2. Definition
Inflammation is a non specific, localized complex
immune reaction of the organism, which tries to localize
the injurious agent and leading to the exudation and
accumulation of protein-rich fluids and
leucocytes, provided that the injury does not destroy the
tissue.
It consist in vascular, metabolic, cellular
changes, triggered by the entering of pathogen agent in
healthy tissues of the body.
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. 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
5. Etiology
The causes of inflammation are many and varied:
Exogenous causes:
Physical agents
Mechanical agents: fractures, foreign corps, sand, etc.
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 deposals – uric acid, urea
Immune reactions e.g. allergic rhinitis, acute
glomerulonephritis
6. Cardinal Signs
Celsus described the local reaction of injury in terms that
have come to be known as the cardinal signs of
inflammation.
These signs are:
rubor (redness)
tumor (swelling)
calor (heat)
dolor (pain)
functio laesa, or loss of function (In the second
century AD, the Greek physician Galen added this fifth
cardinal sign)
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
Vasodialation: 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
Vasodialation 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 minuets 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. Mechanism of Vascular
Leakage
1. Formation of endothelial gaps in venules
This is the most common mechanism of vascular leakage
It is elicited by histamine, bradykinin, leukotrienes, the
neuropeptide substance P, and many other classes of
chemical mediators.
It occurs rapidly after exposure to the mediator and is usually
reversible and short-lived (15 to 30 minutes). It is known as
immediate transient response.
It affects venules (20 to 60 μm in diameter), leaving capillaries
and arterioles unaffected
12. 2. Direct injury (Immediate sustained reactions)
Direct endothelial injury (necrosis and detachment)
Direct damage to the endothelium by the injurious
stimulus, as, severe burns or lytic bacterial infections.
Neutrophils may also injure the endothelial cells.
In most instances, leakage starts immediately after injury and is
sustained at a high level for several hours until the damaged
vessels are thrombosed or repaired.
All levels of the microcirculation are affected:
venules, capillaries, and arterioles
13. 3. Delayed prolonged leakage
Relatively common type of increased permeability that begins
after a delay of 2 to 12 hours, lasts for several hours or even
days
Involves venules as well as capillaries.
Such leakage is caused by mild to moderate thermal injury, x-
radiation or ultraviolet radiation, sunburn and certain bacterial
toxins.
The mechanism of such leakage is unclear. It may result from the
direct effect of the injurious agent, leading to delayed endothelial
cell damage (perhaps by apoptosis), or the effect of cytokines
causing endothelial retraction.
14. 4. Leukocyte-mediated endothelial injury.
Leukocytes adhere to endothelium relatively early in
inflammation.
Such leukocytes may be activated in the process, releasing toxic
oxygen species and proteolytic enzymes, which then cause
endothelial injury or detachment, resulting in increased
permeability.
In acute inflammation, this form of injury is largely restricted to
vascular sites, such as venules and pulmonary and glomerular
capillaries.
15. 5. Increased transcytosis across the endothelial cytoplasm
Transcytosis occurs across channels consisting of clusters of
interconnected endothelial cells
This mechanism of increased permeability is induced by histamine
and most chemical mediators
16. 6.Leakage from new blood vessels
It occurs during angiogenesis in early healing phases that follow
inflammation.
17. Exudation of Blood
Constituents
Exudation is the leaking of blood constituents
from blood vessels into interstitial tissue.
Exudate (or inflammatory edema) contains
protein and leukocytes
Fluid exudate
• Fluid exudate is formed by the plasma constituents-
fluid, solute and proteins. It may have the same
chemical composition as that of plasma
Cellular exudate
• Circulating leucocytes constitute the cellular
exudate. In most cases, the cells are neutrophils and
monocytes
Leukocyte extravasation
18. Leukocyte Extravasation
It is the sequence of events of migration of
leucocytes from vessel lumen to the interstitial
tissue
Leukocyte regulates the inflammatory
reactions of cytokines and other arachidonic
acid metabolites such as
prostaglandins, thrombroxane A2 etc.
19. 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
20. 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
21. Chemical Mediators of
Inflammation
Changes in inflammatory responses are due to
the production of chemical mediators in and
around the area. These mediators performs
their activity by binding to specific receptors or
by some oxidative or enzymatic activity
These mediators can be derived from cells or
plasma
22. Chemical mediators from cells:
• Histamine
• Serotonin
• Lysosomal enzymes
• Prostaglandins
• Leukotrienes and lipoxins
• Platelet activating factors
• Cytokines
• Nitric oxide
• Activated oxygen species
23. Chemical mediators from plasma:
• Complement fragments- C3a, C5a, C3b etc
• Kinins- bradykinins, kallikrein
• Thrombin, fibrinopeptides etc
Histamine
It is found in high concentration in platelets,
basophils, and mast cells
Causes dilation and increased permeability
of capillaries
24. Prostaglandins
The prostaglandins are ubiquitous, lipid soluble molecules
derived fro arachidonic acid, a fatty acid liberated from cell
membrane phospholipids, through the cyclooxygenase pathway.
Prostaglandins contribute to vasodilation, capillary
permeability, and the pain and fever that accompany
inflammation.
The stable prostaglandins (PGE1 and PGE2) induce
inflammation and potentiate the effects of histamine and other
inflammatory mediators
They cause the dilation of precapillary arterioles (edema), lower
the blood pressure, modulates receptors activity and affect the
phagocytic activity of leukocytes.
The prostaglandin thromboxane A2 promotes platelet
aggregation and vasoconstriction.
