Inflammation

Craig Goodman
and Michael
Mathai
HBM3204

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 Inflammation
Definitions:
1. Inflammation is a defensive process that a living body initiates
against local tissue damage. It takes the form of a complex
reaction of blood vessels, certain plasma components and blood
cells, and cellular and structural components of connective
tissue.

• Terms ending in the suffix “itis” denote inflammation.

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 Inflammation
Causes of inflammation
Physical agents:
extreme temperatures, electric shock, radiation, mechanical
injures, etc.
Chemical agents:
Products of metabolism, acids, alkalis, drugs, corrosive chemicals
(acids, alkalis, oxidizing agents)
Biological agents:
Microorganisms (bacteria, viruses, fungi), parasites (helmints,
insects), immune cells and complexes
Tissue Necrosis:
death of tissues from lack of oxygen or nutrients resulting from
inadequate blood flow (infarction) is a potent inflammatory
stimulus.

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 Inflammation
Why inflammation?
• To dilute, destroy or otherwise neutralize the offending agents.

• Followed by a set of repair processes designed to regenerate the

damaged tissue and/or fill the gaps with fibrous tissue (scar).

• Both the initial inflammatory reaction and the subsequent repair

reactions can potentially cause harm

• The pathology of almost every single disease includes

inflammation, thus it is impossible to study pathology without
understanding inflammation

• The immune system is largely responsible for producing many

of the
inflammatory mediators
 Inflammation
Inflammatory Phases:
1. Alteration – degeneration and necrosis of cells/tissues

2. Exudation formation – the reaction of microcirculation, of liquid

exudate, migration of leukocytes and increased phagocytosis

3. Proliferation - proliferation of macrophages and lymphocytes

and
fibroblasts

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Inflammation

Cardinal local features:

• Calor (heat)
• Rubor (redness)
• Tumor (swelling)
• Dolor (pain)
• Functio laesa
(loss of function)

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 Inflammation

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 Inflammation
Inflammation - local vs systemic

The effects of inflammation can be both local and systemic.

The systemic effects of acute inflammation include, fever, malaise, and

leukocytosis.

Leukocytosis
An increase in the number of circulating white blood cells.
- increased neutrophils indicate a bacterial infection
- Increased lymphocytes are most likely to occur in viral infections.

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 Inflammation
Inflammation - local vs systemic
Fever
• a common systemic response to inflammation.
• most often associated with inflammation that has an infectious
cause, although there are some non-infectious febrile diseases.
• fever is coordinated by the hypothalamus and involves a wide range
of factors (including pyrogens)

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 Inflammation
Inflammation - good or bad?

Beneficial effects of inflammation

• Dilution of toxins
• Entry of antibodies
• Fibrin formation
• Delivery of nutrients and oxygen
• Stimulation of immune response

Harmful effects of inflammation

• Persistent cytokine release
• Destruction of normal tissues
• Swelling
• Inappropriate inflammatory response

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 Inflammation
Cytokines
• Broadly classified as interleukins (ILs) or interferons (IFNs)
• Produced locally and act over short or long distances
• Bind to receptors on target cells
• Activate immune cells e.g. phagocytes and lymphocytes
• Stimulate immune cell proliferation, cell growth and differentiation

Interleukins – produced predominantly by macrophages and lymphocytes in

response to microorganisms or other inflammatory products
• Enhance the adaptive immune response
• Can be produced by other cell types independent of infection
e.g. fibroblasts

Proinflammatory - IL-1β, TNFα, IL-6, IL-15, IL-17, and IL-18.

Anti-inflammatory - IL-4, IL-10, and IL-13.

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 Inflammation
Chemokines
e.g. C, CC, CXC, CX3C
• a family of low molecular weight peptides (~40)
• primary function is to induce leukocyte chemotaxis
i.e. chemotactic cytokines
• can be soluble or cell surface bound to membrane glycoproteins
• synthesised by several cell types, including macrophages, fibroblasts
and endothelial cells
• produced in response to proinflammatory cytokines
• bind to chemokine receptors (GPCRs) on target immune cells
e.g. CC-chemokines affect monocytes, lymphocytes and eosinophils
CXC-chemokines affect neutrophils

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 Inflammation
Vascular endothelial cell permeability in response to inflammation
WBC migration to a site of injury is a rapid component of the early
inflammatory response

Cytokines and other proinflammatory molecules diffuse and affect leukocyte

and endothelial cells
e.g. TNF-α, histamine, bradykinin, prostaglandins etc…

The response is to produce new adhesion molecules

on the surface of the cells. i.e. Selectin proteins

These facilitate the slowing of leukocytes by

increasing their ability to adhere in the endothelial
walls of blood vessels

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 Inflammation
Vascular endothelial cell permeability in response to inflammation

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 Inflammation
Vascular endothelial cell permeability in response to inflammation

