patho 3.pptx

General features and
Historical highlights
3

Inflamm…
• A complex reaction to injurious agents( microbes
and damaged ,usually necrotic cells…) that
consists of vascular responses, migration and
activation of leukocytes and systemic reactions
• Inflame-‘to burn’ , ‘set a fire’
4

• Invertebrates, no
vascular system,
single- celled
organisms
• Get rid of injurious
agents (microbes) by
phagocytosis E.g
Specialized cells
(hemocytes) 5

Inflamm…
Unique feature
• Reaction of blood vessels, leading to accumulation
of fluid and leukocytes in extravascular tissues
6

Inflamm…
Purposes
• Destroy
• Dilute
• Wall off injurious agents
• Brings defense to the area
• Initiates healing
NB: Inflammatory response is closely intertwined with
the process of repair
7

Inflamm…
• Fundamentally a protective response
• Non-specific
Ultimate goal
• To rid the organism of both the initial cause of
injury (e.g toxins, microbes) and the consequences
of such injury (necrotic cells and tissues)
8

Inflamm…
Without inflammation
• Infections would go unchecked
• Wounds would never heal
• Injured organs remain permanent festering sores
9

Inflammation & repair may be potentially harmful
• Rheumatoid arthritis
• Atherosclerosis
• Lung fibrosis
• Hypersensitivity reactions to insect bites, drugs and
toxins
• Repair by fibrosis….disfigured scars and fibrous
bands e.g intestinal obstruction, pericardial fibrous
bands ,joint limitation
10

Two components
• Vascular reaction
• Cellular reaction
11

Many tissues and cells involved
• Fluid and proteins of plasma
• Circulating cells (neutrophils, monocytes,
eosinophils, lymphocytes, basophils and platelets)
• Blood vessels
12

Cellular and extracellular constituents of connective
tissue
• Mast cells, fibroblasts, resident macrophages and
lymphocytes
• Structural proteins (collagen, elastin)
• Adhesive glycoproteins (fibronectin, laminin,
nonfibrillar collagen,tenacin…)
• Proteoglycans
• Basement membrane (esp. ECM with adhesive
glycoproteins & proteoglycans)
13

Classification
• Based on duration of occurrence and morphologic
differences
• Acute inflammation
• Chronic inflammation
16

Acute inflammation- short duration (lasting for
minutes, hrs or few days)
• Characterized by exudation of fluid and plasma
proteins and migration of leukocytes( predominant
PMNs)
17

Chronic inflammation- longer duration (weeks, months,
even years)
• Predominant cells- lymphocytes and macrophages
• Proliferation of blood vessels, fibrosis and tissue
necrosis
18

• The vascular and cellular events of both
inflammatory patterns are mediated by chemical
factors derived from the plasma proteins or cells and
are produced in response to or activated by the
inflammatory stimulus
19

Termination
• When the offending agent is eliminated
• Mediators broken down or dissipated
Anti inflammatory mechanisms
Control response and prevents excessive damage to the
host
20

Naming of inflammatory lesions
The suffix ‘itis’, after the involved organ’s name
• Pancreatitis
• Meningitis
• Arthritis
• Appendicitis …..
21

Historical Highlights
• Description of clinical features of inflammation in
an Egyptian papyrus(~3000BC)
Four cardinal signs
• Rubor-redness
• Tumor-swelling
• Dolor –pain
• Calor-heat
• ‘Functio laesa- loss of function- Virchow ,1882
22
Cornelius Celsus, first century AD,
Roman writer

23
Heat Redness Swelling Pain Loss Of Func.

Calor, Rubor, Dolor, Tumor, Loss of function.
Surgical wound inflammation
24

Laryngitis:
25

Acute Enteritis:
26

Pneumonia
Inflammation of lung
27
Calor, Rubor, Dolor, Tumor, Loss of function..!

