Acute inflammation

• Classification of inflammation

  • acute and chronic
  • Some overlap
• acute inflammation meaning 


  • sudden onset of illness etc
  • may last a few hours to a few days
• signs of an inflammatory response

  • heat/ redness
  • pain
  • swelling
  • loss of function
• heat/ redness response

  • redness is to due dilation of blood vessels - arterioles
  • heat due to increased blood flow gives impression of heat
  • affected by mediators produced by local immune cells or local neurons

  
• swelling - oedema - response

  • endothelial cells (type of immune cell)
  • contract resulting in increased vascular permeability
  • contraction caused by mediators released by innate immune cells
  • results in escape - exudation of protein rich fluid from blood into surrounding tissue
  • gap junctions of vessel increase
  • contents of fluid include complement and immunoglobulins
  • process is different from endothelial cell damage
• vasodilation caused by what cells?

  • effect on endothelial cells
  • respond to inflammation - relax and dilate
• swelling oedema process


  • blood pumped into capillary bed, blood pressure increases
  • Osmotic pressure looks for reabsorption into the blood vessels
  • Leads to swelling
• how swelling is different from endothelial cell damage 


  • if you damage endothelial cells that make up blood vessel - other cells will get out into extra vascular space— leads to bruising.
  • swelling leads to swelling
• Nociception (pain)

  • nociceptors are sensory nerve endings that react to damaging stimuli and send signals to spinal cord and brain - cause the perception of pain
  • Affected by mediators released by immune cells
• types of pain 


  • fast sharp pain - transmitted rapidly in sensory A nerve fibres- myelinated, sensation does not outlast the stimulus, accurately localised- small receptive field + leads to avoidance behaviour - move hand away.
  • slow chronic pain - transmitted by sensory type C nerve fibres- not myelinated, slow conduction, duration of sensation outlasts the stimulus- phantom limb - still feel pain after limb removed. pain associated with infection.
  • both affected by mediators
• Mediators released by immune cells

  • sensitisation - cytokines, histamine, bradykinis and prostaglandins
  • Analgesia - endorphins and enkephalins - work to numb pain - counteract pain
• Vasodilation is caused by effects of mediators on which cells?


  • smooth muscle cells
• Would mediators released from activated immune cels affect pain perception 


  • yes due to endorphin and cytokine release - desensitise pain
  • Makes more sensitive but painful -
• Inflammatory cells - tissue cells

  • macrophages, mast cells, dendritic cells - release mediators
  • Sensory nerves and endothelial cells
• Circulating cells -inflammatory cells

  • cells that aren’t normally at site of inflammation but are called over in response to inflammation - platelets + polymorphonuclear leucocytes- neutrophils ,eosinophils and basophils - also called granulocytes
  • depending on the stimulus - neutrophils most common, eosinophils and basophils far rarer may be recruited to the site of inflammation.
  • Monocytes- macrophage thats still in the blood
• tissue resident cells - macrophages- also dendritic cells 


  • macrophages - big eater - express non specific or pattern recognition receptors (PRR)
  • Once morphogen identifies bacteria through PRR they engulf and kill them. Antibodies help macrophages identify pathogens with the Fc receptor.
• Macrophage and dendritic cells process

  • antibody grabs pathogen through its fab region Fc region interacts with phagocytes
  • Macrophages recognise pathogens - pathogen associated molecular patterns (PAMPs) or tissue damage - damage associated molecular patterns (DAMPs) and initiate inflammation.
  • Macrophages can phagocytose (Engulf) and kill bacteria and release specific mediators - such as cytokines, chemokines and prostaglandins. - also send signals to bring other WBC etc in.
• Tissue resident cells ( sentinels) 1st line of defence 


  • Mast cells are found predominantly at mucosal surfaces
  • Degranulation of mast cells release histamine
• what is histamine 


  • a major mediator of some allergic reactions
  • such as hayfever
• platelets 


  • first thing to stop loss of blood
  • small anuclear cells derived from a megakaryocyte
  • Activated by
  • thrombin part of the coagulation cascade
  • Phosphatidylserine on cell surfaces (damaged cells)
  • Collagen exposed following endothelial cell damage.
• Platelets function

  Adhere/ aggregate to damage tissue - initiate clotting and help prevent blood loss.

  Too low platelets- Excessive bleeding

  Too high platelets - intravascular clotting
• platelet rich plasma function

  • are a grow factor that help with regeneration
  • can be injected into sites of damage - eg tendons
• 2nd line of defence infiltration of polymorphs


  Formed in the bone marrow

  • multilobed nuclei, all have granules (performed mediators) the type varies between cells.
  • Differentiated by staining
  • 1-neutrophil , 2 - basophil, 3- eosinophil

  
• what do polymorphs respond to?