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 Inflammation
Vascular endothelial cell permeability in response to inflammation

e.g. Thrombin-induced activation of platelet integrins

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 Inflammation
Vascular endothelial cell permeability in response to inflammation

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 Inflammation
Vascular endothelial cell permeability in response to inflammation
• Extravasation

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 Inflammation
Chemokine-induced migration of leukocytes to the site of injury

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 Inflammation
Chemokine-induced migration of leukocytes to the site of injury

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 Inflammation
Stages of wound repair
Acute inflammation
Healing begins with acute inflammation
Begins with phagocytosis of particulate matter
at the site of the injury
e.g. fibrin from dissolved blood clots
microorganisms, RBCs, dead tissue cells

Angiogenesis
Helps the removal of debris and increase
delivery of growth factors and nutrients

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 Inflammation
Reconstruction (up to ~2 weeks)
Epithelialisation
• Increased proliferation of epithelial cells
• Helps ‘close’ the wound
Granulation tissue
• New connective tissue
• Filled with new capillaries
• Neutrophils continue to remove debris
• Surrounded by fibroblasts and macrophages

Macrophages secrete the cytokine TGF-β,

VEGF, and MMPs
TGF-β stimulates fibroblasts to synthesis and
secrete collagens
VEGF stimulates angiogenesis
MMPs promote degradation and remodeling
of the ECM

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 Inflammation
Stages of wound repair
Maturation (can take years)

• Blood vessels removed

• Scar tissue is remodeled
• The extent of scar tissue may impact the
function of the tissue/organ
esp. in response to chronic inflammation

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 Inflammation
Acute inflammation
−can last for several days
−induced by tissue trauma, microbial invasion or noxious compounds

Subacute inflammation
− between acute and chronic inflammation
- May last from 2- 6 weeks

Chronic inflammation
− lasts from a few months up to tens of years
− alternating exacerbations and remissions
− presence of fibrosis is essential

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 Inflammation
Chronic inflammation can result from the following:

1. Failure of eliminating the agent causing an acute inflammation, such as

infectious organisms, including Mycobacterium tuberculosis, protozoa,
fungi, and other parasites, that can resist host defenses and remain in the
tissue for an extended period.

2. Exposure to a low level of a particular irritant or foreign materials that

cannot be eliminated by enzymatic breakdown or phagocytosis in the body
including substances or industrial chemical that can be inhaled over a long
period, for example, silica dust.

3. An autoimmune disorder in which the immune system is sensitized to the

normal component of the body and attacks healthy tissue giving rise to
diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE).

Pahwa and Jialal, 2019, Chronic Inflammation, www.ncbi.nlm.nih.gov/books/NBK493173/

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 Inflammation
Chronic inflammation can result from the following:

4. Recurrent episodes of acute inflammation. However, in some cases, chronic

inflammation is an independent response and not a sequel to acute
inflammation for example diseases such as tuberculosis and rheumatoid
arthritis.

5. Inflammatory and biochemical inducers are causing oxidative stress and

mitochondrial dysfunction, such as increased production of free radical
molecules

Pahwa and Jialal, 2019, Chronic Inflammation, www.ncbi.nlm.nih.gov/books/NBK493173/

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 Inflammation
Tissue remodeling during Acute vs Chronic Inflammation
Repair of damaged tissue is fundamentally important and usually has
negligible effect on tissue function
…but, abnormal healing and repair can lead to severe dysfunction of organs
Perpetual remodeling and repair can itself result in end-stage disease

Common chronic inflammatory disorders include:

• Pulmonary fibrosis
• Systems sclerosis
• Progressive kidney disease
• Rheumatoid Arthritis
• Osteoarthritis
• Cardiaovascular Disease
• Endometriosis
• Muscular dystrophy
• Liver cirrhosis

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 Inflammation
Anti-TNFα Treatment for Inflammatory Disease
TNFα – master regulator of
pro-inflammatory immune response
Stimulates the activation of the transcription
Factor, NF-κB

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 Inflammation
Anti-TNFα Treatment for Inflammatory Disease
TNFα – master regulator of pro-inflammatory
Immune response

Monoclonal antibodies
e.g. infliximab (Remicade)
adalimumab (Humira)
certolizumab pegol (Cimzia)
golimumab (Simponi)

Circulating Receptor-fusion protein

e.g. etanercept (Enbrel)

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 Inflammation
Anti-TNFα Treatment for Inflammatory Disease
Approved for use with:
• Rheumatoid arthritis
• Juvenile idiopathic arthritis
• Crohn’s disease
• Psoriasis
• Psoriatic arthritis
• Ankylosing spondylitis
• Ulcerative colitis

Side Effects:
• Infections due to suppressed immune function
• Cancer – Hepatosplenic T-cell lymphoma

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