29
Acute inflamm…
• a rapid response to injury or microbes and other
foreign substances that is designed to deliver
leukocytes and plasma proteins to sites of injury

Two major components
– Vascular changes: vasodilation and
increased vascular permeability
– Cellular events: cellular recruitment and
activation
– The principal leukocytes are neutrophils
(polymorphonuclear leukocytes)
31

32
Terminologies
– Exudation-the escape of fluid, proteins and blood cells
from the vascular system into the interstitial tissue or
body cavities
– Exudate - inflammatory extravascular fluid that has
high protein concentration, cellular debris and specific
gravity above 1.020
– Transudate - fluid with low protein content and
specific gravity less than 1.012
– Edema - an excess of fluid in the interstitial or serous
cavities ,can be either exudate or transudate
– Pus , a purulent exudate , an inflammatory exudate
rich in leukocytes (mostly neutrophils ), debris of dead
cells , microbes

34
Stimuli (causes)
Infections (bacterial, viral, fungal, parasitic)
Trauma (blunt and penetrating)
Physical and chemical agents (thermal injury,
e.g., burns or frostbite; irradiation; chemicals)
Tissue necrosis (from any cause)
Foreign bodies
Immune reactions ( hypersensitivity reactions)
against environmental substances or against self
tissues

36
Vascular changes
• changes in vascular flow and caliber
• Changes in blood vessels begin rapidly after
infection or injury and occur in the following
order
Vasodilation – occurs after transient
vasoconstriction (lasting only for seconds),
- results in locally increased blood flow

Vasodilation – Increases nutrient and cellular supply,
pressure, fluid filtration
• Mediators of Vasodilation
• Histamine
• Nitric oxide
• Bradykinin other kinins
• Serotonin
37

39
Increased permeability – leads to outpouring
of protein rich fluid to the extracellular
environment
Stasis- as a result of increase in concentration
of RBCs , increased viscosity of blood , flow
slows
Margination - leukocytes (principally
neutrophils) begin to accumulate along the
vascular endothelial surface

41
• Increased vascular permeability
– Escape of protein rich fluid (exudate)
– Outflow of fluid and accumulation in the
interstitial tissue(edema )
What are mechanisms of increased
permeability ?

42
Cellular events :
leukocyte extravasation and phagocytosis
• Critical function of inflammation is to deliver
leukocytes to the site of injury and to activate them
to perform their function
• The sequence of events in the extravasation of
leukocytes from the vascular lumen to the
extravascular space is divided into
(1) margination and rolling,
(2) adhesion and transmigration between endothelial cells,
and
(3) migration in interstitial tissues toward a chemotactic
stimulus

45
Margination and rolling
-leukocytes are pushed out of the central axial
column and thus have a better opportunity to
interact with lining endothelial cells
- leukocyte accumulation at the periphery of
vessels…margination
- Subsequently, leukocytes tumble on the
endothelial surface, transiently sticking along
the way….rolling

46
• The weak and transient adhesions involved in
rolling are mediated by the selectin family of
adhesion molecules
• Selectins…. receptors expressed on leukocytes
and endothelium
• The three members of this family are
E-selectin , expressed on Endothelial cells;
P-selectin , present on endothelium and Platelets; and
L-selectin , on the surface of most Leukocytes

47
• After being arrested on the endothelial surface,
leukocytes migrate through the vessel wall primarily by
squeezing between cells at intercellular junctions
(diapedesis)
• occurs mainly in the venules of the systemic
vasculature
• Chemokines act on the adherent leukocytes and
stimulate the cells to migrate through interendothelial
spaces
• After passing through the endothelium, leukocytes
cross vascular basement membranes by focally
degrading them with secreted collagenases

• The type of emigrating leucocytes depends on
the duration of inflammatory response and
type of stimulus
• 6-24hrs-neutrophils predominate
• 24-48hrs-monocytes
• Viral-lymphocytes
• Allergy, parasites-eosinophils, main cells
52

53
Chemotaxis
• After extravasation leukocytes migrate toward sites of
infection or injury along a chemical
gradient…..Chemotaxis
• Chemotactic factors -exogenous and endogenous
substances
(1) bacterial products, particularly peptides with N-
formylmethionine termini;
(2) cytokines, especially those of the chemokine family;
e.g.IL-8
(3) components of the complement system, particularly C5a;
and
(4) products of the lipoxygenase pathway of arachidonic
acid (AA) metabolism, particularly leukotriene B4 (LTB4)

54
How does the leukocyte sense the chemotactic agents and
how do these substances induce directed cell movement ?
• Chemotactic molecules bind to specific cell surface
receptors
• This results in G-protein-mediated signal transduction
events, which triggers the assembly of cytoskeletal
contractile elements necessary for movement
• Leukocytes move by extending pseudopods that anchor to
the ECM and then pull the cell in the direction of the
extension
• The direction of such movement is specified by a higher
density of receptor-chemotactic ligand interactions at the
leading edge of the cell

