Chronic inflammation

• Phases of wound healing

  • inflammatory phase - neutrophil increase, macrophage inc
  • Proliferation phase - macrophage start to decline, inc in lymphocyte and fibroblasts
  • Maturation phase - decrease of fibroblast
• decline of inflammatory phase

  • key cell is the macrophage
  • Dominate site of inflammation
  • Once they have removed any foreign microorganisms, dead neutrophils or tissue debris
  • loss of inflammatory stimulus occurs
• decline of inflammatory phase repair/ regeneration phase underway


  • regeneration - replacement of damaged tissue by normal tissue of the same type. The functional status of the tissue is restored.
  • Repair of damaged tissue by fibrous scar tissue (fibrosis). The scar tissue does not retain the functional characteristics of the tissue that it has replaced
• macrophage response in the decline of inflammatory phase 


  • Macrophages can respond to the low oxygen content of their surroundings to produce factors that induce angiogenesis (formation of new blood vessels)
  • macrophages secrete growth factors and cytokines that attract cells involved in the healing process and lay down a new extracellular matrix.
  • they also recruit cells that re- epithelialise the wound.
• angiogenesis 


  • formation of new blood vessels
  • pre existing blood vessels send out capillary buds in response to factors produced by macrophages to produce new vessels.
  • endothelial cells migrate towards angiogenic stimulus.
  • remodelling occurs here of endothelial cells into capillary tubes
  • recruitment of peri- endothelial cells - smooth muscle around arterioles.
  • stimulated by TGF-b, FGF, PDGF.
  • transforming growth factor, fibroblast growth factor and platelet- derived growth factor.
• tissue repair fibroblast role

  • fibroblasts and fibrocytes are two states of the same cell, the former being the activated state.
  • fibrocytes are less active state, concerned with tissue maintenance.
  • fibroblasts/cytes are the most common cells of connective tissue.
  • repair/ regeneration- migration and proliferation of fibroblasts triggered by growth factors (TGFb, FGF, PDGF) - mostly macrophage derived.
  • a fibroblast synthesises the extracellular matrix and collagen.- can be useful to print organs
• collagen in tissue repair

  • Collagen - many different forms - is the main structural framework for animal tissues
  • Peptide therapy - peptides derives from the stomach that reported to accelerate recovery (BPC-157)
• Which immune cell predominates in the infiltrate of a chronic infection?

  • macrophages
• what factors do macrophages produce during the recovery phase

  TGF, FGF, PDGF
• why do macrophages change which proteins they release between the inflammatory and recovery phase

  • they’re no longer being stimulated by foreign infectious agents or damaged tissue in the recovery phase so produce various growth factors - no cytokines
• which cell responsible for producing the extracellular matrix 


  • fibroblast
• what is the extracellular matrix made up of

  • collagen mainly
• What is fibrosis


  the formation of excess fibrous connective tissue in an organ
• what is scarring


  • confluent (merging) fibrosis that obliterates the architecture of the underlying organ or tissue
• Can altered composition of new tissue affect the function of the affected organ

  • yes
  • heart- after myocardial infarction - have death of some of the muscle cells and scarring - changes the way depolarisation passes over the heart
  • liver- cirrhosis - scaring -can no longer detoxify
  • Spinal injuries- prevents neurons reconnecting
• factors affecting healing 


  • the nature of the damaged tissues - tissues with a greater capacity to regenerate are more likely to regain normal function after damage. - eg liver
  • Specialised tissue however rarely repairs successfully - neurons
  • Extent of tissue damage
  • Age of patient
• macrophage use in wound healing

  • key cell that initiates would healing
  • this is in response to different signals - mainly the loss of microorganisms, it initiates 3 important processes
  • proliferation phase- attraction and activation of fibroblasts that produce ECM.
  • angiogensis - formation of new blood vessels.
  • epithelialisation - attraction of epithelial cells - if wound involves damage to the skin
• How does chronic inflammation occur

  • can follow on from unresolved acute inflammation
  • Or be chronic from the offset.
• acute inflammation responses

  • usual result is resolution - tissue repair/ regeneration .
  • excessive exudate - give rise to suppuration- discharge of pus
  • excessive necrosis - affects repair and organisation - lead to fibrosis
  • persistent causal agent- non living- shrapnel/ sutures or a living agent like mycobacteria Lead to fibrosis
• Purulent or suppurative inflammation 


