Acute and Chronic Inflammation

DEFINITION AND CAUSES

➢ Inflammation is defined as the local response of living mammalian tissues to injury from 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.
The injurious agents causing inflammation may be as under:
1. Infective agents like bacteria, viruses and their toxins, fungi, parasites.
2. Immunological agents like cell-mediated and antigenantibody reactions.
3. Physical agents like heat, cold, radiation, mechanical trauma.
4. Chemical agents like organic and inorganic poisons.
5. Inert materials such as foreign bodies
The 4 cardinal signs of inflammation as:
• Rubor (redness);
• Tumor (swelling);
• Calor (heat); and
• Dolor (pain).
• Fifth sign functio laesa (loss of function)
TYPES OF INFLAMMATION
Tissues and cells involved in inflammatory response :
The fluid and proteins of plasma, circulating cells, blood vessels and connective tissue
• The circulating cells: neutrophils, monocytes, eosinophils, lymphocytes, basophils, and
platelets.
• The connective tissue cells are the mast cells, the connective tissue fibroblasts, resident
macrophages and lymphocytes.
• The extracellular matrix, consists of the structural fibrous proteins (collagen,
(fibronectin, laminin, proteins (collagen, (fibronectin, laminin, adhesive
glycoproteins collagen, tenascin, andothers), and proteoglycans.
• The basement membrane is a specialized component of the extracellular matrix consisting of
adhesive glycoproteins and proteoglycans.
ACUTE INFLAMMATION
• Acute inflammatory response by the host to any agent is a continuous process
– Vascular events
– Cellular events
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.
Haemodynamic Changes
• Inflammatory response result from changes in the vascular flow and calibre of small blood vessels in
the injured tissue.
1. Irrespective of the type of cell injury, immediate vascular response is of transient
vasoconstriction of arterioles. – With mild form of injury(3-5 seconds) reestablished – with
more severe injury (5 minutes)
2. Persistent progressive vasodilatation Involves mainly the arterioles like venules and
capillaries.
3. Progressive vasodilatation, in turn, may elevate the local hydrostatic pressure Transudation
of fluid into the extracellular space. Swelling at the local site of acute inflammation.
4. Slowing or stasis of microcirculation follows which causes increased concentration of red cells,
and thus, raised blood viscosity.
5. leucocytic margination Or peripheral orientation of leucocytes (mainly neutrophils) Along the
vascular endothelium. Leucocytes stick to the vascular endothelium migrate through the gaps
between the endothelial cells into the extravascular space emigration
Altered Vascular Permeability
The appearance of inflammatory oedema due to increased vascular permeability of microvascular
bed is explained on the basis of Starling’s hypothesis i) Forces that cause outward movement of
fluid from microcirculation: These are intravascular hydrostatic pressure and colloid osmotic
pressure of interstitial fluid. ii) Forces that cause inward movement of interstitial fluid into
circulation: These are intravascular colloid osmotic pressure and hydrostatic pressure of
interstitial fluid

PATTERNS OF INCREASED VASCULAR PERMEABILITY

Contraction of endothelial cells
– 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 – begins
immediately after injury, is usually reversible, and is for short duration (15-30 minutes)
Contraction or mild endothelial damage
• In this mechanism, there is structural re-organisation of the cytoskeleton of endothelial cells
that causes reversible retraction at the intercellular junctions or mild form of endothelial damage.
• This change affects venules and capillaries and is mediated by cytokines such as interleukin-1
(IL-1) and tumour necrosis factor (TNF)-a.
• The onset of response occurs after delay of 4-6 hours following injury and lasts for several hours
to days
Direct injury to endothelial cells
– Direct injury to the endothelium causes cell necrosis and appearance of physical gaps at the
sites of detached endothelial cells.
– Process of thrombosis involving platelets and fibrin is initiated at the site of damaged
endothelial cells.
– The increased permeability may either appear immediately after injury and last for several hours
– may occur after a delay of 2-12 hours and last for hours or days
Leucocyte-mediated endothelial injury
– 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 which may cause
endothelial injury and increased vascular leakiness.
– This form of increased vascular leakiness affects mostly venules and is a late response
Leakiness in neovascularisation
– In addition, the newlyformed capillaries under the influence of vascular endothelial growth
factor (VEGF) during the process of repair and in tumours are excessively leaky