55
Leukocyte activation
• Stimuli for activation include microbes,
products of necrotic cells. . .
• Leukocyte activation includes
– Production of arachidonic acid metabolites
– Degranulation and secretion of lysosomal
enzymes, and generation of the oxidative burst
– Modulation of leukocyte adhesion molecules
– Secretion of cytokines

56
Phagocytosis
• Phagocytosis consists of three distinct but
interrelated steps :
(1)recognition and attachment of the particle to
the ingesting leukocyte;
(2) engulfment, with subsequent formation of a
phagocytic vacuole; and
(3)killing and degradation of the ingested
material

57
• Recognition and attachment of leukocytes to
most microorganisms is facilitated by serum
proteins generically called opsonins
• The most important opsonins are
– immunoglobulin G (IgG) molecules (specifically the
Fc portion of the molecule),
– the C3b fragment of complement (and its stable
C3bi form), and
– plasma carbohydrate-binding lectins called
collectins

58
• Binding of opsonized particles triggers
engulfment;
• In engulfment, pseudopods are extended
around the object, eventually forming a
phagocytic vacuole
• The membrane of the vacuole then fuses with
the membrane of a lysosomal granule,
resulting in discharge of the granule's contents
into the phagolysosome

60
Killing and degradation
• accomplished largely by reactive oxygen
species
• The generation of the oxygen metabolites is
due to rapid activation of a leukocyte NADPH
oxidase, which oxidizes NADPH and, in the
process, converts oxygen to superoxide ion

61
• Superoxide is then converted by spontaneous
dismutation into hydrogen peroxide
(O2
· + 2H+ → H2O2)
• the lysosomes of neutrophils contain the enzyme
myeloperoxidase (MPO), and in the presence of a
halide such as Cl-, myeloperoxidase converts H2O2 to
HOCl· (hypochlorous radical)
• HOCl· is a powerful oxidant and antimicrobial agent
• (NaOCl is the active ingredient in chlorine bleach) that
kills bacteria by halogenation, or by protein and lipid
peroxidation)

63
• The dead microorganisms are then degraded by
the action of the lysosomal acid hydrolases
• other constituents of the leukocyte granules
– bactericidal permeability-increasing protein (causing
phospholipase activation and membrane phospholipid
degradation),
– lysozyme (causing degradation of bacterial coat
oligosaccharides),
– major basic protein (an important eosinophil granule
constituent with potent cytotoxicity for parasites), and
– defensins (peptides that kill microbes by forming holes
in their membranes)

Chemical mediators of
inflammation
66

67
Chemical Mediators…..
 Direct the vascular and cellular events
• Mediators may be:
– Plasma derived (typically synthesized by the liver), or
– produced locally by cells at the site of inflammation
• Plasma-derived
– Complement proteins
– kinins,
– coagulation factors
• Circulate as inactive precursors
67

• Cell-derived
– Sequestered in intracellular granules (e.g., histamine in mast cells) or
– Synthesized de novo in response to a stimulus (e.g., prostaglandins,
cytokines)
68

Cellular sources
• Platelets
• Mast cells
• Neutrophils
• Monocytes/macrophages
• Lymphocytes
• Mesenchymal cells (endothelium, fibroblasts)
• Some epithelia
69

70
Characteristics of mediators
 Most have specific receptors on target cells
 Some have direct enzymatic activity (e.g. lysosomal
proteases)
 Some mediate oxidative damage (e.g. reactive oxygen or
nitrogen intermediates)
 Mediators may stimulate target cells to release secondary
effector molecules
 pleiotropic and redundant effects
70

Once activated & released, most are short lived
• Decay (e.g. AA products)
• Inactivated (e.g. kianase- bradykinin)
• Scavenged (e.g. antioxidants)
• Inhibited (e.g. complement regulatory proteins)
• Most mediators have the potential to cause harmful effects
71

HISTAMINE
• Mast Cells,
basophils
• POWERFUL
Vasodilator
• Vasoactive
“amine”
• IgE on mast cell
72

73
Vasoactive Amines
Histamine
-preformed in granules of mast cells, basophils and platelets
- Degranulation in response to:
(1) physical injury
(2) immune reactions (IgE mediated on mast cells)
(3) C3a and C5a, the so-called anaphylatoxins ;
(4) leukocyte-derived histamine-releasing proteins;
(5) neuropeptides (e.g., substance P); and
(6) certain cytokines (IL-1,IL-8)
73