25. Leukotrienes
The leukotrienes are formed from arachidonic acid, but through
the lipoxygenase pathway.
Histamine and leukotrienes are complementary in action in that
they have similar functions.
Histamine is produced rapidly and transiently while the more
potent leukotrienes are being synthesized slowly.
Leukotrienes C4 and D4 are recognized as the primary
components of the slow reacting substance of anaphylaxis (SRS-
A) that causes slow and sustained constriction of the
bronchioles.
The leukotrienes also have been reported to affect the
permeability of the postcapillary venules, the adhesion properties
of endothelial cells, and stimulates the chemotaxis and
extravascularization of neutrophils, eosinophils, and monocytes.
27. Platelet-activating factor (PAF)
It is generated from a lipid complex stored in cell membranes
It affects a variety of cell types and induces platelet aggregation
It activates neutrophils and is a potent eosinophil
chemoattractant
It contributes to extravascularization of plasma proteins and
so, to edema.
Plasma Proteases
The plasma proteases consist of:
Kinins
Bradykinin - causes increased capillary permeability
(implicated in hyperthermia and redness) and pain
Clotting factors
The clotting system contributes to the vascular phase of
inflammation, mainly through fibrin peptides that are
formed during the final steps of the clotting process.
28. 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).
29.
30. Regeneration
Regeneration involves the restitution of tissue
components identical to those removed or
killed. Tissue with high proliferative capacity,
such as epithelia of skin, GIT and
hematopoietic system, renew themselves
continuously and can regenerate after injury
Based on regenerative capacity, cells are
divided into three groups, such as:
continuously dividing cells (Labile cells),
quiescent cells (Stable cells) and non-dividing
cells (Permanent cells)
31. 1. Continuously dividing cells (labile cells) such as
hematopoietic cells of the bone
marrow, stratified squamous
epithelium, cuboidal epithelium of excretory
ducts, and gastrointestinal tract. These tissues
can easily regenerate after injury as long as
stem cells are intact.
2. Quiescent cells (stable cells): They are
quiescent and have minimal replication activity.
However, cells are able to replicate in response
to injury or loss of tissue mass. Stable tissues
constitute the parenchyma of most solid organs
such as the liver, kidney, and pancreas, as well
as endothelial cells, fibroblasts, and smooth
32. 3. Permanent cells: They are terminally
differentiated in post-natal life. Cardiac muscle
cells and most neurons are in this category.
Injury to brain and heart muscle results in
liquefaction, necrosis and scar formation. The
liver has a great regenerative capacity that
occurs after surgical removal or injury of hepatic
tissue. As much as 40% to 60% of the liver may
be removed in a procedure called living-donor
transplantation. In this situation, replication after
partial hepatectomy is initiated by the cytokines
TNF and IL6 that trigger the transition of
hepatocytes
33. Repair by Healing
Healing by connective tissue replacement occurs
in chronic inflammatory process, wound, and cell
necrosis incapable of regeneration
Components of healing: Healing involves a
number of orderly processes. But all processes do
not occur in every healing. The components are:
a) Inflammation in response to injury with removal
of damaged tissues
b) Proliferation and migration of parenchymal and
connective tissue cells
c) Formation of granulation tissues, scar and
fibrosis
d) Wound contraction
e) Acquisition of wound strength
34. Formation of Granulation
Tissue, Scar and Fibrosis
Angiogenesis and Vasculogenesis
Blood vessels are formed by angiogenesis
and vasculogenesis originated by
angioblasts (endothelial precursor cells
(EPCs)) present in the bone marrow
Angiogenesis is involved in the
development of collateral circulation at
sites of ischemia and allowing tumors to
increase in size. EPCs may migrate from
the bone marrow to areas of injury but the
mechanism is not known.
35. Migration of fibroblasts and ECM deposition (scar
formation)
Scar formation takes place on the network of the
newly formed granulation tissue and loose ECM.
The scar develops in two steps:
a) Migration and proliferation of fibroblasts at the
injury site, and
b) Deposition of ECM by fibroblasts
36. The migration and proliferation of fibroblasts is triggered
by several growth factors synthesized by activated
endothelial and inflammatory cells, especially
macrophages which also clear extracellular debris and
elaborate mediators that induce fibroblast proliferation
and ECM components.
The fibroblast migration starts early in wound healing,
and continues for several weeks, depending on the size
of the wound.
As the healing progresses, there is a decrease of the
number of proliferating fibroblasts and newly formed
blood cells but there is an increase in the deposition of
ECM, particularly collagen.
Eventually, the granulation tissue becomes a scar
composed of inactive spindle-shaped fibroblasts, dense
collagen, fragments of tissue, and other ECM
37. ECM tissue remodeling
After scar deposition, the ECM continues to be
modified and remodeled. The outcome of the
repair process depends on the balance
between ECM synthesis and degradation.
The degradation of collagen and ECM is done
by matrix metalloproteinases (MMPs) which
are zinc dependent. ECM can also be
degraded by neutrophil
elastase, cathepsin, plasmin, and other serine
proteases.
38. Scar: The richly vascularized granulation tissue is
converted into a scar composed of spindle-shapped
fibroblasts, dense collagen, fragments of elastic
tissue and other ECM components. The scar is
collagenous at first and then a pale, avascular
fibrous scar is formed
Fibrosis: Refers to the heavy deposition of collagen
that occurs in organs such as lungs, liver and
kidney following chronic inflammatory processes or
in the myocardium after extensive ischemic necrosis
(infarction).
Organization: It is the replacement of damaged
