The ‘chemical mediators’ of inflammation
Chemical mediators are substances released from injured or activated cells that contribute to the inflammatory response.
There are 2 types of mediators: 1.Cellular mediators –derived from cells
2. Plasma derived mediators These are present in the plasma in a precursor form and are activated.
HISTAMINE :
Mast cells
Basophils
Vascular dilatation Increases vascular permeability
SEROTONIN
Nitrous oxide
NITRIC OXIDE
• Endothelium,macrophages • Potent vasodilator
• NO –also microbicidal
Cell Damage Membrane Phospholipids Arachidonic Acid 5-Lipoxygenase Cyclooxygenase
Leukotrienes LTC4, D4, E4
Prostaglandins
Prostaglandins
ARACHIDONIC ACID C. Arachidonic acid Metabolites: Generated from membrane phosphlipids.. METABOLITES
CYCLO-OXYGENASE PATHWAY Prostaglandins Vasodilation Increases vascular permeability LIPO-OXYGENASE PATHWAY Leukotreines LTB4 Chemotactic for neutrophils
Cell Damage Cell Membrane Phospholipids Arachidonic Acid 5-Lipoxygenase
Steroids
Cyclooxygenase
NSAID
Leukotrienes
LTC4, D4, E4
Prostaglandins
Cytokines IL-1 ,IL-6 ,TNF
- induce FEVER - release acute phase reactants from liver C-reactive protein
Oxygen derived free radicals
can destroy phagocytosed microbes
When released extracellularly, damage the host
LYSOSOMAL CONSTITUENTS OF NEUTROPHILS
Granules – MPO, lysozyme
Plasma Derived Mediators - 4 interconnected mediator producing systems - which are activated when tissue damage occurs.
i. Complement system ii. Clotting system
.
iii.Fibrinolytic system
iv. Kinin system.
iv. Complement system
Activation of the complement system results in the formation of a number of complement split products that serve as important mediators of inflammation.
Complements in inflammation
Complement.
ANTIGEN-ANTIBODY REACTIO NS
MICROBES Alternate (C3)
Classical (C1,4,2)
C3
• A complex series of about 20 proteolytic enzymes in the blood. • ‘Classical’ and ‘alternate’ pathways act in a cascade fashion.
C5
The Membrane Attack Complex
C5a
C5
C6 C5b C7
C9C9 C9 C9 C9 C9 C9 C9 C9 C9C9 Microbe
C8
Complement components
C5a, C3a
(ANAPHYLOTOXIN) Increased vascular permeability
C5a
. C3b
Chemotaxis
Opsonisation of cells and lysis.
C5b-9
Cell lysis.
Complements in inflammation
SUMMARY
Chemical mediators: Chemotactic factors: -C5a -LTB4 -Cytokines
Vasodilatation Histamine Serotonin Prostaglandins Nitrous oxide
Increased Permeability Histamine Serotonin -Prostaglandins
-
PAIN: Bradykinin Fever: Cytokines (IL-6,TNF)
Anaphylatoxin s (C3a,C5a)
Systemic effects of acute inflammation acute phase response
• Fever (temperature > 37.8oC or >100 F)
• Increased pulse, blood pressure • Chills • Anorexia
• Leukocytosis
• Neutrophilia and left shift of neutrophils points to bacterial infection
• Acute phase reactants- production in liver
C-Reactive Protein, Serum amyloid associated (SAA) Raised ESR
Chronic inflammation
Definition of chronic inflammation
an inflammatory response of prolonged duration (weeks – months - years)
provoked by the persistence of the causative stimulus
Causes of chronic inflammation
• Infectious organisms that resist clearance and form a persistent infection in tissue e.g mycobacterium tuberculosis, actinomycetes, treponema palidum • Exposure to irritant non-living foreign material that can not be removed
– implanted materials into wounds (wood splinters), inhaled materials (silica, asbestos), deliberately introduced material (surgical suture material or prosthesis)
• Potentially normal tissue components as seen in auto-immune diseases
– Beta islet cell in diabetes mellitus
Characteristics of chronic inflammation
• Infiltration of chronic inflammatory cellslymphocytes,plasma cells,macrophages
• Tissue destruction • Healing with scar formation and fibrosis
Tissue macrophage
and differentiate
Is the dominant cellular player in chronic inflammation
TISSUE INJURY
- toxic oxygen metabolites - Nitric oxide - AA metabolites
FIBROSIS Growth factors –for fibroblast proliferation FGF,PDGF Angiogenesis factors
Tissue macrophage
IFN-g
Activated T cell
Cytokines
Activated macrophage
Mechanisms by which macrophage accumulation occurs in chronic inflammation
Chronic Granulomaous Inflammation
Some agents evoke a distinctive pattern of chronic inflammation, referred to as GRANULOMATOUS INFLAMMATION. Eg: Tuberculosis, leprosy,and schistosomiasis
Granulomatous inflammation
Granulomas are millimeter size nodules of chronic inflammatory cells Granuloma formation is the result of dealing with indigestible substances or pathogens and walls them off The essential component are modified macrophages named epithelioid cell (because of shape). Epithelioid cells can form multinucleated giant cells. Epithelioid cells are surrounded by a collar of lymphocytes and occasionally plasma cells. Fibrous connective tissue often surrounds granulomas Areas within the granuloma can undergo necrosis (eg: caseous necrosis in tuberculosis).
Granuloma composed of epithelioid macrophages. Also seen here are two Langhans type giant cells in which the nuclei are lined up around the periphery of the cell.
Thank you