74
Effects
 arteriolar dilation
increased vascular permeability( endothelial
gap formation)
74

SEROTONIN
• (5HT, 5-Hydroxy-
Tryptamine)
• Platelets and
EnteroChromaffin Cells
• Also vasodilatation, but
more indirect
• Evokes N.O. synthetase (a
ligase)
75

76
Serotonin (5-hydroxytryptamine)
- a preformed vasoactive mediator,
- similar effects with histamine
- found primarily within platelet granules
- released during platelet aggregation
76

77
Neuropeptides
-are small proteins, such as substance- P,
- transmit pain signals,
- regulate vessel tone, and
- modulate vascular permeability
77

78
Plasma Proteases
- three interrelated plasma-derived factors:
- the kinin system
- the clotting system, and
- Complement system
78

79
Kinin system
 elaborate bradykinin from its precursor, high-
molecular-weight kininogen(HMWK) by kallikrein
 Effects of bradykinin
increased vascular permeability,
arteriolar dilation, and
bronchial smooth muscle contraction
Pain
 Short-lived actions-rapidly inactivated by
kininases present in plasma and tissues
79

COMPLEMENT SYSTEM
• >20
components,
in circulating
plasma
• Multiple sites
of action, but
LYSIS is the
underlying
theme
81

82
The complement system
a cascade of plasma proteins that play an
important role in both immunity and
inflammation
generate a pore like membrane attack complex
(MAC) that effectively punches holes in the
membranes of invading microbes
In the process, a number of complement
fragments are produced, including
C3b - opsonins
82

Arachidonic Acid
Leukotrienes
LTC4, D4, E4
Cyclooxygenase
5-Lipoxygenase
Prostaglandins
Prostacyclins
Cell Damage
Cell Membrane
Phospholipids
5-LO inhibitors
Steroids
NSAID
83
83

Effects include
• platelet stimulation ,
• vasoconstriction,
• bronchoconstriction,
• Vasodilation (low doses)
• chemotaxis ,
• leukocyte degranulation. . .
84

Morphologic Patterns of Acute
Inflammation
85

Morphology modifiers
• Nature & severety of injury
• Site &tissue affected
• Host responsiveness
• Important to associate with stimuli & clinical situation
• Variation in the proportion of the exudative products is
responsible for the patterns
86

87
Serous Inflammation
• characterized by outpouring of a watery, relatively protein-
poor fluid
• either from the serum or secreted by mesothelial cells lining
the peritoneal, pleural, and pericardial cavities…edema
fluid…… Effusion
• E.g. burn- skin blister or viral infection

90
Fibrinous Inflammation
• more severe injuries, greater vascular permeability
• Excess fibrinogen extravasation
• Microscopy- eosinophilic meshwork of threads or, sometimes,
as an amorphous coagulum
• Fates
• Resolution-fibrinolysis, debris removed by macrophages
• Organization- may lead to scarring

93
Suppurative (PURULENT) Inflammation
• large amounts of purulent exudate (pus)
• consisting of neutrophils, necrotic cells, and edema fluid
• Certain organisms (e.g., staphylococci) are more likely to
induce this localized suppuration………pyogenic
• Abscess-focal collection of pus
• caused by deep seeding of pyogenic organisms into a tissue
or by secondary infections of necrotic foci

Catarrhal inflammation
• inflammation of mucous membranes
• Marked secretion of mucus.
• Infections, eg, common cold (rhinovirus); allergy (eg, hay
fever).
96

Membranous (pseudomembranous) inflammation
• Necrotizing inflammation involving mucous membranes.
• The necrotic mucosa and inflammatory exudate form an
adherent membrane on the mucosal surface.
• Toxigenic bacteria, eg, Corynebacterium diphtheriae and
Clostridium difficile.
97

100
Ulceration
• a site of inflammation where an epithelial surface (skin, gastric
epithelium, colonic mucosa, bladder epithelium) has become
necrotic and eroded
• toxic or traumatic injury to the epithelial surface (e.g. peptic
ulcers) or may be due to vascular compromise
• There is usually an early intense neutrophilic infiltrate with
associated vascular dilation
• Chronic ulcer- base with mononuclear infiltrates) lymphocytes,
plasma cells, macrophages)

