Inflammation and infection lecture
Book Chapter – Inflammation and Repair
1. Overview of Inflammation
What is inflammation? Inflammation is a response of vascularized
tissues to infections and tissue damage that
brings cells and molecules of host defense from
the circulation to the sites where they are
needed, to eliminate the offending agents.
What are the 2 types of Inflammation may be of two types, acute and
inflammation? chronic
What mediates the Inflammation is induced by chemical mediators
inflammatory process? that are produced by host cells in response to
injurious stimuli.
What are the external The external manifestations of inflammation,
manifestations/cardinal often called its cardinal signs, are heat (calor in
signs of inflammation Latin), redness (rubor), swelling (tumor), pain
(dolor), and loss of function (functio laesa).
Is inflammation only Although normally protective, in some situations,
protective? the inflammatory reaction becomes the cause of
disease, and the damage it produces is its
dominant feature.
Under what condition is Inflammation is terminated when the offending
inflammation terminated? agent is eliminated.
(reaction resolves because inflammatory mediators are broken
down/dissipate, leukocytes have short life spans in tissues,
and anti-inflammatory processes are set in motion)
Under normal conditions After inflammation has achieved its goal of eliminating the
inflammation should offending agents, it sets into motion the process of tissue
conclude with what repair. Repair consists of a series of events that heal damaged
process? tissue. In this process, the injured tissue is replaced
through regeneration of surviving cells and filling of residual
defects with connective tissue (scarring) .
2. Causes of Inflammation
Name 4 causes Infections (bacterial, viral, fungal, parasitic) and microbial
of inflammation toxins
Tissue necrosis regardless of the cause of cell death
(e.g. ischemia, trauma , and physical and chemical injury)
Foreign bodies (splinters, dirt, sutures) and even some
Endogenous substances if large amounts are deposited in
tissues (e.g. urate crystals (gout) and cholesterol crystals
(atherosclerosis).
Immune reactions (also called hypersensitivity ) are reactions
in which the normally protective immune system damages the
individual's own tissues. The injurious immune responses may be
directed against self antigens, causing autoimmune diseases , or
may be inappropriate reactions against environmental
substances, as in allergies , or against microbes.
3. Recognition of Microbes and Damaged Cells
What is the first Recognition of microbes and necrotic cells by cellular
step in all receptors and circulating proteins.
inflammatory
responses?
4. Acute Inflammation
What are the 3 Acute inflammation has three major components: (1)
major dilation of small vessels, leading to an increase in blood
components of flow, (2) increased permeability of the
acute microvasculature, enabling plasma proteins and
inflammation? leukocytes to leave the circulation, and (3) emigration of
the leukocytes from the microcirculation, their
accumulation in the focus of injury, and their activation
to eliminate the offending agent
5. Acute Inflammation – Reactions of Blood Vessels in Acute Inflammation
What changes The vascular reactions of acute inflammation consist of
are seen in the changes in the flow of blood and the permeability of
vasculature vessels, both designed to maximize the movement of
during acute plasma proteins and leukocytes out of the circulation
inflammation and into the site of infection or injury.
and what is the
1° function of
such changes?
6. Acute Inflammation –Leukocyte Recruitment to Sites of Inflammation
What is the key Leukocytes that are recruited to sites of
function of those inflammation perform the key function of
leukocytes (WBCs) eliminating the offending agents.
recruited during
acute inflammation?
What mediates and The journey of leukocytes from the vessel lumen to
controls the the tissue is a multistep process that is mediated and
movement of controlled by adhesion molecules and cytokines.
leukocytes from the
circulatory
compartment to the
interstitial
compartment?
What is the x (e.g. Selectins mediate the initial weak interactions
4) step process by between leukocytes and endothelium.
which leukocytes
are recruited to the Firm adhesion of leukocytes to endothelium is
site of inflammation mediated by a family of leukocyte surface proteins
(give specific called integrins.
examples of
molecules)
Describe how the The nature of the leukocyte infiltrate varies with the
composition/nature age of the inflammatory response and the type of
of the leukocyte stimulus.
infiltrate changes
over time
What is the among Agents that block TNF, one of the major cytokines in
the most successful leukocyte recruitment, are among the most
therapeutic every successful therapeutics ever developed for chronic
developed for the inflammatory diseases,
treatment of chronic
inflammatory
diseases
7. Acute Inflammation –Phagocytosis and clearance of the Offending Agent
Recognition of Recognition of microbes or dead cells induces several
microbes or responses in leukocytes that are collectively
necrotic tissue called leukocyte activation
results in what?
