Inflammtion

• Vascularized connective tissue response to cell injury

Acute Inflammation

What is inflammation?

• Inflammation -– protective response intended to eliminate the initial

cause of cell injury and the necrotic cells and tissues arising from the injury

• Inflammation is intimately associated with the repair process which includes parenchymal cell regeneration and scarring

• Acute - minutes to days– Characterized by fluid and protein – PMN’s

• Chronic - weeks to years– Lymphocytes and macrophages

• ACUTE Inf - PMN’s (Polymorphonuclear Cells)

• CHRONIC Inf - Mononuclear Cells

Inflammation

EXUDATE

Acute inflammation

• The immediate and early response to injury

• The point? Get the pmn’s to the site as fast as possible

• Vasodilatation

• Endothelial permeability

• Extravasation of pmn’s

Acute inflammation major components

• Vasodilatation

• Endothelial permeability

• Extravasation of pmn’s

Five classic local signs of acute inflammation

These were known– Heat– Redness– Swelling– Pain

– Loss of function

by the Romans– Calor– Rubor

– Tumor– Dolor– Functio laesa

Added Later

Five classic local signs of acute inflammation

• The major components responsible for these local signs are – Heat - vasodilatation– Redness - vasodilatation– Swelling - vascular permeability– Pain - mediator release/pmn’s– Loss of function - mediator release/pmn’s

Vascular changes

• Vasoconstriction (seconds)

• Vasodilatation (forget the few seconds of vasoconstriction)

• Exudation of protein rich fluid

• Blood stasis

• Margination

• Emigration/Transmigration

Fig 2.1 Graphic of

Acute Inflammation

Vascular permeability

• Vasodilatation, increased blood flow

• Increased intravascular hydrostatic pressure

• Transudate - ultrafiltrate blood plasma (contains little protein)– Again, this is very transient and just gets the process

started. Think Acute Inflammation, think EXUDATE

• Increased vascular permeability

Vascular permeability

• Exudate - (protein-rich with pmn’s)– Exudate is the characteristic fluid of acute

inflammation

• Intravascular osmotic pressure decreases

• Osmotic pressure of interstitial fluid increases

• Outflow of water and ions - edema

Fig 2.2 Graphic

of Vascular Changes

How do endothelial cellsbecome leaky?

• Endothelial cell contraction

• Junctional retraction

• Direct endothelial injury (immediate sustained response)

• Leukocyte-dependent endothelial injury

• Increased transcytosis of fluid

Direct endothelial injury (immediate sustained response)

• Endothelial cell necrosis and detachment

• Result of severe injury or burn

• Occurs immediately and lasts until vessel repaired

• Occurs at sites of leukocyte accumulation

• Due to leukocyte activation which releases proteolytic enzymes and toxic oxygen

Leukocyte-dependent endothelial injury

Leukocyte Cellular Events

• Margination and Rolling

• Adhesion and Transmigration

• Migration into interstitial tissue

Fig 2.4

Margination

• Normal flow - RBC’s and WBC’s flow in the center of the vessel

• A cell poor plasma is flowing adjacent to endothelium

• As blood flow slows, WBC’s collect along the endothelium (this is “Margination”)

Endothelial Activation

• The underlying stimulus causes release of inflammatory mediators which activate the endothelium causing selectins and other mediators to be moved quickly to the surface of the cell

Selectins

• Selectins bind selected sugars – Selected + Lectins (sugars) = Selectins

• Some selectins are present on endothelial cells (E-Selectin)• Some selectins are present on leukocytes (L-Selectin)• Some selectins are present on platelets and endothelial cells

(P-Selectin)

Fig 2.5 A Endothelial Activation

Rolling

• Selectins transiently bind to receptors

• PMN’s bounce or roll along

• This is Rolling

Fig 2.5 B Rolling

Fig 2.5 C Firm

Adhesion

Adhesion

• Mediated by *Integrins (LFA-1, mac-1 & VLA-4) * Immunoglobulins (ICAM-1 and VCAM-1)

• ICAM-1: intercellular adhesion molecule-1

• VCAM-1: vascular cell adhesion molecule-1

Transmigration

• Mediated by PECAM-1

• Diapedesis

Fig 2.5 DTransmigration

Chemotaxis

• Movement toward the site of injury along a chemical gradient– Chemotactic Factors include

• Complement components (C5a)• Arachadonic Acid (AA) metabolites(LTB-4)• Soluble bacterial products• Chemokines (IL-8

• CASCH

Leukocyte Activation

• Chemokines also “activate” PMN’s– AA metabolite production

– Degranulation and Secretion of lysosomal enzymes– Oxidative burst (free radicals)– Modulation of adhesion molecules

Phagocytosis & Degranulation

• Phagocytosis (to eat and destroy)– Attach– Engulf– Kill

• Degranulation and the oxidative burst destroy the engulfed particle

Leukocyte-induced tissue injury

• Lysosomal enzymes are released into the extracellular space during phagocytosis causing cell injury and matrix degradation

• Activated leukocytes release reactive oxygen species and products of arachidonic acid metabolism which can injure tissue and endothelial cells

• These events underlie many human diseases (e.g. Rheumatoid arthritis)

Leukocyte adhesion deficiency 1 (LAD-1)

• Recurrent bacterial infections

• Inflammatory lesions lack neutrophil infiltrate

• High numbers of neutrophils in the circulation

• Neutrophils from patients can roll but do not stick

• Transfuse patients with normal neutrophils and they can emigrate

Mechanism of leukocyte adhesion deficiency 1 (LAD -1)

• Absence of integrins on neutrophils

• Mutation in n-terminal region of the integrin β chain inhibits proper integrin assembly

• Normal function is restored following transfection of patient cells with cDNA for β chain

Chediak-Higashi Syndrome

• This syndrome has been on every board test since Noah• It is a disease caused by defects in microtubules (too much

MSG ) • there is a defect in chemotaxis , and lysosomal degranulation

into phagosomes (due to defects in microtubules)• Autosomal recessive

Chronic Granulomatous Disease

• Defect in NADPH oxidase system

• Marked decrease in ability to kill microorganisms

Normal Lung

Pneumonia

Pneumonia

Another picture of the same thing…At a higher power!

They really are PMN’s

Abscess

*

AbscessMicro

Meningitis

Brain

PMN’s and

Exudate

Normal Meninges