Response of the vascularized living tissue to
To defend against and to eliminate the
injurious agent responsible for injury
Rid the tissue of the consequences of injury
(necrotic cells ) and
To start healing and repair of injured tissue.
Inflammation and repair both can cause
harm to the body.
Harmful effects of inflammation seen in:
Harmful effects of repair
Formation of scars
e.g Intestinal obstruction
Do not get confused
Stimuli for Acute Inflammation
Infections (bacterial, viral, fungal, parasitic)
Trauma (blunt and penetrating)
Physical and chemical agents (thermal injury, e.g., burns or
Tissue necrosis (from any cause),
Foreign bodies (splinters, dirt, sutures)
Immune reactions (also called hypersensitivity reactions)
Each of these stimuli may induce reactions with some
distinctive characteristics, but all inflammatory reactions
have the same basic features.
Types of inflammation
Short duration (minutes – days)
Fluid and plasma protein (edema)
Longer duration (days – years)
Influx of lymphocytes & macrophages.
Acute inflammation is an immediate and early
response to injury.
Short duration: Minutes, hours, days.
To get the neutrophils to the site of injury.
To clear the invading organism/agents and
begin the process of healing.
Five signs of acute inflammation
2. Calor (heat)
3. Tumor (swelling)
4. Dolor (pain)
5. Functio lasea (loss of function)
Important components of acute
Change in vessel caliber (vasodilatation)
Structural changes: permit flow of plasma
proteins = increased vascular permeability.
Emigration of leucocytes
Accumulation at the site of injury
Initial transient vasoconstriction
Massive vasodilatation mediated by
histamine, bradykinin and
prostaglandins. (heat and redness).
Increased vascular permeability
Blood flow slows (stasis) due to increased
viscosity, allows neutrophils to marginate.
Increased vascular permeability
Arteriolar vasodilation and increased blood
flow - rise in intravascular hydrostatic
pressure, resulting in movement of fluid from
capillaries into the tissues.
This fluid, called a Transudate, is essentially
an ultrafiltrate of blood plasma and contains
Mechanism of increased vascular permeability.
Endothelial cell contraction and
Direct endothelial injury
Leukocyte dependent endothelial
Leakage from new blood vessels
Gaps due to endothelial
•the most common cause of
increased vascular permeability.
•elicited by histamine, bradykinin,
•Endothelial cell contraction occurs
rapidly after binding of mediators to
•usually short-lived (15-30 minutes)
Direct endothelial injury
•usually seen after severe injuries (e.g.,
burns and some infections).
•begins immediately after the injury and
persists for several hours (or days
•this reaction is known as the immediate
•Venules, capillaries, and arterioles can
all be affected
activated leukocytes release many toxic
mediators that may cause endothelial
injury or detachment.
Endothelial and leukocyte adhesion molecule pairs
LFA-1 & MAC-1 Adhesion
Rolling, adhesion and transmigration : The
Step -1:Endothelial activation
At the sites of inflammation, the
endothelial cells have increased
Neutrophils weakly bind to the
endothelial selectins and roll along the
Step 3: Leukocyte activation
Neutrophils are stimulated by
chemotactic agents (chemokines and
C5a ) to express their integrins.
Activation of leukocytes
(chemokines and C5a)
Step 4: Adhesion
Firm attachment of leukocytes to the endothelial
Is mediated by complementary adhesion
molecules on the surface of neutrophils and
binding of the integrins firmly adheres the
neutrophil to the endothelial cell.
Leukocytes emigrate from the vasculature by
extending pseudopods between the
Interaction of platelet endothelial cell
adhesion molecule 1 (PECAM-1) on
leukocytes and endothelial cells mediates
transmigration between cells.
Chemotaxis is the movement of cells toward a
chemical mediator that is released in the area of
Important chemotactic factors for neutrophils
Leukotrine B4 (LTB4)
Complement system products (C5a)
Recognition and attachment
Engulfment with subsequent formation of a
Killing and degradation of the ingested
Recognition and attachment
Facilitated by OPSONINS.
Opsonins enhance recognition and phagocytosis
Plasma protein – Collectins (bind to bacterial cell
Binding of opsonised particle triggers engulfment.