CELLULAR EVENTS
The cellular phase of inflammation consists of 1. Exudation of leucocytes 2. Phagocytosis
Exudation of Leucocytes
• The escape of leucocytes from the lumen of microvasculature to the interstitial tissue.
• In acute inflammation, polymorphonuclear neutrophils (PMNs),monocytes and macrophages
The changes leading to migration of leucocytes are as follows
1. Changes in the formed elements of blood
2. Rolling and adhesion
3. Emigration
4. Chemotaxis
Changes in the formed elements of blood
– 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, neutrophils of the central column come close to the vessel wall;
this is known as pavementing.
Rolling and adhesion
• The following cell adhesion molecules (CAMs) bring about rolling and adhesion phases
1. Selectins
2. Integrins
3. Immunoglobulin gene superfamily adhesion molecules
–Selectins
»CAMs expressed on the surface of activated endothelial cells
»Structurally composed of lectins or lectin-like protein molecules
»recognise and bind to glycoproteins and glycolipids on the cell surface of neutrophils
Types of selectins
– P-selectin stored in endothelial cells and platelets, also called CD62) is involved in rolling.
– E-selectin (synthesised by cytokine-activated endothelial cells, also named ECAM) is associated
with both rolling and adhesion.
– L-selectin (expressed on the surface of lymphocytes and neutrophils, also called LCAM) is
responsible for homing of circulating lymphocytes to the endothelial cells in lymphnodes.
• Integrins – These are a family of endothelial cell surface proteins having alpha (or CD11) and
beta (CD18) subunits – Activated during the process of loose and transient adhesions between
endothelial cells and leucocytes
• Immunoglobulin gene superfamily adhesion molecules
– Intercellular adhesion molecule-1 (ICAM-1, also called CD54) – Vascular cell adhesion molecule-
1 (VCAM-1, also named CD106)
– Tighter adhesion and stabilise the interaction between leucocytes and endothelial cells.
– Platelet-endothelial cell adhesion molecule-1 (PECAM-1) or CD31 is involved in leucocyte
migration from the endothelial surface
EMIGRATION
– 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
– Neutrophils are the dominant cells in acute inflammatory exudate in the first 24 hours –
Monocyte-macrophages appear in the next 24- 48 hours
– Emigration of leucocytes, escape of red cells through gaps between the endothelial cells,
diapedesis
CHEMOTAXIS
– The transmigration of leucocytes after crossing several barriers (endothelium, basement
membrane, perivascular Myofibroblasts and matrix) to reach the interstitial tissues is a
chemotactic factor-mediated process called chemotaxis.
– The following agents act as potent chemotactic substances for neutrophils:
• Leukotriene B4 (LT-B4), a product of lipooxygenase pathway of arachidonic acid metabolites
• Components of complement system (C5a and C3a in particular)
• Cytokines (Interleukins, in particular IL-8)
• Soluble bacterial products (such as formylated peptides)

Phagocytosis
– Phagocytosis is defined as the process of engulfment of solid particulate material by the cells
(cell-eating).
– The cells performing this function are called phagocytes
• Types of phagocytic cells
– Polymorphonuclear neutrophils (PMNs) which appear early in acute inflammatory response,
sometimes called as microphages.
– Circulating monocytes and fixed tissue mononuclear phagocytes, commonly called as
macrophages.
– Neutrophils and macrophages on reaching the tissue spaces produce several proteolytic
enzymes
—lysozyme, protease, collagenase, elastase, lipase, proteinase, gelatinase, and acid hydrolases.
Cell-derived Mediators
• VASOACTIVE AMINES

Histamine
– It is stored in the granules of mast cells, basophils and platelets. – Stimuli or substances inducing
acute inflammation – e.g. heat, cold, irradiation, trauma, irritant chemicals, immunologic
reactions etc.
– vasodilatation, increased vascular (venular) permeability, itching and pain

5-Hydroxytryptamine (5-HT or serotonin)

– The actions of 5-HT are similar to histamine but it is a less potent mediator of increased vascular
permeability and vasodilatation than histamine.

Neuropeptides
Another class of vasoactive amines is tachykinin neuropeptides such as substance P, neurokinin
A, vasoactive intestinal polypeptide (VIP) and somatostatin.
 The major proinflammatory actions of these neuropeptides are as follows: a) Increased vascular
permeability. b) Transmission of pain stimuli. c) Mast cell degranulation.
ARACHIDONIC ACID METABOLITES (EICOSANOIDS)

PLATELET ACTIVATING FACTOR (PAF)

– i) increased vascular permeability; vasodilatation in low concentration and vasoconstriction – iii)
bronchoconstriction; – iv) adhesion of leucocytes to endothelium; and – v) chemotaxis
CYTOKINES
• Cytokines are polypeptide substances produced by activated lymphocytes (lymphokines) and
activated monocytes (monokines).
• The term chemokine is used for a family of substances which act as chemoattractants for
inflammatory cells

• IL-1,IL-6,IL-8,IL-12,TNF-Alpha,IFN-Gama,MCP-I,Eotaxin,PF-4.
• increased vascular permeability; vasodilatation in low concentration and vasoconstriction
– iii) bronchoconstriction; – iv) adhesion of leucocytes to endothelium
FREE RADICALS: OXYGEN METABOLITES AND NITRIC OXIDE
• Oxygen-derived metabolites are released from activated neutrophils and macrophages and include
superoxide oxygen (O’2), H2O2, OH’ and toxic NO products.
• Endothelial cell damage and thereby increased vascular permeability.
THE KININ SYSTEM
i)smooth muscle contraction; ii) vasodilatation; iii) increased vascular permeability; and iv) pain.
THE CLOTTING SYSTEM
The actions of fibrinopeptides in inflammation are: i) increased vascular permeability; ii) chemotaxis
for leucocyte; and iii) anticoagulant activity
THE FIBRINOLYTIC SYSTEM
Increase vascular permeability and are chemotactic to leucocytes
THE COMPLEMENT SYSTEM
anaphylatoxins (C3a, C4a and C5a), and membrane attack complex (MAC)

MORPHOLOGICAL PATTERN OF ACUTE INFLAMMATION

Serous inflammation
Is a form of inflammation where the predominant feature is the production of a serum-like exudate
The fluid may be derived from the plasma as a result of increased vascular permeability
Fibrinous inflammation
– Is a form of inflammation which is characterised by fibrin deposition.
– A fibrinous exudate develops when the vascular leaks are large or there is a local procoagulant
stimulus
Purulent (Suppurative) Inflammation, Abscess
Purulent inflammation is characterized by the production of pus, an exudate consisting of neutrophils,
the liquefied debris of necrotic cells, and edema fluid
Ulcers
– An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by the
sloughing(shedding) of inflamed necrotic tissue. – Ulceration can occur only when tissue necrosis and
resultant inflammation exist on or near a surface

OUTCOMES OF ACUTE INFLAMMATION

In a perfect world, all inflammatory reactions, after they have succeeded in eliminating the offending
agent, should end with restoration of the site of acute inflammation to normal.
• Resolution involves removal of cellular debris and microbes by macrophages, and resorption of
edema fluid by lymphatics
• Healing by connective tissue replacement (scarring, or fibrosis).
• Progression of the response to chronic inflammation
CHRONIC INFLAMMATION
Chronic inflammation is a response of prolonged duration (weeks or months) in which inflammation,
tissue injury, and attempts at repair coexist, in varying combinations.
Causes of Chronic Inflammation
• Persistent infections
• Hypersensitivity diseases
• Prolonged exposure to potentially toxic agents, either exogenous or endogenous

Persistent infections
– by microorganisms that are difficult to eradicate, such as mycobacteria and certain viruses, fungi,
and parasites.
– These organisms often evoke an immune reaction called delayedtype hypersensitivity
– inflammatory response sometimes takes a specific pattern called granulomatous inflammation –
Unresolved acute inflammation evolves into chronic inflammation.
Hypersensitivity diseases
– Chronic inflammation plays an important role in a group of diseases that are caused by excessive
and inappropriate activation of the immune system – autoimmune diseases
• results in chronic inflammation and tissue damage
• Rheumatoid arthritis and multiple sclerosis – allergic diseases
• Chronic inflammation is the result of excessive immune responses against common environmental
substances, as in bronchial asthma
Prolonged exposure to potentially toxic agents
– Exogenous -silica, a nondegradable inanimate material that, when inhaled for prolonged periods.
– results in an inflammatory lung disease called silicosis
– Atherosclerosis
– is a chronic inflammatory process affecting the arterial wall that is thought to be induced, at least in
part, by excessive production and tissue deposition of endogenous cholesterol and other lipids.

