Inflammation

Deske Muhadi

Rheumatology - Internal Medicine Dept.

University of Sumatera Utara - Medan
Definition
• Inflammation: protective response to eliminate the initial cause of cell
injury from the original insult and than initiates repair
• Cardinal signs
• heat (calor)
• redness (rubor)
• swelling (tumor)
• pain (dolor)
• loss of function (functio laesa),
The components of acute and chronic inflammatory responses
 Acute Chronic
Onset • Rapid • Insidious

Duration • Minutes-days • Days-years

Characteristic • Fluid & plasma protein • Vascular proliferation & scarring

exudation

• Neutrophil accumulation • Influx lymphocyte & macropage

Steps of the inflammation (the 5R)

Recognition of the injurious agent

Recruitment of leukocytes

Removal of the agent

Regulation (control) of the response

Resolution (repair).
Acute Inflammation
Stimuli for Acute Inflammation

 Infections
 Trauma
 Physical and chemical agents
 Injure host cells
 Tissue necrosis
 Foreign bodies
 Immune reactions (Hypersensitivity)
Vascular Changes in Acute Inflammation

Arteriolar Protein-rich fluid Concentration of

vasodilation & moves into the erythrocyte
increase extravascular (increasing
permeability tissues viscosity)

Extravasation of
Margination Stasis.
leukocyte
Leukocyte Recruitment and Activation

• Important inflammation function: deliver & activate leukocytes 

ingest, kill & eliminate offending agents, but also can damage normal
adjacent tissue.
• Multistep leukocyte recuitment:
• Loose attachment to & rolling on endothelium
• Firm attachment to endothelium
• Migration through inter-endothelial spaces
• Chemotaxis to site of infection.
Pathogen Degradation
• Leukocyte-Induced Tissue Injury

• Once activated, they don’t distinguish between offender and host.

• Happened in:
• Infections that are difficult to eradicate
• Normal attempt to clear damaged and dead tissues
• Inappropriately directed against host tissues ( autoimmunity)
• Reacts excessively against non-toxic environmental substances (allergy)
Outcomes of Acute Inflammation
• Termination & resolution (short time or minimal injury)
• Neutralization: decay or enzymatic degradation of the various chemical
mediators
• Normalization of vascular permeability
• Cessation of leukocyte emigration with by apoptosis of extravasated
neutrophils
• Transition to chronic inflammation
• Extensive destruction of the tissue resulting in scarring.
 MORPHOLOGIC PATTERNS OF ACUTE
INFLAMMATION
Serous inflammation
is characterized by the
outpouring of a watery,
relatively protein-poor
fluid (e.g skin blister after
burn injury)
Fibrinous inflammation:
consequence of more
severe injuries  allows Suppurative (purulent)
fibrin pass the inflammation: presence of
endothelium. characteristic large amounts of purulent
of inflammation in the exudate (pus) consisting of
lining of body cavities neutrophils, necrotic cells,
(meninges, pericardium, and edema fluid. Caused
and pleura) by certain organism
(pyogenic)
CHEMICAL MEDIATORS OF INFLAMMATION

Source:
• Produced locally by cells
• Sequestered in intracellular granules
• Synthesized de novo in response to a stimulus
• Circulating in the plasma as inactive precursors

How they work:

• Direct enzymatic and/or toxic activities
• Stimulate target cells to release secondary effector molecules.
• Similar action
• Opposing action
• The actions of most mediators are tightly regulated:
• Quickly decay (e.g., arachidonic acid metabolites)
• Inactivated by enzymes (e.g., kininase inactivates bradykinin)
• Eliminated (e.g., antioxidants scavenge toxic oxygen metabolites)
• Inhibited (complement-inhibitory proteins).
 CELLULAR MEDIATORS SOURCE

Histamine Mast cell, basophil, platelets

Preformed mediators Serotin Platelets
in secretary granules Lysosomal enzymes Neutrphils, macrophage

Prostaglandin All leukocytes, platelets, EC

Leukotrienes All leukocytes
Platelet-activating factors All leukocytes, EC
Newly synthesized Activated oxygen species All leukocytes
Nitric oxide Macrophages
Cytokines Lymphocytes, macrophage, EC

Factor XII (Hageman Kinin system (bradykin)

factor) activation Coagulation/ fibrinolysis system

PLASMA
C3a
anaphylaxotins
Complement
C5a
activation C3b
LIVER C5b-9 (membrane attack complex)
(major source)

Chemical mediators of inflammation 19

 The Actions of the Principal Mediators of Inflammation
Mediator Source Principal Action
Cell - Derived

Histamine Mast cells, basophils, platelets Vasodilation, increased vascular permeability, endothelial activation

Serotonin Platelets Vasodilation, increased vascular permeability

Prostaglandins Mast cells, leucocytes Vasodilation, pain, fever

Leukotrienes Mast cells, leucocytes Increased vascular permeability, leucocytes adhesion, chemotaxis, degranulation, oxidative burst