Neutrophil sends out cytoplasmic processes that surround
The bacteria are internalized within a phagosome
The phagosome fuses with lysosome (phagolysosome).
Release of lysosomal contents (degranulation).
The final step in Phagocytosis of
microbes is killing and
Oxygen dependent killing
When a phagocyte ingests bacteria (or any
material), its oxygen consumption increases. The
increase in oxygen consumption, called
a respiratory burst, produces reactive oxygencontaining molecules that are anti-microbial.
The oxygen compounds are toxic to both the
invader and the cell itself, so they are kept in
compartments inside the cell.
This method of killing invading microbes by using
the reactive oxygen-containing molecules is
referred to as oxygen-dependent intracellular
Oxygen dependent killing
Requires oxygen and NADPH oxidase
Produce superoxide, hydroxyl radicals, and hydrogen
The enzyme from neutrophil granules.
Requires hydrogen peroxide and Halide (CL-)
Produces HOCL (hypochlorous acid)
Lysozymes, these enzymes break down the
bacterial cell wall.
Lactoferrins, are present in neutrophil granules and
remove essential iron from bacteria.
Hydrolytic enzymes these enzymes are used to
digest the proteins of destroyed bacteria.
Defensin are host defense peptides which assists in
killing phagocytosed bectaria.
If cells encounter materials that cannot be easily
ingested, such as immune complexes deposited on
immovable flat surfaces (e.g., glomerular basement
membrane), the attempt to phagocytose these
substances is not successful.
Defects in adhesion
Leukocyte adhesion deficiency
LAD-1 and LAD-2
Recurrent bacterial infections
Acute alcohol intoxication
Defects in phagocytosis
Autosomal recessive condition
Neutrophils have giant lysosomes
Defects in degranulation.
Chédiak–Higashi syndrome is a
rare autosomal recessive disorder that arises
from a mutation of a lysosomal trafficking
regulator protein, which leads to a decrease
The decrease in phagocytosis results in
recurrent pyogenic infections,
peripheral neuropathy etc.
Outcome of acute inflammaton
Complete resolution with regeneration.
Complete resolution with scarring.
Abscess (localised collection of pus)
Transition to chronic inflammation.
Chemical Mediators in Acute inflammation
Chemical mediators are responsible for these
Mediators may be produced locally by cells at
the site of inflammation
or they may be circulating in the plasma
(synthesized by the liver) as inactive precursors
and activated at the site of inflammation
Cell-derived mediators are stored in intracellular
granules and are rapidly secreted on cellular activation
(e.g., histamine in mast cells)
or are synthesized de novo in response to a stimulus
(e.g., PGs and cytokines).
Is characterized by the outpouring of a watery,
relatively protein-poor fluid that, derives either from
the serum or from the secretions of mesothelial
cells lining the peritoneal, pleural, and pericardial
The skin blister resulting from a burn or viral
infection is a good example of a serous effusion
accumulated either within or immediately beneath
the epidermis of the skin.
Fluid in a serous cavity is called an effusion.
Occurs in more severe injuries, resulting in
greater vascular permeability that allows
large molecules (such as fibrinogen) to pass
the endothelial barrier.
The reaction is most common in serosal
surfaces, mucous membrane, and in the
Such as Rheumatic pericarditis, Dysentry,
Fibrinous pericarditis: Gross and Microscopic views
Suppurative (purulent) inflammation
Is manifested by the presence of large
amounts of purulent exudate (pus)
consisting of neutrophils, necrotic cells,
and edema fluid.
Certain organisms (e.g., staphylococci) are
more likely to induce such suppuration and
are therefore referred to as pyogenic.
Example : Abscess.
Some infection e.g meningococcemia
induced vascular damage followed by
Of prolonged duration (weeks to months to years) in
which active inflammation, tissue injury, and healing
Is characterized by:
Infiltration with mononuclear cells, including
macrophages, lymphocytes, and plasma cells.
Tissue destruction, largely induced by the products of the
Repair, involving new vessel proliferation (angiogenesis)
May progress to chronic inflammation when the acute response
cannot be resolved, either because of the persistence of the
injurious agent or because of interference with the normal
process of healing.