  • neutrophils - bacterial infection
  • eosinophils and basophils - response to allergy and some parasitic infections - worms
• cell accumulation / leukocyte migration 


  • normally polymorphs are confined to the bloodstream.
  • polmorphs need to be directed to the site of injury - localised effect.
  • Factors that attract polymorphs include some bacterial toxins but mostly chemokines - proteins produced by activated immune cells.
• polymorphs travel in the body


  • need to be directed to site of injury by bacterial toxins and mostly chemokines
  • the process by which they cross the blood vessel wall and migrate to the site of injury/ infection is called the trans-endothelial cell migration
• what is trans-endothelial cell migration


  • insult cross epidermis - bacteria
  • sentinel cells such as macrophages or DC will respond - produce cytokines -which will diffuse away from the site of infection and activate local endothelial cells - these start expressing new receptors.
  • polymorphs going by in the bloodstream react with those receptors- become stimulated themselves - up regulate their own receptors and roll along the endothelium. they stop make their way trough gap junctions into extracellular space, migrate to site of infection - where they kill invading bacteria
• trans-endothelial cell migration requires


  • happens in the absence of endothelial cell injury
  • occur in capillaries and post capillary venues - lower pressure so blood cells can easily roll along the cell surface
• trans-endothelial cell migration simplified 


  • Local Endothelium activated by mediators released from activated innate immune cells,
  • endothelium expresses new proteins - selectins and intengrins
  • Neutrophils react to newly expressed proteins and attach to the endothelium (marination)
  • Initially neutrophils roll along endothelium - this activated both endothelium and neutrophils
  • Neutrophils stop rolling and slip through endothelial cell junctions - without damaging endothelial cells
• neutrophil infiltration

  • 50-60% of circulating blood cells
  • migrate into tissue under specific signals - chemotaxis
  • highly phagocytic
  • neutrophils do not return to the blood - die in the act of killing bacteria
  • send signals that attract monocytes
• eosinophil and basophil infiltration


  • small % of circulating WBC under normal conditions
  • numbers dramatically increase in allergic reaction and in response to som parasites - worms
  • migrate into tissue under specific signals - chemotaxis - respond to different chemokines than neutrophils
  • NOT phagocytic
  • have preformed granules containing proteases, bactericidal peptides that they dump on surface of parasite - worm
• 3rd line of defence - monocyte infiltration


  • stay in blood for 12-24 hours - 10% of circulating blood cells 1mill/ml blood
  • move out of circulation into inflamed tissue in response to chemokines secreted by neutrophils or in response to bacterial toxins
  • respond to different chemokines than neutrophils - rate of recruitment is slower than for neutrophils
  • monocytes transformed into macrophages upon entering tissue.
• monocyte infiltration

  • macrophages clear dead host cells - neutrophils, - bacteria/ parasites
  • dont die in the process
  • highly phagocytic - also release mediators including cytokines when activated
  • usually dominate cellular infiltrate and can persist in the tissue for weeks in chronic infection.
  • macrophages express MHC molecules and present antigen to T cells - start adaptive immune response - (neutrophils are poor at this)
• 4th line of defence

  • increased production of monocytes and polymorphs
  • mediators released by macrophages can stim the production of polymorphs/ monocytes by bone marrrow
  • occurs through stimulation of progenitor cells in bone marrow by colony stimulating factors (CSFs)
  • bring in new recruits
  • in inflammation there may be a blood neutrophilia/ eosinophilia or increased monocytes.
• mediators of acute inflammation


  • symptoms of inflammation generally cased by mediators released from innate immune cells in response to tissue injury or invading microorganisms
  • in some cases just 1 mediator is responsible for the majority of symptoms, in other cases many different mediators contribute to the symptoms - eg hayfever
  • the main mediator is histamine which increased blood flow and causes swelling - inc capillary permeability
• different mediators dominate in different settings

  • nettle sting- hypersensitivity - histamine
  • bacteria - PGE2
  • they feel and behave differently
  • the action of drugs that affect these pathways are also different.
• treatment of acute inflammation


  • non steroidal anti-inflamatory drugs (NSAIDs) commonly used to treat acute inflammation
  • these drugs inhibit cycle-oxygenates (COX) that are involved in the production of prostaglandins (PGs) - there are multiple different PGs that have different effects
  • PGE2 is a major prostaglandin that drives inflammation
  • can eat anti- inflammatory foods- fish oils containing DHA or EPA
• mediators of acute inflammation


  • cytokines- proteins produced by immune cells that affect other immune cels -activate or deactivate
  • chemokines - proteins that attract immune cells
• exposure of inflammatory insult causes

  • activation of cells present at site of exposure and release of mediators leading to
  • change in blood flow and vessel wall permeability
  • and recruitment and activation of circulating cells which release mediators + plasma leakage, bringing in more mediators
• Why is trans-endothelial cell migration localised. 


  • cells need to be concentrated at a specific part where you’ve got invading bacteria - not throughout the whole body