Platelet-activating factor Leucocytes, endothelial cells Vasodilation, increased vascular permeability, leucocyte adhesion, chemotaxis, degradation, oxidative burst

Reactive oxidative species leucocytes Killing of microbes, tissue demage

Nitric oxide Endothelium, macrophages Vascular smooth muscle relaxation, killing of microbes

Cytokines (e.g TNF, IL-1) Macrophages, lymphocytes, endothelial cells, mast Local endothelial activation (expression of adhesion molecules), systemic acute – phase response; in severe infection,
cells septic shock
Chemokines Leucocytes, activated macrophages Chemotaxis, leucocyte activation

Plasma Protein-Derived

Complement Plasma (produced in liver) Leucocyte chemotaxis and activation, opsonization, vasodilation (mas cell stimulation)

Kinins Plasma (produced in liver) Increased vascular permeability, smooth muscle contraction, vasodilation, pain

Protein activated during coagulation Plasma (produced in liver) Endothelial activation, leucocyte recrutment
 Bacterial products, immune
complexes, toxins, physical injury,
other cytokines

Activation of Macrophages (and

other cells)

TNF / IL-1
Chronic iInflammation
• Prolonged duration (weeks to months to years)
• Characterized by:
• Active inflammation: Infiltration with mononuclear cells
• tissue injury
• Healing: angiogenesis and fibrosis
 Chronic Inflammation Acute Inflammation

Chronic inflammation in the lung:

acute inflammation of the lung :
collection of chronic inflammatory
neutrophils fill the alveolar spaces
cells (asterisk), destruction of
and blood vessels are congested.
parenchyma (normal alveoli are
replaced by spaces lined by cuboidal
epithelium, arrowheads), and
replacement by connective tissue
(fibrosis, arrows).
Conditions Promoting Chronic Inflammation
Persistent infections by microbes that are difficult to eradicate (e.g
mycobacteria, Treponema pallidum)

Immune-mediated inflammatory diseases (hypersensitivity diseases)

autoimmune diseases

Prolonged exposure to potentially toxic agents (e.g nondegradable

silica, endogenous agents such as chronically elevated plasma lipid
components)
Chronic Inflammatory Cells and Mediators
• Macrophages
• derived from circulating blood monocytes
Chronic Inflammatory Cells and Mediators
• Lymphocytes
• Both T & B cells play role
(cont’d)
• Plasma cells develop from activated B and produce
antibodies directed either against persistent antigens in the
inflammatory site
 Chronic Inflammatory Cells and Mediators
(cont’d)
• Mast cells
• Found in connective tissues
• Participate in acute and chronic inflammatory responses.
• In atopic individuals mast cells are "armed" with IgE antibody specific for
certain antigens release histamines and Arachidonic acid metabolites 
vascular changes of acute inflammation
• IgE-armed mast cells are central players in allergic reactions
Granulomatous Inflammation
• Distinctive pattern of chronic inflammation characterized by
aggregates of activated macrophages
• Only limited conditions produce it
• Formed in:
• Persistent T-cell responses to certain microbes (Mycobacterium, Treponema,
fungi, Gram-negative bacillus)
• Response to relatively inert foreign bodies (e.g., suture or splinter)
• granuloma effectively "walls off" the offending agent
• But does not always lead to eradication of the causal agent
• granulomatous inflammation with subsequent fibrosis may be the
major cause of organ dysfunction
Systemic Effect of Inflammation (Acute-
phase response)
• Fever:
• produced in response to pyrogens stimulated by prostaglandin
• Bacterial products also stimulate stimulate the release of IL-1 and TNF 
increase the levels of COX  convert Arachidonic acid into prostaglandins 
pyrogen
 Systemic Effect of Inflammation (Acute-
phase response)
• Elevated plasma levels of acute-phase protein
• mostly synthesized in the liver up regulated mostly by IL-6
• C-reactive protein (CRP), fibrinogen, and serum amyloid A (SAA) protein
• Fibrinogen binds to erythrocytes and causes them to form stacks (rouleaux)
 increase ESR
 Systemic Effect of Inflammation (Acute-
phase response)
• Leukocytosis
• usually climbs to 15,000 or 20,000 cells/μL, may reach extraordinarily high
levels until 40,000 to 100,000 cells/μL (leukemoid reaction)
• Viral infections are associated with lymphocytosis
• Bronchial asthma, hay fever, and parasite infestations lead to eosinophillia
• Certain infections (typhoid fever, some viral infection, rickettsiae, and certain
protozoa) are associated with leukopenia, caused by cytokine-induced
sequestration of lymphocytes in lymph nodes
 Systemic Effect of Inflammation (Acute-
phase response)
• Other feature of acute-phase response
• increased heart rate and blood pressure
• decreased sweating
• rigors (shivering)
• anorexia, somnolence, and malaise due to the actions of cytokines on brain
cells
• Severe infection can lead to secretion of high levels of TNF cause DIC,
hypoglycemia, and hypotensive shock.
Corticosteroids effects

Anti-inflammatory and immunosuppresive effects

of corticosteroids
Wassalamualaikum
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