Inflammation and cellular responses Prof Orla Sheils

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2nd Yr Pathology 2010

Inflammation and cellular responses

Prof Orla Sheils

Inflammation

Is a protective response The body’s response to injury

Interwoven with the repair process

Inflammation Types

Acute (sec, mins, hrs) Chronic (days, weeks, months, yrs)

Causes of inflammation Bacterial Viral Protozoal Metazoal Fungal Immunological Tumours Chemicals, toxins etc Radiation

Acute inflammation

Inflammation

The Cardinal Signs of Acute Inflammation

FUNCTIO LAESA

Cardinal signs of inflammation

Inflammation The basis of the five cardinal signs

Increased blood flow due to vascular dilatation gives redness and heat.

Increased vascular permeability gives oedema causing tissue swelling.

Certain chemical mediators stimulate sensory nerve endings giving pain. Nerves also stimulated by stretching

from oedema.

Pain and swelling result in loss of function.

Components of acute and chronic inflammation

Cell of the acute inflammatory response

Polymorphonuclear leukocyte

The process of inflammation

The phases of inflammation

FIRST THERE IS VASCULAR DILATATION followed by exudation of protein-rich oedema fluid which floods the area, dilutes toxins, allows immunoglobulins to opsonise bacteria and provides substrate (fibrinogen) for fibrin scaffold.

SECOND THERE IS ACTIVE EMIGRATION OF POLYMORPHS through vessel wall and along the chemotactic gradient to the site of injury

THE VASCULAR PHASE OF INFLAMMATIONFluid escapes from vessels because of endothelial cell (EC)retraction, opening up gap-junctions. The vessels which are normally involved are the post-capillaryvenules where the EC have high affinity receptors for histamine.

Severe EC injury leads to leakiness of all vesselscapillaries, venules and arterioles - giving acute local oedema,e.g. blister formation after a burn.

The phases of inflammation

Local vascular manifestations of acute inflammation

Leukocyte migration in inflammation

Molecules modulating endothelial-neutrophil interactions

LFA-1 and MAC-1(activated integrins)

Acute inflammation: tissue effects

Pavementation and diapedesis

Inflammatory cells in protein exudate

Blood vessel involved in the acute inflammatory process

Bronchopneumonia

Abscess: collection of acute inflammatory cells

Multiple splenic abscesses

Vasoactive amines Histamine Serotonin (5-HT)

Neuropeptides Substance P

Plasma proteases and the complement system Action of Hageman factor

Arachidonic acid metabolites Prostaglandins Leukotrienes Lipoxins

Cytokines IL-1, TNF etc.

Chemokines (CXC and CC) Nitric oxide and oxygen-derived free radicals

Chemical mediators of inflammation

PREFORMEDHistamine, Serotonin NEWLY SYNTHESISEDProstaglandinsLeucotrienesPlatelet activating factorCytokinesNitric oxide

LOCAL AND SYSTEMIC

Chemical mediators of inflammation(local and systemic)

Plasma proteases

The complement system

Arachidonic acid metabolites

HETE = hydroxyeicosatetraenoic acidHPETE = hydroperoxyeicosatetraenoic acid

Cytokines (IL-1 and TNF)

Nitric oxide (NO)

Effects of mediators of inflammationVasodilation:

Prostaglandins, NO

Increased vascular permeability:Histamine, serotonin, C3a, C5a, bradykinin,

Leukotrienes C4, D4, E4, platelet activating factor

Chemotaxis, leukocyte activation:C5a, leukotriene B4, bacterial products, chemokines (IL-8)

Fever:IL-1, IL-6, TNF, prostaglandins

Pain:Prostaglandins, bradykinin

Tissue damage:Neutrophil and macrophage lysosomal enzymes, oxygen metabolites

Phagocytosis

Phagocytosis of bacteria by polymorphs

PHAGOCYTOSIS

Recognition and attachmentForeign objects coated with opsonins IgG and C3b which attach toreceptors on polymorph surface.

EngulfmentCell membrane fuses around an object: at the some time lysosomesempty into the vacuole, often before vacuole has time to seal - this givesrise to 'regurgitation during feeding' and enzymatic damage to surroundingtissue.

Killing or degradationH2O2, hypohalous acid (HOC1) produced by myeloperoxidase andsuperoxides kill bacteria. Lysozyme digests them.

Chronic inflammation

Cells of the chronic inflammatory response

Lymphocytes Monocytes/ macrophages Plasma cells

Maturation of circulating monocytes to macrophages

Macrophage-lymphocyte interactions in chronic inflammation

Cellular interactions in chronic inflammation

Chronic inflammation: tissue effects

Knee joint in rheumatoid arthritis

Chronic cervicitis

Lung abscess

Granulomatous inflammation:

a special form of chronic inflammation

Granuloma Definition

A collection of macrophages, lymphocytes, mononuclear cells and fibroblasts with or without giant cell formation and constitutes a special form of chronic inflammation

Granulomatous inflammation

Bacterial:TB, Leprosy, Syphillis, cat-scratch disease

Parasitic:Schistosomiasis

Fungal:Histoplasma, blastomycosis, cryptococcus

Inorganics, metals, dusts:Silicosis, berrylliosis

Foreign body

Unknown:Sarcoidosis

Granulomatous inflammation: tissue effects

Epithelioid cells

Talc granulomas in the lung

Healing and repair

Wound healing: critical steps

The cell cycle

Cyclins, cyclin dependent kinases and cyclin dependent kinase inhibitors

Cell-cell interactions in repair

Cell surface receptors in healing and repair

The major components of the extracellular matrix (ECM) required for

healing and repair

2nd Yr Pathology 2010 Extracellular matrix re-modelling occurs by the action of

Matrix metalloproteinases

Matrix metalloproteinase regulation

Critical steps in angiogenesis

Major growth factors in wound healing

Wound healing: critical steps

Granulation tissue

Scar tissue

Outcome of healing and repair

When healing goes wrong

Keloid scar

Inflammation and cellular responses Prof Orla Sheils

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