  • Persistent or excessive necrosis & cellular exudate - exudate is dominated by neutrophils ( what pus is mostly Made up of)
  • Induced by specific bacteria ( pyogenic bacteria) or virus.
  • Excessive neutrophil accumulation can be due to toxins produced by specific bacteria. Neutrophil products can cause extensive tissue damage - collateral damage
• Apoptosis 


  • programmed cell death - limited activation of immune system
• necrosis 


  • premature cell death of cell/ tissue caused by factors external to the cells
• Excessive necrosis

  • causes-
  • Injury- burns, infection - flesh eating bacteria
  • Infarction / stroke - hypoxia- blood supply and nutrients blocked
  • Reduce blood flow - gangrene
  • Poisons - snakebites / spider venom
  • Neutrophil derived toxins - cycle
• neutrophil derived toxins role in necrosis 


  • neutrophils produce these toxins which damage the tissue.
  • immune cells respond to this and bring in more neutrophils
  • continuous damage occurs
• monocyte maturation to macrophage 


  • monocytes in blood are of Bone marrow origin
  • move into tissue - become a macrophage and have a 30-60 day life span in tissues as they have an altered phenotype
• macrophages role in chronic inflammation

  • efficient digestion of particulates, degenerative neutrophils and microorganisms (via phagocytosis)
  • macrophages accumulate due to - inability to lose irritants - foreign material
  • survival of infectious agents within macrophages - mycobacteria - strong cell wall
  • chronic infections often give rise to increased monocyte count in the blood
• Macrophage recruitment of other cells in chronic inflammation

  • macrophages present antigen and produce mediators which regulate inflammation and further immune responses - adaptive immune responses– recruitment of T and B cells
  • Macrophages produce mediators which stimulate the repair processes - angiogenesis and tissue remodelling
• Epitheliod macrophages


  • lose some macrophage functions and morphologically start to resemble epithelial cells - less phagocytic / different set of markers
  • look like squamous epithelial cells with a pink cytoplasm and indistinct borders.
• multinucleated giant cells 


  • formed by the fusion of epithelioid macrophages around a chronic stimulus.
  • seen in tissues in association with stable foreign material or intracellular bacteria
• What is suppuration


  • production of lots of neutrophils - known as pus - leaks to outside usually
• where do macrophages in a chronic infection come form 


  • the blood
• what does an increase in monocytes in a patients blood mean


  • its an on going chronic infection
• how do macrophages change in a chronic infection


  • change in shape to epithelioid structure which can fuse to make a multinucleated cell
• T cell lymphocytes in chronic inflammation


  • produce inflammatory mediators - regulate chronic inflammation - important in immune response
  • attracted by chemokines to site of chronic inflammation
• fibroblasts in chronic inflammation


  • produce an extra layer of connective tissue
  • attracted by signals sent out by macrophages - eg chemokines
• Drugs in chronic inflammation

  - primarily concerned with changing the underlying defect than with treating the symptoms

  • glucocorticoids - general immunosuppressant - reduces cytokine production from many different immune cells - may also suppress function of some immune cells - such as phagocytosis
  • Cyclosporine - mainly suppress T cell
  • Still a role for non- steroidal anti - inflammatory drugs - aspirin/ ibuprofen
  • But biologics are increasingly seen as more effective (anti TNF or anti - IL-1 for arthritis ) inhibits cytokines and seem to last much longer.
• what is the problem with chronic inflammation drug treatment 


  • they block part of a normal immune response involved in acute inflammation - eg anti - TNF - blocking of this can cause problems
  • However so far it just seems to damped the immune response to normal levels
• Granulomatous inflammation


  • an important type of chronic inflammation usually caused by organisms of low virulence but great persistence in the tissues or by implanted foreign bodies- eg shrapnel
  • or sometimes due to defects in immune cells killing mechanisms - - eg- defects in NADPH oxidase -reduced production of free oxygen radicals - lead to them having granuloma formation
• granuloma structure 


  yellow part- caseous necrosis

  large pink cell - giant cell

  smaller pink cel - activated macrophage

  blue cells - lymphocyte

  outermost cell - fibroblast

  
• Granuloma formation

  • different types of granuloma but they share some basic characteristics-
  • Macrophages including epithelioid or giant cells cluster around the Infectious agent or area of necrosis or accumulation of neutrophils.
  • T and B cells then form a collar around this as part of the normal adaptive immune response
  • Surrounded by a layer of fibroblasts and connective tissue.