Serous inflammation
Fibrinous inflammation
Purulent inflammation
ulcers
103

Outcomes of acute inflammation
104

105
Acute inflammation generally has one of three outcomes:
Resolution
Healing by fibrosis
Progression to chronic inflammation

• E.g.Viral pneumonia, mild sun
burn…resolution
• Bacterial pneumonia resolution
• Acute osteomyelitis chronic
osteomyelitis
107
Lung abscess Chronic lung
abscess/pus
cavity
Fibrosis

109
Inflammation of prolonged duration (weeks
to months to years) in which active
inflammation, tissue injury, and healing
proceed simultaneously

• Morphologic Features:
– Infiltration with mononuclear cells (macrophages,
lymphocytes & plasma cells)
• indicates persistent reaction to injury
– Tissue destruction
• Done by way of Inflammatory cells
– Repair involving angiogenesis and fibrosis
• Attempt to replace lost tissue
110

111
Causes
Chronic inflammation arises in the following settings:
• Persistent microbial infections,
– mycobacteria , Treponema pallidum , and certain
fungi, viruses, parasites
– These organisms are of low direct pathogenicity,
but typically they evoke an immune response
called delayed hypersensitivity , which may
culminate in a granulomatous reaction
– Intracellular infections of any kind typically
require lymphocytes (and macrophages) to
identify and eradicate infected cells

112
• Prolonged exposure to potentially toxic agents
• Endogenous or exogenous
– e.g. exogenous nondegradable material-inhaled particulate
silica………silicosis
– endogenous agents -chronically elevated plasma lipid
components….. atherosclerosis

• Autoimmune diseases,
• in which an individual develops an immune response to
self-antigens and tissues
• Because the responsible antigens are in most
instances constantly renewed, a self-perpetuating
immune reaction results
e.g. rheumatoid arthritis, systemic lupus
erythematosus
113

115
Chronic inflammatory cells and mediators
Macrophages
• Dominant cells
• Mononuclear Phagocyte System
– Circulating blood monocytes →Tissue
macrophages
↓
Kupffer cells (liver)
Sinus Histiocytes (spleen,LN)
Microglia (CNS)
Alveolar Macrophages (lung)

116
Maturation of Mononuclear Phagocytes

117
• In chronic inflammation macrophage
accumulation persists and is mediated by
– Recruitment of monocytes from circulation
– Local proliferation of macrophages
– Immobilization of macrophages

119
Macrophages produce
• Acid and neutral proteases
• Complement components and coagulation
factors
• Reactive oxygen species and NO
• AA metabolites (eicosanoids)
• Cytokines, such as IL-1 and TNF, as well as a
variety of growth factors

• Activated macrophage products serve to
eliminate microbes, initiate repair process and
responsible for tissue injury in chronic
inflammation
• Tissue destruction is one of the hall marks
121

122
Other cells in chronic inflammation
Lymphocytes,
Plasma Cells,
Eosinophils, and Mast Cells

• Though neutrophils are the predominant cells
in acute inflammation they can be seen in
some persistent inflammatory lesions
• E.g. acute osteomyelitis……chronic
osteomyelitis
123

124
Mast cells
• participate in both acute and chronic inflammatory
responses
• are "armed" with IgE to certain antigens
• Upon antigen encounter , the prearmed mast cells are
triggered to release histamines and AA metabolites
• IgE-armed mast cells- central players in anaphylactic
shock , but they also play a beneficial role in a variety
of infections, particularly those involving parasites

Morphologic patterns
• Based on the causal association and
inflammatory cell distribution in a tissue, if it
has given a specific pattern or not.
• Specific (granulomatous)
• Non-specific e.g. chronic non-specific cervicitis,
126

127
Granulomatous Inflammation
• a distinctive pattern characterized by formation of
epithelioid granuloma
• Granulomas can form in the setting of persistent T-
cell responses to certain microbes (e.g. M.TB),
where T-cell-derived cytokines are responsible for
persistent macrophage activation

• GRANULOMA – microscopic nodular collection of
Epithelioid macrophages surrounded by a rim of
LYMPHOCYTES, occasional plasma cells, in long
standing granuloma …fibrosis
• In tuberculosis with central caseous necrosis
• ‘Epithelioid’- epithelial-like, squamous cell-like
activated macrophages
• H&E-With a pale pink granular cytoplasm &
indistinct cell borders
128

130
• Frequently epithelioid cells fuse to form giant cells
• The giant cells have a large mass of cytoplasm
containing 20 or more nuclei arranged peripherally
(langhans- type) or haphazardly (foreign body-
type)