What are the 3 Phagocytosis involves three sequential steps: (1)
sequential steps recognition and attachment of the particle to be
involved in ingested by the leukocyte; (2) engulfment, with
phagocytosis? subsequent formation of a phagocytic vacuole; and (3)
killing or degradation of the ingested material
How is the The killing of microbes and the destruction of ingested
intracellular materials are accomplished by reactive oxygen species
destruction of (ROS, also called reactive oxygen intermediates),
ingested reactive nitrogen species, mainly derived from nitric
microbes and oxide (NO), and lysosomal enzymes
debris the
accomplished
after
phagocytosis?
What is the Neutrophils and monocytes actively secrete granules
direct source of containing Granule Enzymes and Other Proteins. Such
tissue damage enzymes and anti-microbial proteins that degrade
during microbes and dead tissues, are thus distinct from classical
inflammation? lysosomes, and contribute to tissue damage.
From which
immune cell
types do these
factors come
from?
Name one Neutrophil extracellular traps (NETs) are extracellular
immunological fibrillar networks that concentrate anti-microbial
defense substances at sites of infection and prevent the spread
mechanism of the microbes by trapping them in the fibrils.
specific to
neutrophils?
Explain its
function.
8. Acute Inflammation – Leukocyte-Mediated Tissue Injury
How do leukocytes cause tissue Leukocytes damage tissues by actively
injury? secreting granules containing injurious molecules
such as Granule Enzymes and Other
Proteins.
Under what circumstances do Leukocytes are important mediators of
leukocytes produce more tissue injury to normal cells during: (1) a
damage than is to be expected Prolonged host response – e.g. when the
from a normal defense infection is difficult to eradicate, such as in
reaction? tuberculosis (2) a Hypersensitivity reaction (which
refers toundesirable reactions produced by the
normal immune system, including allergies and
autoimmunity.)
9. Acute Inflammation – Other Functional Responses of Activated Leukocytes
10. Acute Inflammation – Termination of the Acute Inflammatory Response
11. Mediators of Inflammation
Define a The mediators of inflammation are the substances that
“mediator” of initiate and regulate inflammatory reactions.
inflammation?
Give 2 Aspirin (which is chemically acetyl-salicylic acid) and
examples of Acetaminophen (which has the generic brand of Panadol)
anti-
inflammatory n.b. anti-inflammatory drugs would act to decrease one or more
drugs (those of the cardinal signs of inflammation – e.g. aspirin and
drugs that target acetaminophen reduce fever (antipyretic), pain (analgesic), and
inflammatory swelling
mediators)
Mediators of Mediators may be produced locally by cells (e.g. resident
inflammation tissue macrophages) at the site of inflammation, or may be
are derived derived from circulating inactive precursors (e.g. from
from what 2 complement) that are activated at the site of inflammation
sources?
What are the The major cell types that produce mediators of acute
major cell types inflammation are tissue macrophages, dendritic cells,
that produce and mast cells
mediators of
acute
inflammation?
How are the One mediator can stimulate the release of other
effects of these mediators. (e.g. products of complement stimulate release of
mediators histamine, TNF acts on endothelial cells to stimulate IL-1
amplified? production)
How are the Most of the mediators are short-lived – (they rapidly decay,
effects of these they are inactivated by enzymes, they are scavenged or inhibited)
mediators of
inflammation
kept in check?
12. Mediators of Inflammation – Vasoactive Amines: histamine and Serotonin
Name the 2 The two major vasoactive amines, are
major histamine (vasodilator) and serotonin (vasoconstrictor).
vasoactive
amines?
What are the Histamine causes dilation of arterioles and increases the
2 major permeability of venules.
effects of
histamine on
blood
vessels?
