Inflammation

Ms P. Manyau
School of Pharmacy
University of Zimbabwe
Intended Learning Outcomes
• General features and cells of inflammation
• Acute inflammation
• Vascular and cellular stage
• Inflammatory mediators
• Chronic Inflammation
• Systemic manifestations of inflammation
• Fever
Introduction
• Inflammation is a complex non-specific response to tissue injury intended to
• Minimise tissue injury/ infection
• Remove damaged tissue
• Generate new tissue and facilitate healing
• First described over 2000 years ago the immune system is the subject of
intense research
• Involved in the pathogenesis of cancer, cardiovascular disease, obesity, diabetes,
asthma dementia etc
• Inflammation can be acute or chronic
• Acute inflammation is the result of noxious stimuli e.g. infection/ injury
• Chronic inflammation lasts years
Cells of Inflammation
• Endothelial cells that line blood vessels
• Platelets
• Leukocytes
• Connective tissue (mast cells, macrophages)
Cells of the immune system
Cell Mediated Responses- Innate Immunity
• Leukocytes are the major mediators
of the inflammatory response
• The include granulocytes
(eosinophils, basophils, neutrophils)
• These have multilobed nuclei, and
granular cytoplasm (enzymes and
antibacterial substances)
• Agranulocytes have a single nucleus
and have no granules
(macrophages, monocytes,
lymphocytes)
Neutrophils
• The most numerous leukocytes, the
account for 60-70% of circulating
leukocytes.
• Their cytoplasms do not stain (neutro-)
• Sometimes referred to
polymorphonuclear cells because of
multi-lobed nuclei
• They can form pseudopods and
therefore are highly mobile
• Usually the first cells to arrive at the site
of inflammation
• Phagocytes
Other Granulocytes
• Eosinophils: reach site of inflammation about 2-3hr after neutrophils
• Granules stain pink with acid dye eosin, they contain a protein that is highly
toxic to parasitic worms that cannot be phagocytosed
• They appear to have a role in allergic reactions (eosinophilia), and have a long
lifespan and are involved in chronic inflammation
• Basophils stain blue with basic dye
• Account for <1% of circulating leukocytes, but they are important in
inflammatory reactions, and allergic reactions mediated by IgE
• Binding to IgE triggers release of histamine and vasoactive substances from
basophil granules
Mast Cells
• Mast cells are derived from the
same stem cells as basophils,
they mature enter tissue
• Prevalent on mucosal surfaces
• Granules release histamine,
proteases, cytokines, growth
factors, arachidonic acid
metabolites
Arachidonic Acid Pathway
Monocytes/ Macrophages
• They have a single kidney
shaped nucleus
• Monocytes are blood precursors
of macrophages
• Circulating monocytes have been
linked to a number of
inflammatory disorders including
atherosclerosis, where they are
transformed into macrophages,
that turn into foam cells
Monocytes/ Macrophages
• Produce potent vasoactive mediators (PGs, LTs, platelet activating
factors, cytokines, growth factors)
• Macrophages are phagocytes and have a larger phagocytotic potential
than neutrophils
• Macrophages circulate for longer than granulocytes, they are
important in chronic inflammation
Lymphocytes
• Lymphocytes are the smallest of the leukocytes and have a large
nucleus and a small cytoplasm.
• They migrate to the site of infection through chemotaxis using the
same substances that attract the other leukocytes
• Macrophages and lymphocytes communicate in a bi-directional way
• Antigen presenting cells
• Antibodies on cell surface that recognise antigens
Macrophages/ Lymphocyte Interaction
• Macrophages also act as antigen-
presenting cells (APCs) which
stimulates the adaptive system
• They internalise the organism and
digest it into small peptide
fragments
• The antigenic fragments together
with the histocompatibility complex
(MHC) proteins are presented on the
surface.
• The MHC is recognised by T-
lymphocytes
Plasma Cells
• Plasma cells develop from B-
lymphocytes that have become
activated after encountering an
antigen
• In the inflammatory site they produce
antibodies directed at persistent
antigens and altered tissue
components
• In intense activation/ chronic
inflammation they accumulate to form
geminal centres that resemble lymph
nodes e.g. inflamed synovium in
rheumatoid arthritis
Cell Adhesion Molecules
• Several families of adhesion molecules
including
• Selectins, integrins and immunoglobulin
super-family
• They assist in migration of
inflammatory cells e.g. diapedesis
• Leukocyte adhesion deficiency is a
deficiency in integrins leading to severe
leucocytosis and recurrent infections
• Overexpression has been associated to
chronic inflammatory diseases e.g.
