Inflammation
Inflammation is response of the vascularized living tissue to injury.
Purpose
• 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:
• Sever infection
• Chronic Infection e.g. tuberculosis
• Inadequate response
Harmful Effect of Repair
• Formation of scars e.g. Intestinal Obstruction
Infection Due to microorganism
Stimuli for Acute Inflammation
• Infection (Bacterial, viral, fungal, parasitic)
• Trauma (Blunt and penetration)
• Physical and Chemical Agent (Thermal injury e.g. burns, or frost bite; irradiation)
• Tissue Necrosis (form any cause)
• Foreign Bodies (Splinters/dirts, sutures)
• Immune Reaction (also called hypersensitivity reactions)
Each of these stimuli may induce reaction with some distinctive characters but all inflammatory reactions have the same basic features
Type of Inflammation
Acute
• Short Duration (mins-days)
• Fluid and plasma protein (edema)
• Neutrophilic accumulation
Chronic
• Longer duration (days-years)
• Influx of lymphocytes and macrophages
Acute Inflammation
Acute inflammation is an immediate and early response to injury
Short duration mins, hours, days
Purpose
• To get the neutrophils to the site of injury
• To clear the incadin gof organism/agents and began the process of healing
Five Signs of Acute Inflammation (5 Cardinal signs of Inflammation )
1. Rubor (Redness)
2. Color (Heat)
3. Tumor (Swelling)
4. Dolar (Pain)
5. Functio lasen (loss of function)
Important components of acute inflammation
Vascular changes
• Change in vessel caliber (vasodilation)
• Strctural changes: permit flow of plasma
• Protein: Increased vascular permeability
Cellular events
• Emigration of leukocytes
• Accumulation at the site of injury
Chemical mediator
• Bradikynin
Vascular Changes
• Initial transient vasoconstriction
• Massive vasodilation mediated by histamine , bradkinin and prostaglandins (heat and redness)
• Increased vascular permeability
• Blood flood flow (staisis) due to increased viscosity, allow 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 trasudate is essentially an ultrafiltrate of blood plasma and contain little proteins
Exudate fluid + proteins
Mechanism of increased vascular permeability
• Endothelial cell contraction and retraction
• Direct endothelial injury
• Leukocytes dependent endothelial injury
• Increased transcytosis (movement of cells from blood vessels)
• Leakage from new blood vessels
Cellular Events
• Leukocyte extravasation (leakage)
• Chemotaxis
• Phagocytosis
Sequence of events in Extravasation of Leukocyte
• Margination
• Rolling
• Adhesion
• Transmigration (also called dipedesis)
Margination
Accumulation of leukocytes along the endothelial surface
Rolling, Adhesion and transmigration
Mediated by binding of complementary adhesion molecules on leukocytes and endothelial surface
Adhesion Molecules (3 families)
• Selectins
• Integrins
• Immunoglobulin
Rolling Adhesion and Transmigration: The steps Involved
1. Endothelial activation
2. Rolling
3. Leukocyte activation
4. Adhesion
5. Transmigration
Endothelial activation
At the site of inflammation, the endothelial cells have increased expression of
• E selection and P selection
Rolling
Neutrophils weakly binds to endothelial selectins and roll along the surface
Rolling
Leukocyte Activation
Neutrophils are stimulated by chemotactic agents (chemokines and C5a) to express their integrins
Adhesion
• Firm attachment of leukocytes to the endothelial surface
• Is mediated by complementary adhesion molecule on the surface of neutrophils and endothelium
• Binding of integrins firmly adheres the neutrophils to the endothelial cells
Transmigration
• Leukocytes emigrates from the vasculature by extending pseudopods between the endothelial cells
• Interaction of platelets endothelial cell adhesion molecule I (PECAM-I) on leukocytes and endothelial cells mediates transmigration between cells.
Chemotaxis
Chemotaxix is the movement of cells towards a chemical mediator that is released in the area of inflammation
Important chemotactic factor for neutrophils
o Bacerial product
o Leukotrines B4 (LTB4)
o Complement System Product (C5a)
o Chemokines (IL-8)
Phagocytosis
Three Steps:
• Recognition and Attachment
• Engulfments with subsequents formation of phagocytic vacuole
• Killing and degradation of the ingested material
Recognition and Attachment
Facilated by Opsonins
Opsonins enhace recognition and phagocytosis of bacteria
Important opsonins
• IgG
• C3b
• Plasma Protein – Collectin (binds to bacterial cell wall)
Engulfment
• Binding of opsonized particle triggers engulfment
• Neutrophil sends out cytoplasmic process that surround the bacteria
• The bacteria are internalized with a phagosome
• The phagosome fuses with lysosome (phagolysosomes)
• Release of lysosomal content (degradation)
Killing and Degradation
The final step in Phagocytosis of microbes is killing and degradation
Intracellular Killing
• Oxygen Dependent Kiling (aerobic)
• Oxygen Independent Killing (anaerobic)
Outcomes of Acute Inflammation
Four outcomes
• Complete resolution with regeneration
• Complete resolution with scarring
• Abscess (localized collection of pus)
• Transition to chronic inflammation
Chemical Mediators in Acute Inflammation
• Chemical mediators are responsible for these event
• Mediators may be produced locally by cells at the site of inflammation
• Or they may be circulating in the plasma (synthesized by 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 (at that point) in response to a stimulus (e.g. PGs and cytokines)
Mediators Source
Cell Performed Mediateors
in secretory granules Histamine Mast cellsm basophils, platelets
Serotinin Platelets
Newly synthesized Prostagladin All leukocytes, mast cells
Leukotrines All leukocytes, mast cells
Platelets activating factors All leukocytes, EC
Reactive oxygen species All leukocytes
Nitric oxide Macrophages, EC
Cytokines Macrophages, lymphocytes, EC, mast cells
Neropeptides Leukocytes, nerve fibers
Liver Plasma Complement Activation C3a Anaphylotoxins
C5a
C3b
C5b-9 (membrane attack complex)
Factor XII (Hagemann Factor activation) Knin system (bradykinin)
Coagulation/ Firinolysis
Morphologic Pattern of Acute Inflammation
• Serous inflammation (watery) skin
• Fibrinous Inflammation (greater vascular permeability) mucous membrane
• Supprative (purulent) inflammation pus edema fluid abscess
• Hemorrhagic Inflammation
Chronic Inflammation
Of prolonged duration (weeks to months to years) in which active inflammation. Tissue injury and healing proceed simultaneously. It is characterized by:
• Infiltration with monocular cells, including macrophages, lymphocytes and plasma cells
• Tissue destruction , largely induced by the product of inflammatory cells
• Repair involving new vessels proliferation (angiongesis) and fibrosis
May progress to chronic inflammation when the acute response cannot be resolved either because of presistance of the injurious agent or because inference with the normal process of healing
Chronic inflammation arises in the following settings
• Persistent and difficult to eradicate infections: Mycobacteria, Treponema palladium and certain viruses and fungi which initiates T-Lymphocytes mediated immune response called delayed type hypersensitivity
• Immune mediated inflammatory disease (hypersensitivity disease) due to excessive and inappropriate activation of the immune system
• Autoimmune diseases
• Allergic disease such as bronchial asthma
• Prolonged exposure to potentially toxic agents (silicosis) and endogenous agents such as chronically elevated plasma lipid components (atherosclerosis)