
• In acute inflammation,
– Polymorphonuclear neutrophils (PMNs) comprise
the first line of body defense,
– Followed later by monocytes and macrophages.
• The changes leading to migration of leucocytes are as
follows:

31. MECHANISM OF MIGRATION OF LEUCOCYTES
1. CHANGES IN THE FORMED ELEMENTS OF BLOOD/Margination &
Pavementing:
– In the early stage of inflammation,
• The rate of flow of blood is increased due to vasodilatation.
– But subsequently,
• There is slowing or stasis of bloodstream.
– With stasis,
• Changes in the normal axial flow of blood in the
microcirculation take place.
– The normal axial flow consists of
• Central stream of cells comprised by leucocytes and RBCs and
peripheral cell free layer of plasma close to vessel wall.

32. – Due to slowing and stasis,
• The central stream of cells widens and peripheral plasma
zone becomes narrower because of loss of plasma by
exudation.
• This phenomenon is known as margination.
• As a result of this redistribution,
– The neutrophils of the central column come close to
the vessel wall;
– This is known as pavementing.

34. 2. ROLLING AND ADHESION
• Peripherally marginated and pavemented neutrophils
– Slowly roll over the endothelial cells lining the vessel wall
(rolling phase).
• This is followed by
– The transient bond between the leucocytes and endothelial
cells becoming firmer (adhesion phase).
• The following molecules bring about rolling and adhesion
phases:
i) SELECTINS:
– Are expressed on the surface of activated endothelial cells
– Which recognise specific carbohydrate groups found on the
surface of neutrophils.

35. • P-selectin
– Pre formed and stored in endothelial cells and platelets
– Involved in rolling,
• E-selectin
– Synthesised by cytokine activated endothelial cells
– Associated with both rolling and adhesion
• L-selectin
– Expressed on the surface of lymphocytes and
neutrophils
– Responsible for homing of circulating lymphocytes to the
endothelial cells in lymph nodes.

36. ii) Integrins
– On the endothelial cell surface
– Are activated during the process of loose and transient adhesions
between endothelial cells and leucocytes.
– At the same time the receptors for integrins on the neutrophils are
also stimulated.
– This process brings about firm adhesion between leucocyte and
endothelium.
iii) Immunoglobulin gene superfamily
– Adhesion molecule such as intercellular adhesion molecule-1 (ICAM-
1) and vascular cell adhesion molecule-1 (VCAM-1)
– Allow a tighter adhesion and stabilise the interaction between
leucocytes and endothelial cells.
– Platelet-endothelial cell adhesion molecule-1 (PECAM-1) or CD31 may
also be involved in leucocyte migration from the endothelial surface.

37. 3. EMIGRATION
• After sticking of neutrophils to endothelium,
– The former move along the endothelial surface till a suitable site
between the endothelial cells is found
– Where the neutrophils throw out cytoplasmic pseudopods.
• Subsequently,
– The neutrophils lodged between the endothelial cells and basement
membrane
– Cross the basement membrane by damaging it locally with secreted
collagenases and
– Escape out into the extravascular space; this is known as emigration.
–
• The damaged basement membrane is repaired almost immediately.
• Neutrophils are the dominant cells in acute inflammatory exudate in the
first 24 hours, and monocyte-macrophages appear in the next 24-48 hours.
• However, neutrophils are short-lived (24-48 hours) while monocyte-
macrophages survive much longer.

38. • Simultaneous to emigration of leucocytes,
– Escape of red cells
– Through gaps between the endothelial cells,
diapedesis, takes place.
• It is a passive phenomenon
– RBCs being forced out by escape through the
endothelial defects left after emigration of leucocytes.
• Diapedesis gives
– Haemorrhagic appearance to the inflammatory
exudate.

39. 4. CHEMOTAXIS
• The chemotactic factor-mediated
– leucocytes After crossing several barriers
(endothelium, basement membrane, perivascular
myofibroblasts and matrix)
– To reach the interstitial tissues is called chemotaxis.

41. The following agents act as potent chemotactic substances or
chemokines for neutophils:
i) Leukotriene B4 (LT-B4)
– A product of lipooxygenase pathway of arachidonic acid
metabolites
ii) Components of complement system (C5a and C3a in particular)
iii) Cytokines (Interleukins, in particular IL-8)
iv) Soluble bacterial products (such as formylated peptides).
• In addition to neutrophils,
– Other inflammatory cells too respond and involve in
inflammation and there are chemokines for them, e.g.
• Monocyte chemoattractant protein (MCP-1), eotaxin chemotactic for
eosinophils, NK cells for recognising virally infected cells etc.

