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Inflammation an overview. Hal Hawkins, Ph.D.,M.D. Basic Human Pathobiology Course, PATH 6266 May 7, 2012. Inflammation has been defined as the reaction to injury of vascularized tissue. ACUTE INFLAMMATION includes:. 1) Vasodilation and vascular leakage 2) Cellular:

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inflammation an overview
Inflammation an overview

Hal Hawkins, Ph.D.,M.D.

Basic Human Pathobiology Course, PATH 6266

May 7, 2012

acute inflammation includes

ACUTE INFLAMMATION includes:

1) Vasodilation and vascular leakage

2) Cellular:

recruitment

activation

functions

tissue Injury

vascular reactions account for the classical cardinal signs of inflammation
Vascular reactions account for the classical cardinal signs of inflammation:
  • Tumor – edema due to plasma leakage
  • Rubor – dilation of arterioles and engorgement of microvasculature
  • Calor – increased local temperature
  • Dolor –probably due to stretching and prostaglandins
neutrophil recruitment
Neutrophil Recruitment:

MARGINATION

ADHERENCE

EMIGRATION AND CHEMOTAXIS

experiments of cohnheim
Experiments of Cohnheim:

The tongue of the frog provides an opportunity to see the microcirculation and the movements of neutrophils.

adhesion and transmigration
ADHESION and TRANSMIGRATION:
  • Redistribution of adhesion molecules to the neutrophil cell surface:
    • P-selectin from endothelial granules
    • Mac-1 (CD11b/CD18) from neutrophil granules
  • Increased avidity of binding of Mac-1 and LFA-1, another neutrophil integrin: “activation of integrins”
  • Induction of adhesion molecules on endothelium:
    • E-selectin, ICAM-1, VCAM-1
neutrophil activation
Neutrophil Activation:
  • Receptors (complement, IgG, etc.)
  • PAF (platelet activating factor)
  • Phospholipase 

Inositol triphosphate  Ca++ release

Diacylglycerol  Protein kinase C

important chemotactic factors
Important chemotactic factors:
  • Complement fragment C5a
  • Bacterial formylated peptides
  • Arachidonic acid products,

e.g. Leukotriene B4

  • Cytokines called chemokines, e.g. IL-8
neutrophil functions
Neutrophil Functions:
  • PHAGOCYTOSIS
  • FUSION OF GRANULES
  • BACTERIAL KILLING
bacterial killing
Bacterial Killing:
  • O2-, superoxide
  • H2O2, peroxide
  • HOCl, hypochlorous acid 
  • OH•, hydroxyl radical
  • Acid hydrolases (enzymes)
  • Bactericidal proteins, defensins, lactoferrin, lysozyme
mediators of inflammation
MEDIATORS of INFLAMMATION:
  • Plasma proteases, e.g. complement
  • Vasoactive amines, e.g. histamine
  • Platelet-activating factor PAF
  • Arachidonic acid metabolites, e.g. prostaglandin E3
  • Reactive oxygen and nitrogen species
  • Cytokines and chemokines, e.g. IL-8
  • Neuropeptides and endothelin
prostaglandins and leukotrienes
Prostaglandins and leukotrienes
  • Products of arachidonic acid metabolism
  • Potent vasodilators/vasoconstrictors
  • Cyclo-oxygenase (COX), needed for prostaglandin synthesis, is inhibited by aspirin and selective COX2 inhibitors including the notorious Vioxx
  • Important in fever and pain
  • Lipoxygenase leads to leukotrienes, proinflammatory lipids active in asthma
inflammatory tissue injury
Inflammatory Tissue Injury
  • O2-, superoxide
  • H2O2, peroxide
  • HOCl, hypochlorous acid
  • OH•, hydroxyl radical
  • ONOO-, peroxynitrite

(reactive oxygen and nitrogen species)

  • Lysosomal neutral hydrolases
neutrophil apoptosis
Neutrophil apoptosis:
  • Follows emigration and phagocytosis
  • Minimizes tissue injury
regulation of neutrophil apoptosis
Regulation of neutrophil apoptosis
  • DELAY:
    • GM-CSF G-CSF
    • LPS, IL-1, IL-2
    • IFN-gamma
  • STIMULATE:
    • IL-6
    • Phagocytosis
    • Oxidative burst
apoptosis is the key to prevention of tissue injury
Apoptosis is the key to prevention of tissue injury
  • Cellular contents may not be released
  • Clearance by macrophages stimulates activation of macrophages to secrete factors favoring wound healing
what s new

What’s new?

Recognition of Pathogen Activated Molecular Pathways (PAMPs) including Toll Like Receptors, and Damage Activated Molecular Pathways (DAMPs) (together sometimes called Alarmins).

TLR’s stimulate release of multiple pro-inflammatory peptides.

DAMPs lead to assembly of inflammasomes, activation of caspase-1, and production of IL-1beta.

healing after injury repair and fibrosis
HEALING AFTER INJURY:Repair and fibrosis
  • Proliferation and migration of surviving cells
    • Depends on connective tissue matrix
  • GRANULATION TISSUE - “proud flesh”
    • Proliferating capillaries
    • Fibroblasts, migrating and proliferating
    • Follows inflammation, often coexists
    • CONTRACTS to close wound