inflammation and cellular responses prof orla sheils

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

RUBOR

CALOR

TUMOR

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


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

NO


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

Skin


Scar tissue

Lung


Outcome of healing and repair


When healing goes wrong

Keloid scar

inflammation and cellular responses prof orla sheils

Documents

acute local oedema

tissue effectspavementation

tissue effectsabscess

components of acute

diapedesisacute inflammation

vascular dilatation

tissue effectsblood

certain chemical mediators