Process of inflammation and repair

1. BASIC MECHANISM INVOLVED
IN THE PROCESS OF
INFLAMMATION & REPAIR
By:
Dr. Shikha Sachdeva

2. Defination
 Inflammation is a protective mechanism of the
body to remove the injurious stimuli or
complex biological response of vascular tissue
against the harmful stimuli like pathogen,
damaged cells or irritants.
 Aim of inflammation is to localize and get rid of
the injurious agent.
 Inflammation is not the synonyms of infection.
But sometimes inflammation is caused by the
infections.

3. 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.

4. Cardinal Signs of
inflammation
 Rubor (redness) : Dilation of small blood vessels in
damaged area.
 Calor (heat) : Increased blood flow to area.
 Tumour (swelling) : Accumulation of fluid in
extracellular space.
 Dolor (pain) : Stretching of tissue from oedema,
chemical mediators can induce pain.
 Functio laesa (loss of function) : Movement hindered
etc.

5. Types of Inflammation
 Acute Inflammation: It is an immediate and rapid
response of living tissue to an injurious agent and
lasts for minute to few days. Histologically, there is
extravascular accumulation of protein-rich fluid and
leucocytes, mainly neutrophils in many acute
inflammation due to exudation. It is an exudative
lesion.
 Chronic Inflammation: It is the inflammation that
persists for weeks to months. Histologically, there is
extravascular accumulation of lymphocytes and
macrophages, tissue destruction and attempts of
healing by proliferation of small blood vessels and

6. Etiology
The causes of inflammation are many and varied:
Exogenous causes:
Physical agents
Mechanical agents: fractures.
Thermal agents: burns, freezing
Chemical agents: toxic gases, acids, bases
Biological agents: bacteria, viruses, parasites
Endogenous causes:
Circulation disorders: thrombosis, infarction, hemorrhage
Enzymes activation – e.g. acute pancreatitis
Metabolic products deposition – uric acid, urea
Immune reactions e.g. allergic rhinitis, acute
glomerulonephritis

7. Changes/Events at The Injured
Site
 Acute inflammatory reaction and the changes it
causes
is stereotyped and are grouped together as following:
 Vascular changes
a) Changes in vascular calibre and flow
b) Increased vascular permeability (vascular leakage)
 Exudation of blood constituents
a) Fluid exudate
b) Cellular exudate
 Changes in other tissue

8. Vascular Changes
 At the site of injury, the changes occur in the
microvasculature consisting of arterioles,
venules and capillaries. The changes are
 Changes is the calibre of blood vessel and
blood flow
 Structural changes that allows the plasma
proteins and blood cells to leak.

9. Changes in vascular calibre and
flow
 Changes occur in the following order:
 Transient vasoconstriction of arterioles. It disappears
within 3-5 seconds in mild injuries. In more severe injury
It may last several minutes.
 Vasodilatation: It causes opening of sphincters and
capillary beds at the injured site which is temporarily shut
down due to injury and persists for a short time.
Vasodilatation helps to increase the blood flow which
leads to rubor (redness) and calor (heat)
 Slowing of blood flow or stasis due to formation of
exudate and increased viscosity of blood
 In mild injury, it takes 15-30 minutes for these events, and
with severe injury, it may occur in a few minutes.

10. Increased vascular permeability
(vascular leakage)
 A hallmark of acute inflammation (escape of a
protein-rich fluid)
 It affects small & medium size venules, through
gaps between endothelial cells

11. Pathogenesis of acute inflammation:
Pathogenesis of acute inflammation can be explained by two events;
1. Vascular Event
Vascular Event
Tissue Injury
Release of chemical for local effect (Histamine, Prostaglandins, Kinins, Leukotriens,
Complement Etc)
Immediate Response is Vascular Contraction
It may persist for 3-5 second or last for 5 minutes depending on the severity of injury
It is known as transient vasoconstriction

12. After this phase arterioles get dilate known as persistent progressive vasodilatation
It increase the blood flow and this type of vascular expansion produce redness
and heat known as erythema
When the volume of blood flow increases, it increases intravascular hydrostatic
pressure
So fluid from the capillary get migrate in to the tissue and this fluid is known as
Transudate
When the volume of blood flow may raise more and permeability gets
increase
Fluid with the protein migrate from capillary to tissue known as exudates

13. Loss of the Protein rich fluid from the capillary reduces the intravascular
osmotic pressure and increase the osmotic pressure of the interstitial fluid
(Fluid present in to the tissue due to migration from capillary)
So it produces out flow of the water and ions into the extra-
vascular
These fluids accumulate in to the extra vascular space and produce
edema.

15. 2. Cellular Event
Cellular event of the inflammation is described by the two processes;
1. Leukocytes (WBC) movement process
Tissue injury
Produce vasodilation due to increased volume of blood flow
So the permeability of capillary get increases and fluid (Plasma) get move from capillary
to tissue
Plasma or fluid gets discharge from the capillary so the ratio of WBCs and RBCs get
increases, plasma discharge due to the exudates known as migration
So it increases the viscosity of blood and slowing the flow of blood is known as stasis.
Due to the increasing the viscosity, the leukocyte roll on the endothelial of the capillary

16. The leukocyte on their surface consist integrin protein and endothelial cell of blood
capillary consist selectin (E-Selectin & P-Selectin) protein on their surface.
During the leukocyte rolling on to the endothelial cell, integrin and selectin get activated
and produce adhesion of leukocyte on endothelial cell of capillary.
After the adhesion or sticking leukocyte moves in to the extra vascular space from the gap
between endothelial cells or from the capillary
These phenomenon is known as emigration
At the site of injury, several mediators get released which attract the leukocytes
That kind of mediators at a site of injury is known as chemokines (Histamine,
Leukotrines, Platelet activating factors, Prostaglandins, Cytokines, Complementary
proteins etc) and the attraction process of the leukocyte towards the injury is known as
chemotaxis process

17. Leukocyte (WBC) movement process

18. Phagocytosis
Phagocytosis is the process of engulfment of particulate matters
such as microbes, immune complex, cellular debris by phagocytes.
Usually, neutrophils and macrophages are the phagocytes.
Phagocytosis involves three distinct steps:
1. Recognition and attachment
2. Engulfment
3. Killing and degradation
Figure: Phagocytosis

19. Step-1(Recognition and attachment): Neutrophils and
macrophages recognize and attach microbes by several
membrane receptors. Opsonization further enhances this step.
Opsonin is a substance capable of enhancing phagocytosis by
coating the microbes and making it more active for binding to
specific receptors.
Step-2 (Engulfment): Pseudopods flow around the microbes
and enclose it within a phagosome formed by the plasma
membrane of the cell which fuses with the limiting membrane of
lysosomal granule forming phagolysosome.
Step-3 (Killing and degradation): It is the ultimate step
in the elimination of infectious agents i.e. the microbes
within the phagocytes.

20. Process of Phagocytosis

21. 2.Chronic inflammation
 Chronic inflammation is the prolonged tissue reactions following the
initial response.
 It is long lasting. It may persist for weeks, months or even years.
 The symptoms are not as severe as with acute inflammation, but the
condition is insidious and persistent.
 Chronic inflammation may follow on from acute inflammation or
exist by itself.
 An acute inflammation will become chronic if the immune system is
unable to rid the body of the offending foreign agent or if the agent is
constantly able to re-enter the body, such as tuberculosis.
 The main cells involved in chronic infection are macrophages
and lymphocytes.

22. Pathogenesis of chronic inflammation:
When acute phase cannot be resolved Persistent
injury or infection Prolonged toxic agent exposure
Autoimmune disease states
Repeated acute inflammations
Activates the mononuclear cells like phagocyte (Tissue macrophages and
circulating monocytes) and lymphoid cells
It get migrate towards the injured area
Engulf the microorganism
Digestion of microorganism or their particle release bacterial endotoxin or
various cytokines

23. It stimulate the immune response against the dead microbes or dead
cells
It activates the T-Cells
Activated T-cell (CD4+) release lymphokinase IL-1, IL-2, growth factor IFN-γ and
INF-α
It produces tissue injury and inflammation or fibrosis

25. Chemical Mediators of
Inflammation
 A chemical mediator is any substance which acts on
inflammatory cells or other cells to contribute to an
inflammatory response.
 These are: cell derived or plasma protein derived.
 Mediators are the substances that initiate or regulate
inflammatory reactions.
 One mediator can stimulate the release of other
mediators by target cells.
 Life span of mediators are very short.

26. Mediators of inflammation

29. Vasoactive Amines: Histamine and
Serotonin
• Acts on blood vessels.
• First mediators.
Histamine:
• Mast cells are richest source of histamine.
• Histamine stored as granules and released by degranulation in
response to various stimuli.
• Important mainly in early inflammatory responses and in type 1
hypersensitivity reactions.
• Also important in allergic conditions.
• Act via H1 receptors present on micro vascular endothelial cells.

30. Serotonin(5-hydroxytryptamine)
 Present in platelets and certain neuroendocrinal
cells like GIT.
 It acts primarily on venules during the early phase of
acute inflammation.
 Primary function is as a neurotransmitter.
• Vasoconstriction

31. Plasma Proteases
 There are 3 interconnected systems which are
involved in inflammatory response.
 All these systems are found within plasma:
Complement,Kinin and clotting systems.
 All are capable of being activated by activated
Hageman’s factor (factor XIIa of the coagulation
cascade).

32. Complement system
 It is a set of plasma proteins that act together to
attack extracellular forms of microbial pathogens.
 It can be activated directly by certain pathogens or
by antibodies binding to a pathogen.
 Involved in vascular permeability and chemotaxis
of several mediators.

33. Kinin system:
It is a plasma protein cascade.
It is activated by factor XIIa of the coagulation
system.
Its end product is bradykinin ( a polypeptide) which
increases vascular permeability , causes contraction
of smooth muscles and dilation of vessels.
It may directly stimulate pain fibers.

34. Clotting system:
 It is another plasma protein cascade system activated by Factor
XII.
 The result of activation of the coagulation cascade is the
generation of fibrin.
 Fibrinopeptides induce vascular permeability and are chemotactic
for leukocytes.
 The coagulation cascade is actually a dynamic balance between
forming fibrin clots and breaking down fibrin clots.
 The fibrinolytic system generates plasmin which in turn activates
Factor XII (producing bradykinin and activating complement).

35. Clotting system
 The clotting system and inflammation are intimately connected.
Intrinsic clotting system is a component of plasma proteins which
are activated by Hageman factor.
 The final phase of the cascade is the conversion of fibrinogen to
fibrin by the action of thrombin.
 Thrombin binds to a receptor on platelets, endothelium, smooth
muscle cells and causes them to:
 Mobilize P-selectin to the cell membrane and express adhesion
molecules for integrins.
 Produce chemokines
 Induce cyclooxygenase -2 – production of prostaglandins

36. Arachidonic Acid Metabolites
 It is a 20-carbon polyunsaturated fatty acid that is
derived directly from the diet or by conversion
from linoleic acid.
 When cells are activated by diverse stimuli, their
lipid membranes can be rapidly remodelled to
generate biologically active lipid mediators.
 These lipid mediators are short-range hormones
that are formed rapidly and exert their effects
locally and then are inactivated.

37.  Arachidonic acid is not free in the cell but esterified
in membrane phospholipids; in order to be released
from phospholipids it must be activated by cellular
phospholipases,particularly phospholipase A2.
 It results into biosynthesis of metabolities by either
cyclooxygenase pathway or lipooxyggenase
pathway.

38. Cyclooxygenase pathway
 Two enzymes are able to produce these
products:COX-1 and COX-2.
 COX-1 is normally present and necessary for
everyday activities, also synthesized at sites of
inflammation.
 COX-2 is transcriptionally regulated-present in
various circumstances (e.g. inflammation). The main
3 products resulting from this pathway are:

39. a) Thromboxane A2: found in platelets and other
cells is a potent platelet aggregator and
vasoconstrictor.
b) Prostacyclin: found predominantly in
endothelial cells ; a potent inhibitor of platelet
aggregation and vasodilatation.
c) Prostaglandins: cause vasodilation,increased
vascular permeability and pain.

40. Lipoxygenase Pathway :
 It results in the production of leukotrienes and
lipoxins which have opposing effects.
a) Leukotrienes: Exacerbate acute inflammatory
response:
 Increased vascular permeability
 Chemotaxis for leukocytes
 Vasoconstriction
 Bronchoconstriction

41. b) Lipoxins:
 Secreted mainly by platelets.
 Inhibit neutrophil chemotaxis and adhesion to
endothelium but promotes macrophage
adhesion to endothelium.

42. Platelet-Activating Factor (PAF)
 Phospholipid derived mediator
 Secreted by platelets, basophils, mast
cells,neutrophils, macrophages, and endothelial cells.
 It causes- platelets aggregation
 vasoconstriction
 bronchoconstiction
 at low concentrations it induces vasodilation and
increased venular permeability.

43. Nitric Oxide
 Nitric oxide synthetase (NOS) produces nitric oxide
(NO) from L-arginine in the presence of oxygen and
NADPH.
It is a free radical produced by endothelial cells and
macrophages. It causes smooth muscle relaxation in
the vessel wall (vasodilation) and reduces platelet
activation and aggregation.
In macrophages, the free radical nature of NO is toxic
to microbes.

44. Growth Factors
 The major growth factors of importance are EGF (epidermal
growth factor), PDGF (platelet derived growth factor), FGF
(fibroblast growth factor), VEGF (vascular endothelial
growth factor), TGFbeta (transforming growth factor, a
growth inhibitor), and the cytokines (TNF and IL-1).
 These mediators are involved in the proliferation and
production of vessels and collagen (granulation tissue)
during the repair phase of inflammation.

45. Cytokines and Chemokines
• Cytokines are proteins produced by many cell
types (activated lymphocytes, macrophages,
and dendritic cells)
• mediate and regulate immune and inflammatory
reactions.

46. Tumor Necrosis Factor (TNF) and
Interleukin-1 (IL-1)
• roles in leukocyte recruitment
• promoting adhesion of leukocytes to
endothelium and their migration through
vessels.
• Produced by – macrophages and dendritic
cells.
• TNF also via T lymphocytes and mast
cells

47. • Stimulus for secretion- microbial products,
immune complexes, foreign bodies, physical
injury, and a variety of other inflammatory
stimuli.

49. Roles of cytokines in inflammation
Endothelial activation.- by TNF and IL-1
increased expression of adhesion molecules ( P-
and E- selectins and ligands for leukocytes.
• increased production of various mediators
• increased procoagulant activity.
Activation of leukocytes and other cells-
• stimulates microbicidal activity of macrophages by
inducing production of NO.
• IL1 activates fibroblasts to synthesize collagen
and stimulates proliferation of synovial and other
mesenchymal cells.

50. Systemic acute-phase response
• Induced by IL-1, TNF and IL-6
• TNF regulates energy balance by promoting
lipid and protein mobilization and by
suppressing appetite leads to cachexia
• TNF antagonists have been remarkably
effective in the treatment of chronic
inflammatory diseases- Rheumatoid arthritis
and psoriasis.

51. Roles of cytokines

54. Chemokines
• Chemokines are a family of small proteins that
act primarily as chemoattractants for specific
types of leukocytes.
• About 40 different chemokines and 20
different receptors for chemokines have been
identified.

55. • Chemokines mediate their activities by
binding to seven-trans membrane G protein–
coupled receptors.
• Functions of chemokines-
• In acute inflammation-stimulate leukocyte
attachment to endothelium by acting on
leukocytes to increase the affinity of integrins,
• Chemotaxis
• Maintenance of tissue architecture
• homeostatic chemokines-produced
constitutively in tissues.