13. Mediators of Inflammation – Arachidonic Acid Metabolites
What are the 2 The lipid
major lipid mediator’s prostaglandins and leukotrienes are
mediators of produced from arachidonic acid present in membrane
inflammation? phospholipids, and they stimulate vascular and cellular
reactions in acute inflammation.
What molecule
are they both
derived from?
What cells Prostaglandins (PGs) are produced by mast cells,
produce macrophages, endothelial cells, and many other cell
prostaglandins types, and are involved in the vascular and systemic
and what role do reactions of inflammation.
prostaglandins
play in
inflammation?
What cells Leukotrienes are produced in leukocytes and mast cells
produce by the action of lipoxygenase and are involved in
leukotrienes? vascular and smooth muscle reactions and leukocyte
What enzyme recruitment.
inside these cells
is responsible
for the
production of
leukotrienes?
What role do
leukotrienes
play in
inflammation?
Name one lipid Lipoxins also are generated from arachidonic acid by
mediator that the lipoxygenase pathway, but unlike prostaglandins
contributes to and leukotrienes, the lipoxins suppress inflammation
the dampening by inhibiting the recruitment of leukocytes. They inhibit
of neutrophil chemotaxis and adhesion to endothelium.
inflammation?
What molecular
pathway does
this lipid
mediator derive
from?
What is the
mechanism of
action?
Name 4 classes Cyclooxygenase inhibitors include aspirin and other
of drugs that nonsteroidal anti-inflammatory drugs (NSAIDs), such as
inhibit ibuprofen. They inhibit both COX-1 and COX-2 and thus block all
prostaglandin prostaglandin synthesis (hence their efficacy in treating pain and
and leukotriene fever);
action?
Lipoxygenase inhibitors. 5-lipoxygenase is not affected by
Name one drug NSAIDs. Pharmacologic agents that inhibit leukotriene
that fits into production (e.g., zileuton) are useful in the treatment of asthma.
each drug class,
and its Corticosteroids are broad-spectrum anti-inflammatory agents
associated use. that reduce the transcription of genes encoding COX-2,
phospholipase A 2 , proinflammatory cytokines (e.g., IL-1 and
TNF), and iNOS.
Leukotriene receptor antagonists block leukotriene
receptors and prevent the actions of the leukotrienes. These
drugs (e.g., Montelukast) are useful in the treatment of asthma.
(attach diagram)
14. Mediators of Inflammation – Cytokines and Chemokines
What are Cytokines are proteins secreted by many cell types
cytokines and (principally activated lymphocytes, macrophages, and
where are they dendritic cells, but also endothelial, epithelial, and connective
principally tissue cells) that mediate and regulate immune and
derived from? inflammatory reactions.
What 2 TNF and IL-1 serve critical roles in leukocyte
cytokines serve recruitment by promoting adhesion of leukocytes to
critical roles in endothelium and their migration through vessels.
leukocyte
recruitment?
What specific
role do these 2
cytokines play in
assisting
leukocyte
recruitment?
TNF and IL-1 Both TNF and IL-1 activate Endothelial cells – resulting in
contribute to the expression of endothelial adhesion molecules, mostly E- and P-
local and selectins and ligands for leukocyte integrins; increased
systemic procoagulant activity of the endothelium; increased production of
reactions of various mediators (cytokines, chemokines, and eicosanoids)
inflammation.
What are the Both TNF and IL-1 activate leukocytes and other cells – e.g.
most important TNF stimulates the microbicidal activity of macrophages. IL-1
roles of these activates fibroblasts to synthesize collagen.
cytokines in
inflammation? Both TNF and IL-1 (as well as IL-6) induce the Systemic acute-
phase response associated with infection or injury.
TNF antagonists TNF antagonists have been remarkably effective in the treatment
are excellent of chronic inflammatory diseases
treatments for
what type of
diseases?
What’s a Chemokines are a family of small (8–10 kD) proteins
chemokine? that act primarily as chemoattractants for specific types
What is its of leukocytes.
function?
15. Mediators of Inflammation – Complement System
Define the The complement system is a collection of soluble proteins
complement and their membrane receptors that function mainly in host
system defense against microbes and in pathologic inflammatory
reactions.
What is the The proteolysis of the third (and most abundant) component, C3.
critical step in
complement
activation?