rheumatoid arthritis
Endothelial Cells
• Single-cell thick lining of blood vessels
• They normally have a non-thrombogenic surface
• Produce agents that maintain vessel patency such as vasoactive
substances that control blood flow
• They provide a selective barrier for: inflammatory stimuli, leukocyte
extravasation, modulate immune response (mediators)
• Regulate immune cell proliferation through secretion of
haematopoetic colony stimulating factors
Platelets
• Platelets/ thrombocytes are small
membrane bound discs that have a
homeostatic function
• Activated platelets release
inflammatory mediators which
increase vascular permeability and
alter chemotactic, adhesive and
proteolytic properties of endothelial
cells
• Platelet activation has been
associated with atherosclerosis and
SLE
Inflammatory Mediators
• Plasma derived mediators are
the product of 3 protein
cascades
• Kalikrein-kinikogen system
produces kinins (pain)
• Coagulation system which
generates fibrin as an end product
• Complement results in formation
of vasoactive compounds, increase
vascular permeability and
leukocyte adhesion
Cell Derived Inflammatory Mediators
• Serotonin and Histamine
• Arachidonic acid metabolites
• Platelet activating factor
• Cytokines and chemokines
• Act primary as chemoattaractants
• Inflammatory chemokines are produced in response to bacterial toxins e.g.
IL1 and TNFα
• Homing chemokines – production of these is upregulated during an
inflammatory response
Cell Derived Inflammatory Mediators
• Nitric oxide
• Reactive oxygen species – production of these is increased when
leukocytes are exposed to antigens
• They also increase expression of cytokines
Stages of Acute Inflammation
• Vascular stage
• Increased blood flow (vasodilation),
• Increased endothelial permeability which allows passage of proteins and
inflammatory cells
• Cellular stage
• Involves emigration of leukocytes (mainly neutrophils) from microcirculation
to the site of injury
Vascular Stage
Vascular Stage
• This stage involves arterioles, capillaries and venules of the
microcirculation
• Vasodilation is one of the earliest manifestations of inflammation
• Dilation begins in the arterioles increasing blood flow into the capillary bed, the
area then becomes red (erythema) and warm
• The main mediators of vasodilation are histamine and nitric oxide
• Vasodilation is quickly followed by increased permeability of
microvasculature
• Protein rich fluid (exudate) moves into the extravascular space resulting in swelling
• Loss of fluid results in an increased concentration of blood constituents, resulting
in stagnation and clotting at the site of injury
Onset and Duration of Inflammation
• Depending on the severity of injury, the vascular changes that occur with
inflammation follow one of patterns
• Immediate transient response – occurs with minor injury, it develops
rapidly and is reversible (15-30 min)
• Immediate sustained response – occurs with more severe injury and can
continue for several days. Occurs with injuries like burns and infections.
Neutrophils may adhere to the endothelium and cause more injury
• Delayed response – increased permeability begins 2-12hr after exposure
to injurious stimulus and lasts hours to days e.g. sunburn and radiation
injury
Cellular Phase
• This stage of inflammation is marked by changes in the endothelial
cells lining the vasculature, and movement of phagocytes into that
area
• The 4 stages are:
1. Margination and rolling
2. Adhesion and diapedesis
3. Chemotaxis
4. Activation and phagocytosis
Cellular Phase
Cellular Phase
• Early stage of inflammation where there is signalling between blood
leukocytes and endothelial cells ensures arrest of the leukocytes
along the endothelium
• Cell communication through cytokines makes endothelial cells
express more adhesive molecules, these allow transmigration of
leukocytes
• Once in the extravascular space leukocytes are guided to the site of
injury by chemotactic factors
• These are secreted by tissue macrophages and non-immune cells
• The final stage is phagocytosis of microbes
Cardinal Signs of Inflammation
• Vasodilation – histamine, PGs and
nitric oxide
• Vascular leakage – histamine,
bradykinin, LTs, PAF, serotonin (5-
HT)
• Chemotaxis – complement, LTs,
bacterial products, interleukins
(IL)
• Pain – PGs, bradykinin
• Fever – cytokines (Il1, TNFs), PGs
Local Manifestations
• Determined by the degree and cause of
inflammation or site
• Host response may be more damaging than injury
itself e.g. tuberculosis
• Acute inflamation often involves formation of
exudates
• Serous (watery fluid)
• Haemaorrhagic (severe tissue injury and damage to
blood vessels)
• Fibrinous – contain large amounts of fibrin forming
a thick sticky mesh