42. PHAGOCYTOSIS
• Defined as the process of engulfment of solid particulate
material by the cells (cell-eating).
• The cells performing this function are called phagocytes.
• 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.

44. • Neutrophils and macrophages
– On reaching the tissue spaces produce several proteolyitc
enzymes—
• Lysozyme, protease, collagenase, elastase, lipase, proteinase,
gelatinase, and acid hydrolases.
– These enzymes degrade collagen and extracellular matrix.
• The microbe undergoes the process of phagocytosis
– By polymorphs and macrophages
– Involves the following 3 steps:
1. Recognition and attachment
2. Engulfment
3. Killing and degradation

45. • Pus formation: Within a few days, a pocket of dead
phagocytes and damaged tissue forms; this collection of
dead cells and fluid is called pus.
• Pus formation occurs in most inflammatory responses and
usually continues until the infection subsides.
• At times, pus reaches the surface of the body or drains into
an internal cavity and is dispersed; on other occasions the
pus remains even after the infection is terminated.
• In this case, the pus is gradually destroyed over a period of
days and is absorbed.

51. REGULATION OF INFLAMMATION
• The onset of inflammatory responses May have potentially
damaging influence on the host tissues
– as evident in hypersensitivity conditions.
• Such self-damaging effects are kept in check by the host
mechanisms in order to resolve inflammation.
• These mechanisms are as follows:
i) Acute phase reactants
ii) Glucosteroids
iii) Free cytokine receptors
iv) Anti-inflammatory chemical mediators.

52. i) Acute phase reactants-
– A variety of acute phase reactant (APR) proteins are released
in plasma in response to tissue trauma and infection.
– Their major role is to protect the normal cells from harmful
effects of toxic molecules generated in inflammation and to
clear away the waste material.
– The APR are synthesised
• Mainly in the liver, and to some extent in macrophages.
– Deficient synthesis of APR leads to severe form of disease in
the form of chronic and repeated inflammatory responses.

53. APRs include the following:
i) Certain cellular protection factors
• e.g. α1-antitrypsin, α1- chymotrypsin, α2-antiplasmin, plasminogen
activator inhibitor
ii) Some coagulation proteins
• e.g. fibrinogen, plasminogen, von Willebrand factor, factor VIII
iii) Transport proteins
• e.g. ceruloplasmin, haptoglobin
iv) Immune agents
– e.g. serum amyloid A and P component, C-reactive protein
v) Stress proteins
• e.g. heat shock proteins—HSP, ubiquitin
vi) Antioxidants
• e.g. ceruloplasmin are active in elimination of excess of oxygen free
radicals.

54. 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.

56. MORPHOLOGY OF ACUTE INFLAMMATION
• Inflammation of an organ is usually named by adding the suffix-
itis to its Latin name
– e.g. appendicitis, hepatitis, cholecystitis, meningitis etc.
• A few morphologic varieties of acute inflammation are
described below:
1. PSEUDOMEMBRANOUS INFLAMMATION.
– It is inflammatory response of mucous surface (oral,
respiratory, bowel) to toxins of diphtheria or irritant gases.
– As a result of denudation/shifting of epithelium, plasma
exudes on the surface , and together with necrosed
epithelium, forms false membrane that gives this type of
inflammation its name.

57. 2. ULCER.
– Ulcers are local defects on the surface of an organ
produced by inflammation.
– Common sites for ulcerations are
• The stomach, duodenum, intestinal ulcers in typhoid fever, intestinal
tuberculosis, bacillary and amoebic dysentery etc.
3. SUPPURATION (ABSCESS FORMATION).
– When acute bacterial infection is accompanied by intense
neutrophilic infiltrate in the inflamed tissue, it results in tissue
necrosis.
– A cavity is formed which is called an abscess and
contains exudate or pus and the process of abscess formation is
known as suppuration.
– The bacteria which cause suppuration are called pyogenic.

59. SYSTEMIC EFFECTS OF ACUTE INFLAMMATION
• These include fever, leucocytosis and lymphangitis-lymphadenitis.
1. Fever
– Occurs due to bacteraemia.
– It is thought to be mediated through release of factors like
prostaglandins, interleukin-1 and TNF-α in response to infection.
2. Leucocytosis
– Commonly accompanies the acute inflammatory reactions,
– When the counts are higher than this with ‘shift to left’ of myeloid cells.
– Usually, in bacterial infections there is neutrophilia;
– Typhoid fever, an example of acute inflammation, however, induces
leucopenia with relative lymphocytosis.

60. 3. Lymphangitis-lymphadenitis
– One of the important manifestations of localised
inflammatory injury.
– The lymphatics and lymph nodes that drain the inflamed
tissue show reactive inflammatory changes in the form
of lymphangitis and lymphadenitis.
– This response represents either a nonspecific reaction to
mediators released from inflamed tissue or is an
immunologic response to a foreign antigen.