Morphologic Features
• Chronic inflammation is characterized by
• Infiltration with mononuclear cells – which include macrophages, lymphocytes, and plasma cells
• Tissue destruction, – induced by the persistent offending agent or by the inflammatory cells
• Attempts at healing – by connective tissue replacement of damaged tissue, accomplished by
angiogenesis (proliferation of small blood vessels) and, in particular, fibrosis
CELLS AND MEDIATORS OF CHRONIC INFLAMMATION
Role of Macrophages
• The dominant cells in most chronic inflammatory reactions are macrophages
• Contribute to the reaction by secreting cytokines and growth factors that act on various cells, by
destroying foreign invaders and tissues, and by activating other cells, notably T lymphocytes
Classical and alternative macrophage activation.
• Different stimuli activate monocytes/macrophages to develop into functionally distinct populations.
• Classically activated macrophages are induced by microbial products and cytokines, particularly IFN-
γ.
• They phagocytose and destroy microbes and dead tissues and can potentiate inflammatory
reactions.
• Alternatively activated macrophages are induced by other cytokines and are important in tissue
repair and the resolution of inflammation.

Role of Lymphocytes
• Microbes and other environmental antigens activate T and B lymphocytes, which amplify and
propagate chronic inflammation.
• Macrophage–lymphocyte interactions in chronic inflammation. Activated T cells produce cytokines
that recruit macrophages (TNF, IL-17, chemokines) and others that activate macrophages (IFN-γ).
• Activated macrophages in turn stimulate T cells by presenting antigens and via cytokines such as IL-
12.

Other Cells in Chronic Inflammation

Eosinophils
– are abundant in immune reactions mediated by IgE and in parasitic infections – Their recruitment is
driven by adhesion molecules similar to those used by neutrophils, and by specific chemokines(e.g.,
eotaxin) derived from leukocytes and epithelial cell
Mast cells
They have many similarities with circulating basophils, but they do not arise from basophils, are tissue-
resident, and therefore play more significant roles in inflammatory reactions in tissues than basophils
Mast cells (and basophils) express on their surface the receptor FcεRI, which binds the Fc portion of
IgE antibody.
Neutrophils
Neutrophils are characteristic of acute inflammation, many forms of chronic inflammation, lasting for
months, continue to show large numbers of neutrophils, induced either by persistent microbes or by
cytokines and other mediators produced by activated macrophages and T lymphocytes.

Granulomatous inflammation
Granulomatous inflammation is a form of chronic inflammation characterized by collections of
activated macrophages, often with T lymphocytes, and sometimes associated with central necrosis.
The activated macrophages may develop abundant cytoplasm and begin to resemble epithelial cells,
and are called epithelioid cells.
The activated macrophages may fuse, forming multinucleate giant cells. Granuloma formation is a
cellular attempt to contain an offending agent that is difficult to eradicate.
In this attempt there is often strong activation of T lymphocytes leading to macrophage activation,
which can cause injury to normal tissues

There are two types of granulomas, which differ in their Pathogenesis

– Immune granulomas are caused by a variety of agents that are capable of inducing a persistent T
cell–mediated immune response.
– In such responses, macrophages activate T cells to produce cytokines, such as IL-2, which activates
other T cells, perpetuating the response, and IFN-γ, which activates the macrophages.
Foreign body granulomas
Are seen in response to relatively inert foreign bodies, in the absence of T cell mediated immune
responses.
Epithelioid cells and giant cells are apposed to the surface of the foreign body. The foreign material
can usually be identified in the center of the granuloma, particularly if viewed with polarized light, in
which it may appear refractile.