132
• Tuberculosis is the archetypal granulomatous
disease
• Granulomas may also develop in response to
relatively inert foreign bodies (e.g., suture, splinter,
breast implant),…..foreign body granulomas
• the formation of a granuloma effectively "walls off"
the offending agent and is therefore a useful
defense mechanism

133
Two types of granulomas which differ in their pathogenesis
 Foreign body type
 Immune granuloma

Foreign body granulomas
– Are incited by relatively inert foreign bodies (e.g. talc),
– Typically form when material such as sutures and other
fibers are large enough to preclude phagocytosis
– The foreign material can usually be identified in the center
of the granuloma
– Don’t incite any specific inflammatory or immune
responses
134

136
Immune granuloma
– Are caused by insoluble particles ,typically microbes ,that are
capable of inducing a cell mediated response
– Granuloma is produced when the inciting agent is poorly
degradable or particulate
Pathogenesis
• Macrophages engulf the foreign material and process and
present some of it to T-cells
• The responding T-cells produce cytokines such as IL-2,
which activate other T-cells and IFN-γ which activate
macrophages and transform them into epithelioid cells &

139
• Tuberculosis is the prototype of immune
granulomas
• The granuloma is referred to as a tubercle and is
classically characterized by the presence of caseous
necrosis
• The presence of granulomas can suggest many
diseases and it is always necessary to identify the
specific etiologic agent by special stains for
organisms
• E.g. AF stain for tubercle bacilli, cultures (TB,
fungus) , molecular techniques (PCR for TB),
serology for syphilis…
• Sarcoidosis- idiopathic etiology

Systemic effects of inflammation
142

143
• ‘Acute phase response’ or ‘systemic inflammatory
response syndrome (SIRS)’
• Systemic changes are reactions to cytokines whose
production is stimulated by bacterial products and
inflammatory stimuli

Fever
• an elevation of body temperature, usually by 1° to 4°C,
• one of the most prominent manifestations of the acute-
phase response, especially when inflammation is caused by
infection
• produced in response pyrogens that act by stimulating
prostaglandin (PG) synthesis in the vascular and perivascular
cells of the hypothalamus
144

145
Elevated plasma levels of acute-phase proteins
• mostly synthesized in the liver, whose concentrations
may increase as part of the response to inflammatory
stimuli
• Three of the best-known of these proteins:
C-reactive protein (CRP), fibrinogen, and serum amyloid
A (SAA) protein
• Synthesis of these molecules by hepatocytes is up-
regulated by cytokines, especially IL-6
• Many acute-phase proteins, such as CRP and SAA can act

146
• Fibrinogen binds to erythrocytes and causes them
to form stacks (rouleaux) that sediment more
rapidly than individual erythrocytes
• This is the basis for measuring the erythrocyte
sedimentation rate (ESR) as a simple test for the
systemic inflammatory response, caused by any
number of stimuli, including LPS

147
Leukocytosis
• leukocyte count usually climbs to 15,000 or 20,000 cells/μL, but
sometimes it may reach as high as 40,000 to 100,000 cells/μL
• These extreme elevations are referred to as leukemoid reactions
• leukocytosis occurs initially because of accelerated release of cells
from the bone marrow reserve pool (caused by cytokines, including
TNF and IL-1)
• Prolonged infection also stimulates production of colony-stimulating
factors (CSFs) GM-CSF

148
• Most bacterial infections induce neutrophilia
• Viral infections, such as infectious mononucleosis,
mumps. . .are associated with lymphocytosis
• Bronchial asthma, hay fever, and parasite
infestations – eosinophilia
• Certain infections (typhoid fever and infections
caused by some viruses, rickettsiae, and certain
protozoa) are paradoxically associated with
leukopenia

149
Other acute phase responses include
• increased heart rate and blood pressure;
• decreased sweating,
• rigors (shivering),
• chills,
• anorexia,
• somnolence,
• Malaise…….

• In chronic inflammation a
wasting syndrome called
cachexia
• result of TNF-mediated
appetite suppression and
mobilization of fat stores
150

• In severe bacterial infections (sepsis) , large quantities
of cytokines, notably TNF, as well as IL-12 and IL-1 are
produced
• This is associated with disseminated intravascular
coagulation (DIC), hypoglycemia and hypotensive
shock…..septic shock
151

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