• Membranous/ catarrhal – develop on mucous
membranes and are composed of necrotic cells in
fibropurulent exudate
• Purulent/ suppurative exudate – contains pus which
is degraded WBCs, proteins and tissue debris
Outcome of Inflammation
• Resolution
• Replacement of any irreversibly damaged cells with healthy cells with normal
structure and function
• Progression to chronic inflammation
• If offending agent is not removed acute inflammation may become chronic
• Depends on the extent of injury
• Scarring and fibrosis
• Occurs when there is substantial damage
Chronic Inflammation
• Causes of chronic inflammation are typically low grade persistent
infections or irritants
• These may include bacteria, viruses, fungi, large parasites that are of low
virulence
• Injured tissue may induce chronic inflammation e.g. tissue
surrounding a healing fracture
• Inflammation does not fully resolve, and continues with low intensity
• Autoimmune conditions
Obesity and Metabolic Syndrome
• Metabolic syndrome is a combination of
obesity, insulin resistance, dyslipidaemia
and hypertension
• Obesity results in increased production of
proinflammatory mediators that are
involved in the pathogenesis of obesity
related diseases
• Adipose tissue produces TNFα which is
associated with insulin resistance in NIDDM
• Hypoxia and dysregulation of carbohydrate
and fat metabolism disrupts metabolic
processes result in free radical formation
Granulomatous Inflammation
• A granuloma is a small (1-2mm)
lesion in which there is massing of
lymphocytes surrounding
macrophages
• Necrosis in the centre
• Macrophages are modified and
begin to resemble epithelial cells
called epithlioid cells
• Granulomas can form from foreign
bodies, micro-organisms like TB,
syphilis
Systemic Manifestations of Inflammation
• Under optimal conditions inflammation is confined to a localised area
• In some cases local injury can result in systemic manifestations
• In sepsis there are is a large quantity of micro-organisms in the blood
which result in massive amounts of IL1 and TNFα
• Systemic manifestations include
• Acute phase response
• Elevated white blood cell counts (leukocytosis)
• Counts change from 4-12 to 15-30 cells x 10⁶/L
• Fever
Acute Phase Response
• Occurs hours to days within onset of
inflammation/ infection
• There are changes in plasma proteins, skeletal
muscle catabolism, elevated erythrocyte
sedimentation rate and leucocytosis
• Signs and symptoms include fever, anorexia,
malaise and somnolence
• Protein synthesis is triggered by IL6 and TNFα
• Proteins include C-reactive protein (CRP) and
fibrinogen
• CRP is a biomarker of inflammation e.g. in
myocardial infarction
• Fibrinogen increases the makes RBCs form stacks
(elevated ESR)
Pyrexia
• Core body temperature is normally maintained within the range of 36.0 to 37.5°C
• Biochemical processes are controlled by temperature
• Core body temperature is controlled by the thermoregulatory centre in the
hypothalamus
• Temperature is caused by micro-organisms that display pyrogens
(lipopolysaccharides) on their surfaces
• Interaction with innate immunity cells results in production of IL1 which results in fever
• Microbial antigens also cause release of PGE2 which resets the hypothalamus thermostat – this
results in heat generating activities e.g. shivering, vasoconstriction, pilorection and increased
metabolism
• Injured cells or malignant cells can also produce pyrogens
• Some fevers are neurogenic i.e. originate from neurological dysfunction
Atrioventricular Shunt
• If the core temperature rises
above the normal range then
‘dissipation’ mechanisms are
activated
• Skin blood flow is increased
through vasodilation and closing
of AV shunt
• Sweating
• In addition the overheated person
will attempt to cool down
Fever Patterns
• Intermittent fever temp returns to
normal in 24hr. Typical pattern of
sepsis
• With remittent fever doesn’t go to
normal but flutuates
• Sustained fever remains above
38.0°C and fluctuates by about 0.5°C
• A relapsing fever is one that recurs
over several days can be caused by
various infections. E.g. fungal and TB
Stages of Fever
• There are 4 stages
1. Prodromal phase: Non-specific complaints like malaise, headache (vasodilation),
fatigue aches and pains
2. Chills: there is vasocontriction and pilorection which precede shivering
3. Flush: cutaneous vasodilation where skin is red and dry
4. Defervescence is marked by sweating
• Not all people develop all for stages
• Manifestations are related to metabolic rate, increased O2 requirements and use of
body proteins as a source of energy
• Delerium can occur at temperatures above 40°C.
• May result in seizures in childres
Management
• Fluids to prevent dehydration
• Sponging with lukewarm water
• Antipyretics e.g. paracetamol