61. 4. Shock
– May occur in severe cases.
– Massive release of cytokine TNF-α, a mediator of
inflammation
– In response to severe tissue injury or infection results
in profuse systemic vasodilatation, increased vascular
permeability and intravascular volume loss.
– The net effect of these changes is hypotension and
shock.

62. FATE(results) OF ACUTE INFLAMMATION
• The acute inflammatory process can result in one of the following
outcomes:
1. Resolution.
– It means complete return to normal tissue following acute
inflammation.
– This occurs when tissue changes are slight and the cellular
changes are reversible.
2. Healing.
– Healing by fibrosis takes place when the tissue
destruction in acute inflammation is extensive so that there
is no tissue regeneration.
– But when tissue loss is superficial, it is restored by
regeneration.

64. 3. Suppuration.
– When the pyogenic bacteria causing acute inflammation
result in severe tissue necrosis, the process progresses to
suppuration.
– Initially, there is intense neutrophilic infiltration.
– Subsequently, mixture of neutrophils, bacteria, fragments of
necrotic tissue, cell debris and fibrin comprise pus which is
contained in a cavity to form an abscess.
4. Chronic inflammation.
– Persisting or recurrent acute inflammation may progress to
chronic inflammation in which the processes of inflammation
and healing proceed side by side.

65. CHRONIC INFLAMMATION
• Defined as prolonged process in which tissue destruction
and inflammation occur at the same time.
• Caused by one of the following ways:
1. Chronic inflammation following acute inflammation.
– When the tissue destruction is extensive, or the
bacteria survive and persist in small numbers at the site
of acute inflammation.
2. Recurrent attacks of acute inflammation.
– When repeated bouts of acute inflammation culminate
in chronicity of the process

66. GENERAL FEATURES OF CHRONIC INFLAMMATION
• There may be differences in chronic inflammatory response
depending upon
– The tissue involved and causative organisms,
• There are some basic similarities amongst various types of chronic
inflammation.
• Following general features characterise any chronic inflammation:
1. MONONUCLEAR CELL INFILTRATION.
– Chronic inflammatory lesions are infiltrated by
• Mononuclear inflammatory cells like phagocytes and lymphoid cells.
– Phagocytes are represented by
• Circulating monocytes, tissue macrophages, epithelioid cells and
sometimes, multinucleated giant cells.
– The macrophages comprise the most important cells in chronic
inflammation.

67. • 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.
• The blood monocytes on reaching the extravascular space
– Transform into tissue macrophages.
• On activation, macrophages
– Release several biologically active substances
– e.g. acid and neutral proteases, oxygen-derived reactive
metabolites and cytokines.

68. • These products bring about
– Tissue destruction, neovascularisation and fibrosis.
• Other chronic inflammatory cells include
– Lymphocytes, plasma cells, eosinophils and mast cells.
• In chronic inflammation,
– Lymphocytes and macrophages influence each other
and release mediators of inflammation.

69. 2. TISSUE DESTRUCTION OR NECROSIS.
– Tissue destruction and necrosis are central features of most
forms of chronic inflammatory lesions.
– This is brought about by
• Activated macrophages
• Which release a variety of biologically active substances e.g.
protease, elastase, collagenase, lipase, reactive oxygen radicals,
cytokines (IL-1, IL-8, TNF-α), nitric oxide, angiogenesis growth factor
etc.
3. PROLIFERATIVE CHANGES.
– As a result of necrosis,
• Proliferation of small blood vessels and fibroblasts
• Stimulated resulting in formation of inflammatory granulation tissue.
– Eventually, healing by fibrosis and collagen laying takes place.

70. TYPES OF CHRONIC INFLAMMATION
• Subdivided into 2 types
1. Non-specific,
– When the irritant substance produces a nonspecific
chronic inflammatory reaction with formation of
granulation tissue and healing by fibrosis
– e.g. chronic osteomyelitis, chronic ulcer.
2. Specific,
– When the injurious agent causes a characteristic
histologic tissue response
– e.g. tuberculosis, leprosy, syphilis.

71. • Histological features are used for classifying chronic
inflammation into 2 corresponding types:
1. Chronic non-specific inflammation.
– It is characterised by non-specific inflammatory cell
infiltration
– e.g. chronic osteomyelitis, lung abscess.
2. Chronic granulomatous inflammation.
– It is characterised by formation of granulomas
– e.g. tuberculosis, leprosy etc.

72. 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.
• The word ‘granuloma’ indicates a localised inflammatory
mass or collection of macrophages.