Inflammation
an overview
Hal Hawkins, Ph.D.,M.D.
Basic Human Pathobiology Course, PATH 6266
May 23, 2011
Inflammation has been defined
as the reaction to injury
of vascularized tissue.
ACUTE INFLAMMATION
includes:
1) Vasodilation and vascular leakage
2) Cellular:
recruitment
activation
functions
tissue Injury
MICROVASCULAR ENDOTHELIAL CELL
Histamine
Leakage of venules marked with colloidal carbon
(India ink) after application of histamine
Triple Response of Lewis:
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
Time course of acute inflammation
Neutrophil Recruitment:
MARGINATION
ADHERENCE
EMIGRATION AND CHEMOTAXIS
Julius Cohnheim, 1839-1884
Experiments of
Cohnheim:
The tongue of the frog
provides an opportunity to
see the microcirculation
and the movements of
neutrophils.
Selectins (responsible for rolling)
Integrins
(essential for firm adhesion and emigration)
Integrin activation
Transient opening of intercellular junctions
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 emigration does not produce vascular
leakage!)
(from Marchesi and Florey)
Neutrophil Activation:



Receptors (complement, IgG, etc.)
PAF (platelet activating factor)
Phospholipase 
Inositol triphosphate  Ca++ release
Diacylglycerol  Protein kinase C
Platelet-Activating Factor, PAF
Chemotaxis:
Migration toward higher concentration
Important chemotactic factors:




Complement fragment C5a
Bacterial formylated peptides
Arachidonic acid products,
e.g. Leukotriene B4
Cytokines called chemokines, e.g. IL-8
Relative potencies of chemotactic factors
Priorities among chemotactic factors
COMPLEMENT:
a central mediator of
inflammation and immunity
Complement components
From Abbas’ textbook
Neutrophil Functions:

PHAGOCYTOSIS

FUSION OF GRANULES

BACTERIAL KILLING
Opsonization by complement
stimulates phagocytosis
Phagocytosis
The Neutrophil Oxidative Burst
Bacterial Killing:
O2-, superoxide
 H2O2, peroxide
 HOCl, hypochlorous acid 
 OH•, hydroxyl radical
 Acid hydrolases (enzymes)
 Bactericidal proteins, defensins,
lactoferrin, lysozyme

Pneumonia
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
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
O2-, superoxide
 H2O2, peroxide
 HOCl, hypochlorous acid
 OH•, hydroxyl radical
 ONOO-, peroxynitrite
(reactive oxygen and nitrogen species)


Lysosomal neutral hydrolases
Neutrophil apoptosis:

Follows emigration and phagocytosis

Minimizes tissue injury
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

Cellular contents may not be released

Clearance by macrophages stimulates
activation of macrophages to secrete
factors favoring wound healing
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 proinflammatory peptides.
DAMPs lead to assembly of inflammasomes,
activation of caspase-1, and production of IL-1beta.
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
Granulation Tissue
finis