Acute Inflammation I

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Acute Inflammation I

• Husni Maqboul M.D.

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Inflammation

• Definition Reaction of vascularized connective
  tissue to local injury, leading to accumulation
  of fluids and blood cells.
• Causes All causes leading to cells injury may
  provoke an inflammatory response.

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inflammation

• Acute
• The immediate and early response to injury
  lasting for minutes, hours or few days
• Main characteristics are exudation of fluid,
  plasma proteins and blood forming elements.
• Chronic
• Longer duration, associated with mononuclears
• Proliferation of blood vessels, fibroblasts,and
  tissue necrosis

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Acute inflammation, Why?

• Significance
• protective response intended to eliminate,
  destroy, or localize the initial cause of cell
  injury and the necrotic cells and tissues arising
  from the injury.
• Inflammation turns on a series of events that
  would help repair or reconstitute damaged tissue
• Is inflammation good or bad ?

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Acute Inflammation
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Acute inflammation major components

• Vasodilatation
• Endothelial permeability
• Cellular events

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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
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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/pmns
• Loss of function - mediator release/pmns

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Vascular changes

• Changes in vascular flow and Caliber
• Transient Vasoconstriction
• Vasodilatation
• Exudation of protein rich fluid
• Blood stasis
• Margination
• Emigration/Transmigration

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Normal Microcirculation
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Increased Blood Flow
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Vascular changes

• Changes in vascular permeability
• Vasodilation, increased blood flow
• Increased intravascular hydrostatic pressure
• Transudate - ultrafiltrate blood plasma (contains
  little protein)

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Starling Forces
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Vascular permeability

• Exudate - (protein-rich with pmns)
• Exudate is the characteristic fluid of acute
  inflammation
• Intravascular osmotic pressure decreases
• Osmotic pressure of interstitial fluid increases
• Outflow of water and ions - edema

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Inflammation
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How do endothelial cellsbecome leaky?

• Endothelial cell contraction
• (immediate transient response) leading to
  formation of endothelial gaps
• histamine, mild thermal injury, bradykinina and
  leukotreine
• Seen in postcapillary venules
• Short lived response (30-60 m)
• Cytoskeletal reorganization ? endothelial cell
  retraction
• cytokines, hypoxia
• Takes hours to develop, persists for 24 h

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How do endothelial cellsbecome leaky?

• Increased transcytosis
• VEGF
• Direct endothelial injury
• Arterioles, venules and capillaries
• Toxins, burns , chemicals
• Immediate sustained
• May be delayed prolonged (? apoptosis, cytokines )

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How do endothelial cellsbecome leaky?

• Leukocyte mediated
• Delayed prolonged leakage
• Delay of 2-12 h , lasts several hours or days
• Leakage from new blood vessels

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Leukocyte Cellular Events

• Inflammatory cell accumulation is the most
  important feature in inflammatory reaction
• Margination and Rolling
• Adhesion and Transmigration
• Migration into interstitial tissue

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Rolling Activation Adhesion
Transmigration
Selectins (P,E,L)
Integrins/Immunogl.


LFA1,MAC1,VLA4/ICAM1,VCAM1
PCAM-1
Stimulus
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Margination

• Normal flow - RBCs and WBCs flow in the center
  of the vessel
• As blood flow slows, WBCs collect along the
  endothelium
• This is Margination
• Rolling WBCs tumble slowly along the
  endothelium, and adhere transiently.

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Adhesion Endothelial Activation

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

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Activation of Leukocyte Endothelial adhesion
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Activation of Leukocyte Endothelial adhesion
E-Selectin (ICAM-1)
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Activation of Leukocyte Endothelial adhesion
Chemokines, C5a, PAF
LFA-1(CD11a/CD18) with ICAM-1
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Selectins

• Selectins bind selected sugars
• Selected Lectins (sugars) Selectins
• Some selectins are present on endothelial cells
  (E-Selectin, CD62E)
• Some selectins are present on leukocytes
  (L-Selectin, CD62L)
• Some selectins are also present on platelets
  (P-Selectin)

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• Selectins transiently bind to receptors
• PMNs bounce or roll along
• Endothelial P-Selectin Leukocyte Sialyl-Lewis
  X PSGL-1
• GlyCam-1.CD34 L-Selectin
• Endothelial E-Selectin Leukocyte Sialyl-Lewis
  X PSGL-1, ESL-1

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Adhesion

• Mediated by Integrins ICAM-1( Intercellular
  Adhesion Molecule ) and VCAM-1 (Vascular Cell
  Adhesion Molecule ), these are Immunoglobulin
  family molecules, induced by IL-1 and TNF, that
  interact with integrins found on leukocytes.
• ICAM-1 binds to ? integrins LFA-1 (CD11a/CD18)
  and MAC-1 (CD11b/CD18)
• VCAM-1 binds to alpha4 ?1 (VLA-4) and alpha2 ?7

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Transmigration

• Mediated by PECAM-1 (CD31)
• Diapedesis (Cells crawling)

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ICAM-1 I NTEGRINS PECAM-1 ON LEUK. AND ENDOTH.
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Endothelial Activation in Acute Inflammation

• Endothelium The largest endocrine gland in
  the body
• Main factors secreted by endothelium
• Nitric oxide and prostocyclins ? vascular
  relaxation and inhibition of plt aggregation
• Endothelin, thromboxane A2, and angiotensin II ?
  vascular constriction
• PDGF promotes inhibitors such as heparin-like
  substances
• Chemokines

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Endothelial Activation in Acute Inflammation

• In inflammation
• PAF
• Increased synthesis of nitric oxide
• Expression and synthesis of cell adhesion
  molecules
• IL-1 and TNF? Selectins ? rolling
• Signal expression of leukocyte integrins
• ICAM-1 ? adhesion of neutrophils and lymphoid
  cells
• VCAM-1 ? adhesion of lymphoid and monocyte cells

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Chemotaxis

• Movement toward the site of injury along a
  chemical gradient
• Chemotactic Factors include
• Complement components C5a
• Arachadonic Acid (AA) metabolites LTB4
• Soluble bacterial products
• Chemokines IL-8

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Leukocyte Activation

• Chemokines also activate PMNs
• AA metabolite production
• Degranulation and Secretion of lysosomal enzymes
• Oxidative burst
• Modulation of adhesion molecules
• Priming TNF

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Leukocyte Activation
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Phagocytosis Degranulation

• Phagocytosis (to eat and destroy)
• Recognition . and Attachment.
• Opsonization by Fc, C3b and plasma collectins
• Engulfment , degranulation starts
• Kill
• Degranulation and the oxidative burst destroy the
  engulfed particle

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Phagocytosis Degranulation
Recogn Attachm Engulf.
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Killing

• Oxygen Dependent
• NADPH oxidase
  H2O2
• Myeloperoxidase
  HOCL
• Oxygen Independent
• Bactericidal permeability increasing protein
• Lysozyme, lactoferrin , MBP, defensisns

H2O2 CL
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Leukocyte-induced tissue injury

• Lysosomal enzymes are released into the
  extracellular space during phagocytosis causing
  cell injury and matrix degradation
• Regurgitation , frostrated , cytotoxic release
  (urate crystals)
• 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.
  ARDS , Rheumatoid arthritis)

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Defects in Leukocyte Function

• Defects in Leukocyte adhesion
• LAD I ( deficiency of CD18 - ?2 integrin-)
• 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

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Defects in Leukocyte Function

• LAD I ( deficiency of CD18 - ?2 integrin-)
• Absence of integrins on neutrophils
• Mutation in n-terminal region of the integrin ?
  chain inhibits proper integrin assembly
• Normal function is restored following
  transfection of patient cells with cDNA for ?
  chain
• LAD II
• Deficiency of Sialyl-Lewis X ( selectin receptor)

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Defects in Leukocyte Function

• Defects in Phagocytosis
• Chediak-Higashi Syndrome
• Neutropenia with giant granules
• Disordered intracellular trafiking of
  organelles, leading to defective degranulation,
  chemotaxis, and delayed killing
• Reduced transfer of lysozomal enzymes to
  phagosomes , melanocytes,platelets, and cells of
  the CNS
• Autosomal recessive

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Defects in Leukocyte Function

• Defects in Microbicidal Activity
• Chronic Granulomatous Disease
• Most cases are X-linked
• Defect in NADPH oxidase system
• Marked decrease in ability to kill microorganisms

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Normal Lung
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Pneumonia
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Pneumonia
Another picture of the same thing At a higher
power!
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They really are PMNs
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Abscess

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AbscessMicro
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Meningitis
PMNs and Exudate
Brain
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Normal Meninges