General Pathology

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General Pathology

• Basic Principles of Cellular and Organ Pathology
• Inflammation - I

Jaroslava Dušková Inst. Pathol. ,1st Med.
Faculty, Charles Univ. Prague http//www1.lf1.cuni
.cz/jdusk/
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Inflammation

• Definition
• complex reaction
• of organism to damage
• (aim homeostasis maintenance)

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Inflammation

• Sense
• defensive agent elimination
• reparative damage reparation

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Inflammation - Classification

• Time view
• acute (days)
• subacute (weeks)
• chronic (months-years)

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Inflammation - Classification

• Causes
• nonliving
• physical
• chemical

• living
• viral
• bacterial
• mycotic
• parasitic
• AUTOIMMUNE

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Inflammation Celsus features

• rubor
• tumor
• calor
• dolor
• functio laesa

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Phases of Inflammatory Response

• alteration
• exsudation
• proliferation

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Phases of Inflammatory Response

Alteration
Proliferation
Exsudation
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Phases of Inflammatory Response
Proliferation

Alteration
Exsudation
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Vascular Changes in Inflammation

• Flux hyperemia - axonal reflex
• Peristatic hyperemia
• Stasis
• Increased permeability - exsudation
• Inflammatory edema

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Active Hyperemia

• vasodilatation
• slowing of the circulation
• increased microvasculature permeability
  leakage
• ----------
• leucocyte emigration

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Active Hyperemia

• vasodilatation
• leakage
• Chemical mediators
• Cells histamine , serotonin, catecholamins,
  lysosomal enzymes
• Plasma complement, kinin system,
  coagulation/fibrinolysis system

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Mast Cell ruling the process

• Degranulation (immediate response)
• histamin-vasodilation-permeability-exsudation
• neutrofil chemotactic factor (micro)fagocytosis
• eosinophil chemotactic factor -modulation of the
  vascular effect
• Synthesis (long-term response)
• leukotriens (SRS-A) vasodilation-permeability-exs
  udation
• prostaglandins - vasodilation-permeability-exsudat
  ion- PAIN

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Active Hyperemia

• vasodilatation
• slowing of the circulation
• increased microvasculature permeability -
  leakage
• leucocyte emigration
• chemotaxis
• soluble bact. products
• complement components esp. C5a
• products of lipoxygenase pathway of arachidonic
  acid (esp.leukotriene B4)

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Main Inflammatory Mediators

• Vasodilation prostaglandins, NO
• Permeability vasoactive amins, C3,C5,
  bradykinin
• Chemotaxis C5a, bacterial products, leucotriens,
  cytokins
• Fever interleukin 1,6, TNF, prostaglandins
• Pain prostaglandins, bradykinin
• Tissue damage lysosomal enzymes

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Mechanisms and Morphological Features of Immune
Reaction

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Mechanisms of Immune Response

• nonspecific
• antigen specific
• humoral
• cellular

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Mechanisms of Immune Response

• nonspecific
• PHAGOCYTOSIS
• bactericid substances (lysozym)
• complement
• interferon
• proteins distinguishing general microbial
  structures

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Cytokines

• Def.
• polypeptides and proteins - regulatory molecules
  participating by autocrine, paracrine
  endocrine function in homeostasis maintenance

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Cytokines

• Types
• growth fcs.
• colony stim. fcs.
• chemokins (interleukins)
• TNFa, TNF ß LT
• interferons

• Source
• macrophages
• APC
• T- lympho

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Bradley JR.TNF-mediated inflammatory disease.

• TNF was originally described (1975) as a
  circulating factor that can cause necrosis of
  tumours, but has since been identified as a key
  regulator of the inflammatory response.
• TNF interacts with two different receptors,
  designated TNFR1 and TNFR2,
• TNF stimulation leads to a range of cellular
  responses, which include cell death, survival,
  differentiation, proliferation and migration.
• Vascular endothelial cells increase leukocyte
  adhesion, transendothelial migration and vascular
  leak and promote thrombosis.
• J Pathol. 2008 Jan214(2)149-60

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Zhang X, Mosser DM.Macrophage activation by
endogenous danger signals.

• Most microbes have Pathogen Associated Molecular
  Patterns (PAMPS) that are recognized by
  macrophages and trigger this activation response.
  
• J Pathol. 2008 Jan214(2)161-78.

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Interleukin 4

• Th2 stimulation antibody mediated immune
  response
• Th1 interferon ? suppresion
• inhibition of the T-lymphocytes proliferation
  
• inhibition of TNF a Il6 secretion

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Mechanisms of Immune Response

• antigen specific
• humoral B lymphocytes
• cellular T lymphocytes
• INTERACTION
• B-lymphoTh affinity maturation plasmocyte

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Inflammatory cells

• neutrophile granulocytes
• eosinophil granulocytes
• basophil granulocytes heparinocytes
• lymphocytes plasmocytes
• monocytes macrophages
• erythrocytes
• platelets

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Mechanisms of Immune Response

• antigen specific
• cellular T lymphocytes
• APC CD8 precursors Th,Tc

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Heparinocytes

• IgE receptors
• mediators production (heparin, histamin,
  serototnin, catecholamins)
• cytokin production IL4, TNF a
• chemotactic factors for neutrophils
  eosinophils

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Neutrophilic granulocytes

• pavementing (selectins, integrins)
• emigration (chemotactic factors from bacteria,
  complement 3a, 5a, kinins, histamin.)
• fagocytosis (both non specific without
  opsonisation and specific IgG compl.)

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NG disorders 1.

• migration chemotaxis
• lazy leucocytes syndrome
• diabetes (locomotion)
• Chédiak- Higashi syndrome (bacteria killing, lack
  of elastase, locomotion)
• ß2-integrin defect (adhaesion)
• locomotion
• serum changes
• corticoids
• phenylbutazone

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NG disorders 2.

• phagocytosis
• opsonins IgG in sickle cell anaemia
• morphin abusers
• lyzosom fusion (corticoids, antimalaric drugs,
  CH-H sy
• bactericid effect
• chronic granulomatosis in children
• cytochrom oxidase H2O2 defects
• recidives of staphylococcus and aspergillus
  infection

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Eosinophilic Granulocytes

• alergic response
• IgA receptors
• anti parasites defence
• peroxidase, histaminase, acid phophatase,
  cytokins

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Macrophages - Function

• phagocytosis
• bacteria killing
• mediators production
• antigen processing presentation
• modulation of fibroblast proliferation IL-1
• modulation of endothelia proliferation TNFa

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Macrophages - secretion

• acid neutral proteases
• cytokins IL-1 , TNF
• O2, NO
• complement components

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Thrombocytes

• mediators production
• vasoactive substances, thrombosis, mesenchymal
  cell proliferation
• granules serotonin, ADP, acid phophatase,
  thromboxan, Ca cationic protein

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Systemic Inflammatory Response

• lymphatic tissue activation
• fever IL 1, prostaglandins
• leucocytosis
• lymfocytosis in viral infections
• eosinophilia in parasitic diseases

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Inflammation Development
  Complete resolution - ad integrum vessel
permeability normalized migration
stopped necrosis resorption tissue
regeneration Healing with a defect - per
defectum regeneration impossible extensive
necrosis granulation tissue scar Progression
towards a chronic inflammation