Inflammation Notes
Inflammation Notes
Inflammation Notes
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
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)
• 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)
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.
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