Hal Hawkins, Ph.D.,M.D. Fundamentals of Inflammation Course,
BBSC 6210 June 25, 2012 Slide 2 Vasodilation and vascular leakage
Cellular: recruitment activation functions tissue Injury Slide 3
Slide 4 Slide 5 Slide 6 Slide 7 Slide 8 Slide 9 Slide 10 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 Slide 11 Slide
12 Slide 13 Slide 14 Slide 15 MARGINATION ADHERENCE EMIGRATION AND
CHEMOTAXIS Slide 16 Slide 17 The tongue of the frog provides an
opportunity to see the microcirculation and the movements of
neutrophils. Slide 18 With the slowing of blood flow in the dilated
venules leukocytes appear in the marginal stream and tend to stick
to the vessel walls. At first the leukocytes stick momentarily and
are then displaced to be washed away by the blood stream. Slide 19
As they begin to adhere more closely some are pushed slowly along
by the blood stream, becoming flattened and elongated in the
direction of the flow so that they have the appearance of blobs of
jelly being pushed along over a sticky surface. Slide 20 Gradually
some of the cells adhere more firmly until even a relatively swift
stream of plasma and red corpuscles cannot dislodge them. With an
adequate injury some of the leukocytes sticking to the wall begin
to make their way through it by active movements, taking 2 to 12
minutes to do so. Slide 21 Slide 22 Slide 23 Slide 24 Slide 25
Slide 26 Slide 27 Armond Goldmans discovery of neutrophil integrins
Slide 28 Slide 29 http://www.youtube.com/watch?v=9wxK6oLA5 oc
http://www.youtube.com/watch?v=9wxK6oLA5 oc Slide 30
http://www.youtube.com/watch?v=DMvixApKz Ks
http://www.youtube.com/watch?v=DMvixApKz Ks Slide 31 Slide 32 (from
Marchesi and Florey) Slide 33 Receptors (complement, IgG, etc.) PAF
(platelet activating factor) Phospholipase Inositol triphosphate
Ca++ release Diacylglycerol Protein kinase C Slide 34 Slide 35
Slide 36 http://www.youtube.com/watch?v=ZUUfdP87Ssg Slide 37
Complement fragment C5a Bacterial formylated peptides Arachidonic
acid products, e.g. Leukotriene B4 Cytokines called chemokines,
e.g. IL-8 Slide 38 Slide 39 Slide 40 Slide 41 Slide 42 Slide 43
PHAGOCYTOSIS FUSION OF GRANULES BACTERIAL KILLING Slide 44 Slide 45
Slide 46 Slide 47 O 2 -, superoxide H 2 O 2, peroxide HOCl,
hypochlorous acid OH, hydroxyl radical Acid hydrolases (enzymes)
Bactericidal proteins, defensins, lactoferrin, lysozyme Slide 48
Pneumonia Slide 49 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 Slide 50 Slide 51 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 Slide 52 O 2 -, superoxide
H 2 O 2, peroxide HOCl, hypochlorous acid OH, hydroxyl radical ONOO
-, peroxynitrite (all reactive oxygen and nitrogen species)
Lysosomal neutral hydrolases Slide 53 Follows emigration and
phagocytosis Minimizes tissue injury Slide 54 DELAY: GM-CSF G-CSF
LPS, IL-1, IL-2 IFN-gamma STIMULATE: IL-6 Phagocytosis Oxidative
burst Slide 55 Cellular contents may not be released Clearance by
macrophages stimulates activation of macrophages to secrete factors
favoring wound healing Neutrophil apoptosis is the key to
prevention of tissue injury. Slide 56 Recognition of Pathogen
Activated Molecular Pathways (PAMPs) including Toll Like Receptors
(TLRs) and Damage Activated Molecular Pathways (DAMPs) (together
sometimes called Alarmins). TLRs stimulate release of multiple
pro-inflammatory peptides. DAMPs lead to assembly of inflammasomes,
activation of caspase-1, and production of IL-1beta. Slide 57 Slide
58 Slide 59 Slide 60