For example, a peptic ulcer of the duodenum initially shows
acute inflammation followed by the beginning stages of
resolution. However, recurrent bouts of duodenal epithelial injury
interrupt this process and result in a lesion characterized by both
acute and chronic inflammation.
Alternatively, some forms of injury (e.g., viral infections) produce
a response that involves chronic inflammation from the onset
Chronic inflammation arises in the following
Persistent and difficult to eradicate infections : Mycobacteria,
Treponema pallidum , and certain viruses and fungi, which initiate T
lymphocyte-mediated immune response called delayed-type
Immune-mediated inflammatory diseases (hypersensitivity diseases)
due to excessive and inappropriate activation of the immune system
Allergic diseases, such as bronchial asthma
Prolonged exposure to potentially toxic agents (silicosis) and
endogenous agents such as chronically elevated plasma lipid
components (atherosclerosis )
Chronic Inflammatory Cells and Mediators
A fundamental feature of chronic inflammation
is its persistence, and this results from complex
interactions between the cells that are recruited
to the site of inflammation and are activated at
Understanding the pathogenesis of chronic
inflammatory reactions requires an
appreciation of these cells and their biologic
responses and functions.
Dominant cells of chronic inflammation, circulating blood
monocytes after their emigration from the bloodstream.
Macrophages are normally scattered in most connective tissues,
and are also found in organs such as the liver (k/a Kupffer cells),
spleen and lymph nodes (sinus histiocytes), central nervous
system (microglial cells), and lungs (alveolar macrophages).
In all tissues, macrophages act as filters for particulate matter,
microbes, and senescent cells, as well as acting as guard to alert
the specific components of the adaptive immune system (T and
B lymphocytes) to injurious stimuli
When monocytes reach the extravascular tissue,
they undergo transformation into larger
macrophages, which have longer half-lives and a
greater capacity for phagocytosis than do blood
Macrophages may also become activated, resulting
in increased cell size, increased content of
lysosomal enzymes, more active metabolism, and
greater ability to kill ingested organisms.
The roles of activated macrophages in chronic
When monocytes reach the extravascular tissue, they undergo
transformation into larger macrophages, which have longer half-lives
and a greater capacity for phagocytosis than do blood monocytes.
Macrophages are activated by bacterial endotoxin, ECM protein
(Fibronectin) and Cytokines (IFN-γ) which is secreted by sensitized T
After activation Macrophages secrets host of biologically active products
which itself can result in tissue injury and Fibrosis, which is
characteristic feature of Chronic inflammation.
Lymphocyte travels to the site of inflammation
due to any specific immune stimulus (infections)
as well as non-immune-mediated inflammation
(e.g., due to tissue trauma).
Both T and B lymphocytes migrate into
Lymphocytes and macrophages interact in a
bidirectional way, and these interactions play an
important role in chronic inflammation.
Macrophage-lymphocyte interactions in chronic inflammation
Secretions of Macrophages
After activation, macrophages secrete:
Acid and neutral proteases.
Other enzymes, such as plasminogen activator
ROS and NO
Cytokines such as IL-1 and TNF, as well as a
variety of growth factors that influence the
proliferation of smooth muscle cells and
fibroblasts and the production of ECM.
Fate of Macrophages
After the initiating stimulus is eliminated and the
inflammatory reaction completes, macrophages
eventually die or wander off into lymphatics.
In chronic inflammatory sites, however, macrophage
accumulation persists, and macrophages can
IFN-γ can also induce macrophages to fuse into
large, multinucleated cells called giant cells.
Characteristically found in inflammatory sites
around parasitic infections or as part of immune
reactions mediated by IgE, typically associated
Eosinophil granules contain major basic protein, a
highly charged cationic protein that is toxic to
parasites but also causes epithelial cell necrosis.
Widely distributed in connective tissues and they participate
in both acute and chronic inflammation.
Mast cells can also elaborate cytokines such as TNF and
chemokines and may play a beneficial role in some
Types of chronic inflammation
General chronic inflammation :
Active cellular proliferation occurs during healing process.
Cells involved in this process are Macrophages, endothelium, epithelium
In chronic condition lymphocyte and plasma cell are predominant .
Granulomatous Inflammation :
Aggregates of activated macrophages that assume an epithelioid
Rimmed by lymphocytes, plasma cells and fibroblsts
With or without central caseuos necrosis
With or without presence of multinucleated cell.
Infective granuloma :
Common in TB, Fungal infections, Syphillis, Leprosy.
TB granuloma consists of central caseous necrosis surrounded
by epitheloid Macrophages, Giant cells, Lypmocytes and
Foreign body granuloma :
It is due to foreign bodies e.g Sutures, Splinters etc.
Inflammatory polyps :
They form in reaction to Ulceration or Irritation e.g
Ulcerative collitis, Crohn’s disease.
Inflammatory pseudo tumor :
They are pseudo tumor which consists of
Lymphocytes , plasma cell, Histiocytes,
Macrophages and Foam cell.
SUMMARY Of Chronic Inflammation
Features of Chronic Inflammation:
Prolonged host response to persistent stimulus.
Caused by microbes that resist elimination.
Characterized by coexisting inflammation, tissue injury, attempted
repair by scar formation.
Cellular infiltrate consists of macrophages, lymphocytes, plasma
cells; fibrosis is often prominent
Mediated by cytokines (IL12) produced by macrophages and
lymphocytes (notably T lymphocytes);
Bidirectional interactions between these cells tend to amplify
and prolong the inflammatory reaction.
SYSTEMIC EFFECTS OF INFLAMMATION
Systemic effects of inflammation, collectively called
the acute-phase reaction, or the systemic
inflammatory response syndrome (SIRS)
Cytokines TNF, IL-1, and IL-6 are the most important
mediators of the acute-phase reaction.
The acute-phase response consists of several
clinical and pathologic changes
Fever, with elevation of body t°, usually by 1°to 4°C, is
one of the most prominent manifestations of the acutephase response, especially when caused by infection.
Fever is produced in response to pyrogens that
stimulates PG synthesis, in the vascular and
perivascular cells of the hypothalamus.
Bacterial products, such as lipopolysaccharide (LPS;
exogenous pyrogens), stimulate leukocytes to release
IL-1 and TNF (endogenous pyrogens) that increase the
levels of cyclooxygenases that convert AA into
The acute-phase response consists of several clinical and pathologic
In the hypothalamus the PGs, especially PGE2, stimulate the
production of neurotransmitters, which resets the temperature set
point at a higher level.
NSAIDs, including aspirin , reduce fever by inhibiting cyclooxygenase
and thus blocking PG synthesis
Concentrations of plasma levels of acute-phase proteins, mostly
synthesized in the liver, may increase several 100-fold in response to
Three acute phase proteins are: C-reactive protein (CRP), fibrinogen,
and serum amyloid A (SAA) protein.
CRP and SAA, bind to microbial cell walls, and act as
opsonins and fix complement, thus promoting the
elimination of the microbes
Fibrinogen binds to RBCs and causes them to form
stacks (rouleaux) that sediment more rapidly than
This is the basis for measuring the erythrocyte
sedimentation rate (ESR) as a simple test for the
systemic inflammatory response, caused by any
number of stimuli, including LPS.
Leukocytosis is a common feature of inflammatory
reactions, especially those induced by bacterial
Most bacterial infections induce an increase in the
blood neutrophil count, called neutrophilia.
Viral infections, such as infectious mononucleosis,
mumps, and German measles, are associated with
increased numbers of lymphocytes
Bronchial asthma, hay fever, and parasite
infestations all involve an increase in the absolute
number of eosinophils, creating an eosinophilia
Certain infections (typhoid fever & infections caused
by some viruses, rickettsiae, and certain protozoa)
are paradoxically associated with a relatively
decreased number of circulating white cells (relative
Other manifestations of the acute-phase response include
increased heart rate and blood pressure; decreased
sweating, anorexia, and malaise
Chronic inflammation is associated with a wasting
syndrome called cachexia, which is mainly the result of
TNF-mediated appetite suppression and mobilization of
High levels of TNF cause disseminated intravascular
coagulation (DIC), hypoglycemia.