What are the 3 Proteolysis of C3 (activation of the complement cascade) can
ways in which occur in 3 ways:
the complement
system can • The classical pathway which is triggered by fixation of C1 to
become antibody (IgM or IgG) that has combined with antigen
activated
• The alternative pathway which can be triggered by microbial
surface molecules (e.g., endotoxin, or LPS), complex
polysaccharides, and other substances, in the absence of antibody
• The lectin pathway, in which plasma mannose-binding lectin
binds to carbohydrates on microbes and directly activates C1
What is the All three pathways of complement activation lead to the
common formation of an enzyme called the C3 convertase , which
splits C3 into two functionally distinct fragments, C3a
and C3b.
What are the 3 1. Inflammation and Recruitment - C5a can stimulate
main functions histamine release (results in vascular permeability and
of complement? vasodilation) and is also is a chemotactic agent for
neutrophils, monocytes, eosinophils, and basophils.
2. Opsonization and phagocytosis - C3b and its cleavage
product iC3b (inactive C3b), acts as opsonins and promote
phagocytosis by neutrophils and macrophages, which bear
cell surface receptors for these complement fragments.
When an 3. Cell lysis - (c5b, c6, c7, c8, c9 = MAC complex)
individual punctures a hole in bacterial cell walls
suffers from a
complement The MAC complex is important mainly for the killing of microbes
deficiency what with thin cell walls, such as Neisseria bacteria complement
types of deficiencies results in infection with Neisseria species that
infections are produce serious disseminated infections.
they more
susceptible to
and why?
How is the The activation of complement is tightly controlled by
activation of the cell-associated and circulating regulatory proteins.
complement C1 inhibitor blocks the activation of C1 (1st protein of the
system classical complement pathway)
regulated?
Inherited deficiency of C1 inhibitor is the cause of hereditary
angioedema (characterised by recurrent episodes of severe
swelling (angioedema)).
Decay accelerating factor (DAF) and CD59 are
proteins linked to plasma membranes by a
glycophosphatidyl (GPI) anchor.
When these o DAF prevents formation of C3 convertases
regulatory o CD59 inhibits formation of the MAC.
mechanisms are
not present what
conditions do An acquired deficiency of the enzyme that creates GPI anchors
they result in? deficiency of these regulators excessive complement activation
lysis of red cells (which are sensitive to complement-mediated
cell lysis) paroxysmal nocturnal hemoglobinuria
(PNH)
16. Mediators of Inflammation – Other Mediators of Inflammation
What are the Bradykinin increases vascular permeability and causes
effects of contraction of smooth muscle, dilation of blood vessels,
bradykinin? and pain when injected into the skin. These effects are
similar to those of histamine.
17. Morphologic Patterns of Acute Inflammation – Serous Inflammation
What are the The morphologic hallmarks of acute inflammatory
morphologic reactions are (1) dilation of small blood vessels and (2)
hallmarks of accumulation of leukocytes and (3) fluid in the
acute extravascular tissue.
inflammatory
reactions
What are the Serous inflammation is marked by the exudation of cell-
morphologic poor fluid into spaces created by injury to surface epithelia or
hallmark of into body cavities lined by the peritoneum, pleura, or pericardium.
serous Typically, the fluid in serous inflammation is not infected by
inflammation? destructive organisms and does not contain large numbers of
leukocytes (which tend to produce purulent inflammation)
18. Morphologic Patterns of Acute Inflammation – Fibrinous Inflammation
What are the A fibrinous exudate develops when the vascular leaks are
morphologic large or there is a local procoagulant stimulus. With a
hallmark of large increase in vascular permeability, higher-molecular-weight
fibrinous proteins such as fibrinogen pass out of the blood, and fibrin is
inflammation? formed and deposited in the extracellular space. A fibrinous
exudate is characteristic of inflammation in the lining of body
cavities, such as the meninges, pericardium and pleura
Give an example
of a case where
fibrinous
inflammation
would be seen?