56. Other Cytokines in Acute Inflammation
• IL- 6 – Secreted by macrophages involved in
local and systemic reactions
• IL-17 – Produced by T lymphocytes, promotes
neutrophil recruitment.
• Type I interferons – some systemic
manifestations

57. Complement System
• The complement system is a collection of
soluble proteins and membrane receptors
that function mainly in host defense against
microbes and in pathologic inflammatory
reactions.
• The system consists of more than 20 proteins,
some of which are numbered C1 through C9.

58. The activation and functions of the
complement system

59. Functions of complements
• Inflammation- C3a, C5a and C4a
• stimulate histamine release
• They are called anaphylatoxins
• C5a – chemotactic to neutrophils, monocytes,
eosinophils, and basophils.
• Opsonization and phagocytosis- C3b and
iC3b
• Cell lysis- deposition of the MAC on cells
makes these cells permeable to water and
ions and results in death (lysis) of the cells.

60. Regeneration and Repairing
Repair is the replacement of injured or dead cells or
tissues after injury like inflammation, wounds, surgical
resection by proliferation of viable cells
Repair occurs by two distinct processes: Regeneration-
which restores normal tissues, and Healing-which leads
to scar formation and fibrosis. Mostly, repair occurs by a
combination of these two processes
Repair begins early in inflammation sometimes in 24
hours after injury
Repair involves the proliferation of different types of cells
and their interaction with the ECM (extracellular matrix).

61. Wound Healing
 Healing is the body response to injury in an
attempt to restore normal structure and
function .
 2 Distinct processes:-- Regeneration and
Repair
 Regeneration:- Complete restoration of the
original tissues.
 Repair:- When the healing take place by
proliferation of connective tissue element
resulting in fibrosis and scarring

62.  The human adult wound healing process can
be divided into 3 or 4 distinct phases.
1. Inflammatory phase
2. Proliferation
3. Remodeling
4. Homeostasis

63. Inflammatory phase: It is the first phase of
defense to the injury. The blood vessels at the
site of wound contract leading to the formation
of clot.
 After the establishment of homeostasis, blood
vessels start to dilate for the supply of
nutrients at wounded area.
 The characteristic signs of inflammation can
be observed at this stage e.g. erythema,
heat,oedema,pain, and functional
disturbance.

64.  During proliferation, the wound is ‘reconstructed
with new tissue comprising of collagen and
extracellular matrix and a new network of blood
vessels develop (process known as angiogenesis)
into this newly formed tissue.
 The colour and condition of the granulation tissue
is an indicator of wound healing.
 Healthy granulation tissue is pink/red in colour,
granular and uneven in texture and it does not
bleed easily whereas dark granulation tissue
indicated poor perfusion, ischaemia and infection.

65.  Finally , epithelial cells resurface the wound called
as ‘epithelialisation’.
 Maturation is the final phase and occurs once the
wound has closed. This phase involves remodelling
of collagen from type 3 to type 1.

67. Classification of Wounds
Acute wounds: Wounds that repair themselves
and that proceed normally by following a
timely and orderly healing pathway with the
end result of both functional and anatomical
restoration.
 The time course of healing usually ranges
from 5 to 10 days or within 30 days.

68. Chronic Wounds: Chronic wounds are those
that fail to progress through the normal stages
of healing and they cannot be repaired in an
orderly and timely manner.
 The healing process is incomplete and
affected by various factors, which prolong one
or more stages in the phases of homeostasis,
inflammation , proliferation and remodelling.
 These factors include infection, tissue
hypoxia, necrosis, exudates and excess levels
of inflammatory cytokines.

69.  Complicated wounds: It is defined as a
combination of an infection and a tissue defect.
 Infection poses a constant threat to the wound.
 Typical characteristics of infection are:
 Redness
 Heat
 Pain
 Oedema
 Loss or limited function in the affected part.