Inflammatory mediators

• What are the stages in the inflammatory response?

  1. acute microvascular changes such as tissue swelling, oedema formation, increased blood flow
  2. release of inflammatory mediators
  3. accumulation of inflammatory cells
  4. repair and healing
• what is the inflammatory response?

  short term acute response that is defensive and quickly resolved
• Local hormones

  Released locally and act locally - local response
• inflammatory mediators 


  histamine - amine

  bradykinin - peptide

  nitric oxide

  eicosanoid - lipids derived from arachidonic acid - prostaglandins, leukotrienes

  neuropeptides - substance P

  complement pathway - peptides

  cytokines - peptides such as interlurkin-1 - very large

  chemokines
• Role of arterioles in inflammatory response

  They contract and relax to regulate the blood flow and allow for blood to reach the inflammatory site
• role of capillaries in the inflammatory response 


  bring oxygen and nutrients to the tissue
• role of venues in the inflammatory response

  oedema formation and cell accumulation
• Increased blood flow in arterioles

  Mast cells line themselves up against arterioles and sensory nerves and released at inflammatory sites
• where are vasodilators in arterioles found?


  endothelial cells

  inflammatory cells

  sensory nerves
• Increased microvascular permeability in venules 


  Plasma leaks out between endothelial cells to form an oedema

  venules have tight junctions between them which can get unzipped to allow fluid leakage leading to swelling
• Vasodilators in arterioles

  Prostaglandins

  nitric oxide

  neuropeptides - CGRP
• Oedema producing mediators - direct acting

  Histamine, substance P

  Bradykinin

  platelet activating factor (PAF)

  leukotrienes
• neutrophil dependent oedema producing mediators

  agents that stimulate neutrophil activation
• Neutrophil endothelial cell interactions

  1. neutrophils roll in the post capillary venule
  2. cell adhesion molecule (CAM) is expressed
  3. neutrophil adheres to the endothelial cell
  4. extravasation - plasma leaks from the blood vessels
  5. phagocytosis occurs to engulf the bacteria and release more mediators to rid the area of the infection
• mediators that cause neutrophil accumulation in tissues- neutrophil activating agents 


  LTB4

  C5A

  IL-8
• mediators that cause neutrophil accumulation in tissues - endothelial adhesion molecule stimulants 


  TNF and IL-1 (cytokines)
• Bradykinin


  peptide formed in plasma by activity of enzymes on tissue fluid substrates called kininogens
• what is bradykinin metabolised by?

  Angiotensin converting enzyme (ACE) - ACE inhibitors can lead to an accumulation of bradykinin - dry cough

  carboxypeptidases
• how many bradykinin receptors are there?

  b1 and b2
• b1 receptors 


  induced in inflammation and deviate similar responses, especially in pain

  b1 antagonists havent been beneficial in treatment of pain
• b2 receptors 


  mediate increased blood flow, increased microvascular permeability, nociception, bronchocontriction and nasal blockage

  b2 antagonists used to inhibit effect of angioedemas
• what is standard therapy for ACEi-induced angioedema?

  glucocorticoids and antihistamines - which is ineffective as this form of angioedema is not histamine mediated
• icatibant to treat ACEi-induced angioedema?


  significant benefit compared to normal therapy - much faster oedema resolution
• why is ACEi-induced angioedema considered an emergency?

  can cause swelling in the neck which can constrict breathing
• how many ways is the complement pathway activated?

  3
• Role of C3 in complement pathway

  Links the three pathways - classical, lectin, alternative
• role of C3a and C5a 


  inflammation

  mediators of mast cell activation and neutrophil accumulation at the site of infection
• role of C4b and C3b 


  opsonisation

  bind complement receptors and mediate uptake by phagocytes
• Role of C5-C9 - lytic pathway 


  The membrane attack complex and mediates lysis of pathogens and cells
• role of prostaglandins

  vasodilators

  increase pain sensation

  induce fever
• role of leukotrienes 


  increase oedema formation and some are bronchoconstrictors
• what can NSAIDS cause?

  inhibit cox pathway, leading to greater production of leukotrienes
• arthritis 


  Membrane inflammation, fibroblast like synoviocytes stimulation activity

  cartilage degradation and bone erosion
• major mediators in arthritis

  TNF-alpha

  IL-1

  IL-6

  IL-8

  IL-10 - anti-inflammatory

  IL-17

  PGE2

  proteases

  reactive oxygen species
• Anti-inflammatory cytokine

  IL-10
• cytokines and chemokines

  Peptides/ proteins

  secreted by inflammatory cells when activated

  found everywhere in the body

  can be pro and anti inflammatory

  act on specific receptors

  potent effects

  can acct synergistically - work together to amplify their action

  can antagonise each other
• Tumour necrosis factors

  TNF-alpha

  play a large role in chronic inflammation, stimulates emigration of inflammatory cells - neutrophils + macrophages + secretion of cytokines
• IL-1 and TNF-alpha


  combine effects to influence events
• IL-1, IL-6, IL-17


  pro-inflammatory - leukocyte accumulation
• IL-17 


  source T cells