19. Morphologic Patterns of Acute Inflammation – Purulent (Suppurative) Inflammation,
Abscess
What are the Purulent inflammation is characterized by the
morphologic production of pus, an exudate consisting of neutrophils,
hallmark of the liquefied debris of necrotic cells, and edema fluid.
purulent The most frequent cause of purulent (also called suppurative )
(Suppurative) inflammation is infection with bacteria that cause liquefactive
inflammation? tissue necrosis, such as staphylococci; these pathogens are
referred to as pyogenic (pus-producing) bacteria. A common
example of an acute suppurative inflammation is acute
appendicitis.
Define an Abscesses are localized collections of pus caused by
abscess? suppuration buried in a tissue, an organ, or a confined space.
They are produced by seeding of pyogenic bacteria into a tissue.
20. Morphologic Patterns of Acute Inflammation – Ulcers
Define An ulcer is a local defect, or excavation, of the surface of an
an organ or tissue that is produced by the sloughing (shedding) of
ulcer inflamed necrotic tissue
21. Outcomes of Acute Inflammation
What are the 3 acute inflammatory reactions typically have one of three
possible outcomes
outcomes of
acute Complete resolution - Resolution involves removal of cellular
inflammatory debris and microbes by macrophages, and resorption of edema
reactions? fluid by lymphatics.
Healing by connective tissue replacement
(scarring, or fibrosis) - This occurs after substantial tissue
destruction, when the inflammatory injury involves tissues that
are incapable of regeneration, or when there is abundant fibrin
exudation in tissue or in serous cavities (pleura, peritoneum) that
cannot be adequately cleared. In all these situations, connective
tissue grows into the area of damage or exudate, converting it into
a mass of fibrous tissue .
Progression of the response to chronic inflammation. Acute to
chronic transition occurs when the acute inflammatory response
cannot be resolved, as a result of either the persistence of the
injurious agent or some interference with the normal process of
healing.
22. Chronic Inflammation – Causes of Chronic Inflammation
Define Chronic Chronic inflammation is a response of prolonged
inflammation. duration (weeks or months) in which inflammation,
tissue injury, and attempts at repair coexist, in varying
combinations.
Name 3 settings Persistent infections by microorganisms that are difficult to
under which eradicate, such as mycobacteria and certain viruses, fungi, and
chronic parasites. These organisms often evoke an immune reaction
called delayed-type hypersensitivity. The inflammatory response
inflammation sometimes takes a specific pattern called granulomatous
arises. inflammation. In other cases, unresolved acute inflammation
evolves into chronic inflammation, such as when an acute
bacterial infection of the lung progresses to a chronic lung
abscess.
Hypersensitivity diseases. Chronic inflammation plays an
important role in a group of diseases that are caused by excessive
and inappropriate activation of the immune system.
In autoimmune diseases , self (auto) antigens evoke a self-
perpetuating immune reaction that results in chronic
inflammation and tissue damage; examples of such diseases are
rheumatoid arthritis and multiple sclerosis. In allergic diseases ,
chronic inflammation is the result of excessive immune responses
against common environmental substances, as in bronchial
asthma.
Prolonged exposure to potentially toxic agents, either
exogenous or endogenous. An example of an exogenous agent
is particulate silica, a nondegradable inanimate material that,
when inhaled for prolonged periods, results in an inflammatory
lung disease called silicosis. Atherosclerosis is a chronic
inflammatory process affecting the arterial wall that is thought to
be induced, at least in part, by excessive production and tissue
deposition of endogenous cholesterol and other lipids.
23. Chronic Inflammation – Morphological Features
Compare the acute inflammation - vascular changes (dilation/congestion of
morphological blood vessels and increased vessel permeability), edema, and
features of acute predominantly neutrophilic infiltration
and chronic
inflammation chronic inflammation - Infiltration with mononuclear cells
(macrophages, lymphocytes, and plasma cells), Tissue
destruction, and Attempts at healing by connective tissue
replacement of damaged tissue, accomplished by angiogenesis
and, in particular, fibrosis
24. Chronic Inflammation – Cells and Mediators of Chronic Inflammation
What is the role The dominant cells in most chronic inflammatory
of macrophages reactions are macrophages, which contribute to the
in chronic reaction by secreting cytokines and growth factors that
inflammation? act on various cells, by destroying foreign invaders and
tissues, and by activating other cells, notably T
lymphocytes.
What are the 2 There are two major pathways of macrophage activation,
major pathways called classical and alternative
of macrophage
activation?
Classical macrophage activation- e.g. by microbial products
such as endotoxin, or the cytokine, IFN-γ, induce M1 macrophages
which produce NO and ROS and upregulate lysosomal enzymes,
all of which enhance their ability to kill ingested organisms, and
secrete cytokines that stimulate inflammation. These
macrophages are important in host defense against microbes and
in many inflammatory reactions.
Alternative macrophage activation- e.g. by IL-4, induce M2
macrophages which are not actively microbicidal; instead, the
principal function of alternatively activated (M2) macrophages is
in tissue repair. They secrete growth factors that promote
angiogenesis, activate fibroblasts, and stimulate collagen
synthesis.
What determines Which of these two pathways is taken by a given macrophage
which pathway depends on the nature of the activating signals.
is taken by the
macrophage?
25. Systematic Effects of Inflammation
What is the Inflammation, even if it is localized, is associated with
acute phase cytokine-induced systemic reactions that are collectively
response? called the acute-phase response.
List the several Fever (elevation of body temperature by 1-4 °C) is one of the most
clinical and prominent manifestations of the acute-phase response, especially
pathologic when inflammation is associated with infection.
changes which
occur during Acute-phase proteins (e.g. C-reactive protein (CRP),
the acute- fibrinogen, and serum amyloid A (SAA) protein) are plasma
phase proteins, mostly synthesized in the liver, whose plasma
response? concentrations increase several hundred-fold as part of the
response to inflammatory stimuli.
Leukocytosis is a common feature of inflammatory reactions,
especially those induced by bacterial infections.
26. Tissue Repair – Overview of Tissue Repair
What are the 2 Damaged tissue can be repaired by the following 2 types
types of of reactions:
reactions by (1) regeneration = proliferation of residual (uninjured)
which damaged cells and maturation of tissue stem cells
tissue can be (2) the deposition of connective tissue to form a scar
repaired?
What is tissue Regeneration - some tissues are able to replace the damaged
regeneration? components and essentially return to a normal state. E.g. the
rapidly dividing epithelia of the skin and intestines, and in some
parenchymal organs, notably the liver.
Give examples
of 3 tissues that
can regenerate.
What is a scar? A scar is an area of connective (fibrous) tissue that
replaces normal tissue after injury-
When does scar If the injured tissues are incapable of complete restitution, or if
tissue, the supporting structures of the tissue are severely damaged,
formation occur repair occurs by the laying down of connective (fibrous) tissue, a
rather than process that may result in formation of a scar .
tissue
regeneration?
27. Tissue Repair – Cell and Tissue Regeneration
What does The regeneration of injured cells and tissues depends
(parenchymal) on factors (e.g. growth factors and stimuli such as
tissue tissue damage) that can incite cell division and
regeneration migration.
depend on?
Use the liver as an Regeneration of the liver occurs by two major
example of how mechanisms: proliferation of remaining hepatocytes
(which is driven by IL-6 - produced by Kupffer cells, and by
hepatocyte growth factor (HGF)- produced from many cells) and
repopulation from progenitor cells.
-
28. Tissue Repair – Repair by Scarring
What happens when If repair cannot be accomplished by
damaged tissue cannot be regeneration alone, it occurs by replacement of
fully repaired by the injured cells with connective tissue, leading
regeneration/reconstitution? to the formation of a scar, or by a combination
of regeneration of some residual cells and scar
formation.
Repair by connective tissue 1. Within minutes after injury, (1) a hemostatic plug
deposition (scar formation) comprised of platelets is formed, which (a) stops
following severe tissue bleeding and (b) provides a scaffold for
injury (e.g. being stabbed) infiltrating inflammatory cells.
consists of a series of 2.
sequential steps. Describe
these steps from
29. Tissue Repair – Factors that Impair Tissue Repair
Define The term fibrosis is used to denote the excessive deposition of
fibrosis collagen and other ECM components in a tissue. The
terms scar and fibrosis may be used interchangeably, but fibrosis most
often refers to the abnormal deposition of collagen that occurs in internal
organs in chronic diseases.
30. Tissue Repair – Clinical Examples of Abnormal Wound Healing and Scarring
