Inflammation

Inflammation

Protective response of the body to cell injury to remove the noxious stimulus that caused the injury in the first place.

Acute or Chronic if the noxious stimulus persists.

Acute inflammation lasts for minutes to days while chronic inflammation may persist from days to years

Inflammation and repair are the important steps in healing process but the inflammation can cause harm to our native tissues, eg

Anaphylaxis

Autoimmune diseases

Constrictive pericarditis

Cardinal signs of inflammation:

Calor: hot

Rubor: red

Dolor: pain

Tumor: swelling

Function laesa

CellularComponents of inflammation:

Granulocytes:

Polymorphonuclear cells( neutrophils)

Basophils

Eosinophils

Lymphocytes:

B cells and humoral immunity

T cells and cell mediated immunity

Monocytes and macrophages

Endothelium

Fibroblasts

Smooth muscle cells

Mast cells

Natural killer cells

Events in Acute Inflammation:

1.Vascular Events

Vascular dilatation: histamine, bradykinin

Increased vascular permeability and exudation:

Endothelial cell contraction( early) and retraction( late)

Direct endothelial injury: toxins, burn, etc

Leucocyte dependent endothelial injury

Increased transcytosis

Neoangiogenesis: increased gap junctions

2.Cellular events:

Neutrohils initially

Monocytes after 6-24 hours

Rolling and margination

Adhesion: interaction between selectins, integrins and cell adhesion molecules like VCAM

Transmigration by diapedesis

Chemotaxis:

Chemokines: bacterial peptides, C5a, LTB4( Leukotreine), IL 8( interleukin)

Actin myosin interactions in the leucocyte are responsible for diapedesis

Phagocytosis and degranulation

Opsonisation: c3b, IgG, collectins

Oxidative burst

How do neutrophils kill?

Oxidative burst resulting in free radicals

2O2+NADPH ....NADPH.....2O2- ions+NADP+H+

2O2- ions+ 2H+ .....oxidase........ H2O2

H2O2+ Cl-...myeloperoxidase....... HOCl-

Dead organisms digested by lysosomal hydrolases

Bacterial killing also aided by lysozymes and defensins, the latter increase the permeability of bacterial cell.

Body’s defense against free radical injuries

Catalase which neutralises H2O2 into water and O2

Superoxide Dismutase

Glutathione Peroxidase

Antioxidant Vitamins like vitamin A, C and E

Disorders of cellular events of inflammation

Adhesion deficiency

Myeloperoxidase deficiency: Chediak Higasi disease

NADPH Oxidase deficiency: chronic granulomatous diseases

Diabetes

Steroids

leukemia

Chemical mediators of inflammation

Histamine:

Preformed mediator so released early on

Secreted by mast cells and basophils

Secreted in response to

cross linking of IgE during reexposure to allergen in type I hypersensitivity

Anaphylotoxins: C3a, C5a

Substance P: responsible for pain

Chemical mediators of inflammation

Kinin Cascade:

Coagulation factor XIIa activates Prekallikrein into Kallikrein

Kallikrein activates HMWK( High Molecular Weight Kininogen) into Bradykinin

Coagulation cascade:

Fibrinolytic cascade: tPA activates plasmin

Complement cascade:

Proteases that are nine in number: c1 to c9

Activated by

classic pathway due to Ag-Ab complexes

alternative pathway by microbial LPS or endotoxins

One activated complement activates another

C3a and C5a are anaphylotoxins

C5a is a chemokine

C3b along with IgG work as opsonins

C5b to C9 make the MAC: membrance attack complex

Lysosomal proteases, endonucleases and antiproteases to protect the cells against own enzyme, eg α antitrypsin.

NO( previously called EDRF) by NO synthase

Reactive oxygen species

Arachidonic acid metabolites

Cytokines

Interleukins: more than 20 types

Chemokines

Colony stimulating factors eg GM-CSF

IL 1 and TNFα are responsible for all the acute phase response including fever, cachexia, neutrophil aggregation, septic shock and synthesis of acute phase reactants from liver( eg CRP, ceruloplasmin)

Chronic Inflammation

Outcomes of acute inflammation can either be resolution, chronic inflammation or scarring

Persistence of noxious stimulus causes chronic inflam.

Eg. Chronic viral hepatitis, syphilis, TB and fungi( delayed hypersensitivity), silicosis and other pneumoconioses, autoimmune diseases, etc

Interference in the healing process

3 main components

Mononuclear cell( macrophages) infiltration

Tissue destruction

Repair: by either tissue regeneration or fibrosis

Tissue injury in chronic inflammation is caused by Radical oxygen species, proteases and tissue plasmin activator( tPA)

Fibrosis is a common component in chronic inflammation caused by cytokines like PDGF, FGF, TGFβ, VEGF, etc

Granulomatous inflammation

Type IV hypersensitivity

Attempt at walling off the noxious material

CD4 T helper lymphocyes crucial in recruiting monocytes which turn into macrophages( epitheloid cells) and giant cells

Granuloma with caseous necrosis seen in TB

Other examples are

tuberculoid leprosy

syphilitic gumma

fungal infections like histoplasmosis, blastomyces, cryptococcosis, coccidioides

foreign body like suture materials

pneumoconiosis like silicosis

idiopathic like sarcoidosis

Morphology of a granuloma

lymphocytes( esp CD4 type T helper cells)

macrophages( epitheloid cells, so called because of their resemblance to squamous cells)

epitheloid giant cells formed by the fusion of many epitheloid cells with multiple nucleus in different patterns of arrangement like horseshoe pattern in Langhan’s giant cell seen in TB granuloma.

Necrotic material in centre in case of caseous granuloma as seen in TB

Morphologic types of inflammation

Acute:

Exudative Inflammation: excess fluid. TB lung.

Suppuration/Purulent – Bacterial - neutrophils

Fibrinous – pneumonia – fibrin

Serous – excess clear fluid – Heart, lung

Haemorrhagic – b.v.damage - anthrax.

Chronic inflammation:

with healing.

Granulomatous – clusters of epitheloid* cells eg. TB, Fungus, Foreign body.

Lewis Triple Response: