inflammation lecture 3

Lecture 3 Inflammation
Dr.Ahmed Raji
Mediators of inflammation
Cell-derived mediators
1- Vasoactive amines: histamine and serotonin.
2- Arachidonic acid metabolites: prostaglandins, leukotrienes, and lipoxins.
3- Platelet-activating factor.
4- Reactive oxygen species.
5- Nitric oxide.
6- Cytokines.
7- Chemokines.
Plasma protein–derived mediators
1- Complement System.
2- Kinin Systems.
Arachidonic Acid (AA) Metabolites: Prostaglandins, Leukotrienes, and Lipoxins
AA is a polyunsaturated fatty acid normally esterified in membrane phospholipids.
Mechanical, chemical, and physical stimuli release AA from membrane phospholipids
through the action of cellular phospholipases.
AA-derived mediators, are synthesized by two major classes of enzymes:
1- Cyclooxygenases: which generate prostaglandins like PGE2, PGD2, PGF2?, PGI2
(prostacyclin), and TxA2 (thromboxane).
2- Lipoxygenases: which produce leukotrienes like LTB4, LTC4, LTD4, LTE4 and
lipoxins.
Reactive oxygen species
Superoxide anion, hydrogen peroxide, and hydroxyl radical, are the major species, the
physiologic function of these ROS in leukocytes is to destroy phagocytosed microbes,
but release of these potent mediators can be damaging to the host.
Cytokines and Chemokines
Cytokines are proteins produced by many cell types (principally activated lymphocytes
and macrophages) that modulate the functions of other cell types.
TNF and IL-1 are two of the major cytokines that mediate inflammation, they are
produced mainly by activated macrophages, they stimulates expression of endothelial
adhesion molecules, secretion of other cytokines; and produce systemic effects.
Chemokines are a family of small proteins that act primarily as chemoattractants for
specific types of leukocytes, like IL-8 (neutrophil), eotaxin (eosinophil), and
lymphotactin (lymphocytes).
The Actions of the Principal Mediators of Inflammation
Mediator Principal Sources Actions
Cell-derived
Histamine Mast cells, basophils, platelets Vasodilation
Serotonin Platelets Vasodilation
Prostaglandins Mast cells, leukocytes pain, fever
Leukotrienes Mast cells, leukocytes chemotaxis
Platelet-activating factor Leukocytes, mast cells Vasodilation, increased vascular
permeability.
Reactive oxygen species Leukocytes Killing of microbes, tissue damage
Nitric oxide Endothelium, macrophages Vasodilation, killing of microbes
Cytokines (TNF, IL-1) Macrophages, endothelial cells, mast
cells
Local endothelial activation
(expression of adhesion molecules),
fever/pain/anorexia/hypotension,
Chemokines Leukocytes, activated macrophages Chemotaxis, leukocyte activation
Plasma protein–derived
Complement products (C5a,
C3a, C4a)
Plasma (produced in liver)
Leukocyte chemotaxis
Kinins Plasma (produced in liver) pain
Systemic effects of inflammation
The systemic changes associated with acute inflammation are collectively called the
acute-phase response, or the systemic inflammatory response syndrome, these
changes are reactions to cytokines.
The acute-phase response consists of several clinical and pathologic changes:
• Fever (an elevation of body temperature, usually by 1° to 4°C) is one of the most
prominent manifestations of the acute-phase response, especially when
inflammation is associated with infection.
Fever is produced in response to substances called pyrogens that act by
stimulating prostaglandin synthesis in the hypothalamus.
Bacterial products, called exogenous pyrogens, stimulate leukocytes to release
cytokines such as IL-1 and TNF, called endogenous pyrogens that increase the
enzymes (cyclooxygenases) that convert AA into prostaglandins.
In the hypothalamus, the prostaglandins, especially PGE2, stimulate the
production of neurotransmitters such as cyclic adenosine monophosphate, which
function to reset the temperature set point at a higher level.
NSAIDs, including aspirin, reduce fever by inhibiting prostaglandin synthesis.
Fever may induce heat shock proteins that enhance lymphocyte responses to
microbial antigens.
• Acute-phase proteins are plasma proteins, mostly synthesized in the liver,
whose plasma concentrations may increase several hundred-fold as part of the
response to inflammatory stimuli, three of the best-known of these proteins are
C-reactive protein, fibrinogen, and serum amyloid A protein. Synthesis of these
molecules by hepatocytes is up-regulated by cytokines, especially IL-6 and IL-1
or TNF. Many acute-phase proteins, such as C-reactive protein, and serum
amyloid A protein, bind to microbial cell walls, and they may act as opsonins.
Fibrinogen binds to red cells and causes them to form rouleaux, that sediment
more rapidly at unit gravity than do individual red cells, this is the basis for
measuring the erythrocyte sedimentation rate (ESR) as a simple test for the
systemic inflammatory response, caused by any stimulus.
• Leukocytosis is a common feature of inflammatory reactions, especially those
induced by bacterial infections. The leukocyte count usually increase to 15,000
or 20,000 cells/?L.
The leukocytosis occurs because of accelerated release of cells from the bone
marrow (caused by cytokines, including TNF and IL-1) and is therefore
associated with a rise in the number of more immature neutrophils in the blood
(shift to the left).
Most bacterial infections induce an increase in the blood neutrophil count, called
neutrophilia.
Viral infections, cause an absolute increase in the number of lymphocytes
(lymphocytosis).
In bronchial asthma, allergy, and parasitic infestations, there is an increase in the
absolute number of eosinophils, creating an eosinophilia.
Certain infections (typhoid fever) are associated with a decreased number of
circulating white cells (leukopenia).
• Other manifestations of the acute-phase response include increased pulse and
blood pressure; decreased sweating, mainly because of redirection of blood flow
from cutaneous to deep vascular beds, to minimize heat loss through the skin;
rigors (shivering), chills (search for warmth), anorexia, somnolence, and
malaise, probably because of the actions of cytokines on brain cells.
Role of mediators in different reactions of inflammation
Role in Inflammation Mediators
Vasodilation Prostaglandins
Nitric oxide
Histamine
Increased vascular permeability Histamine and serotonin
C3a and C5a (by liberating vasoactive amines
from mast cells, other cells)
Bradykinin
Leukotrienes C4, D4, E4
PAF
Substance P
Chemotaxis, leukocyte
recruitment and activation
TNF, IL-1
Chemokines
C3a, C5a
Leukotriene B4
(Bacterial products, e.g., N-formyl methyl
peptides)
Fever IL-1, TNF
Prostaglandins
Pain Prostaglandins
Bradykinin
Tissue damage Lysosomal enzymes of leukocytes
Reactive oxygen species
Nitric oxide
Consequences of Defective or Excessive Inflammation
• Defective inflammation :
1- Increased susceptibility to infections, because the inflammatory response is
important for the defense mechanisms.
2- Delayed wound healing, because inflammation is essential for clearing
damaged tissues and debris, and provides the necessary stimulus to get the repair
process started.
• Excessive inflammation: is the basis of many types of human disease.
1- Allergies, in which there is unregulated immune responses against commonly
encountered environmental antigens.
2- Autoimmune diseases, in which immune responses develop against normally
tolerated self-antigens.
3- Atherosclerosis and ischemic heart disease.
4- Some neurodegenerative diseases such as Alzheimer disease.