L4 Acute Inflammation

• Acute inflammation


  • Typical clinical features
  • Typical macroscopic and microscopic changes

  
• Elimination of organisms in bacterial infection

  Protein-rich fluid and phagocytic white blood cells (the exudate) function to eliminate organisms
• Formation and action of acute inflammatory exudate

  Exudate forms and acts in an area of injury

  
• Chemical mediators for important changes in acute inflammatory response

  • Histamine
  • Prostaglandin
  • TNF
  • IL1
  • IL-6
  • Bradykinin
  • Leukotrienes
  • C3a
  • C5a
  • IL-8
• Monocyte/macrophage recruitment in acute inflammation

  • Monocytes from blood enter tissues and differentiate into macrophages
  • Can live for days-weeks in tissue and proliferate
  • Contains numerous PRRs for recognition of PAMPs and DAMPs
  • Highly phagocytic
  • Can amplify or reduce inflammation with cytokine production
  • Sets stage for repair by producing anti-inflammatory cytokines and growth factors

  
• Timeline of acute inflammation

  1. Congestion: Oedema; red, heavy, boggy lung tissue

  2. Red hepatization: Predominant neutrophil, fibrin and red cells in exudate

  3. Grey hepatization: Predominant macrophage infiltrate, degradation of red cells

  4. Resolution: Breakdown & ingestion of fibrinous residue by macrophages. Possible adhesions

  
• How inflammation limits damage

  • Allowing antibodies, fibrinogen & other proteins into the area
  • Killing infective organisms
  • Removing debris that remains when cells are damaged or die
  • Triggering the immune response via antigens presented on macrophages
  • Initiating repair triggered by cytokines produced by macrophages

  
• Complement proteins


  • Recruitment via C3a and C5a (anaphylatoxins)
  • Opsonisation by interaction of bound C3b with complement receptors on leukocytes
  • Lysis of microbe by formation of the MAC

  
• 3 main pathways for the activation of complement (fixation) but all result in the formation of the C3 convertase
• Opsonisation


  Coating of microbes to enhance phagocytosis
• Haematology blood screen results for the patient
• Acute phase response


  Liver produces acute-phase reactants in response to inflammatory cytokines produced by macrophages and other immune cells
• Acute phase reactants


  • C-reactive protein (CRP)
  • Erythrocyte Sedimentation Rate (ESR)
  • Serum Amyloid A (SAA)
  • Fibrinogen
  • Haptoglobin
  • Alpha-1 Antitrypsin
  • Ferritin
• Negative acute phase reactants decrease in inflammatory response
• Patient case 1: Right knee injury

  • Swelling, loss of normal contours, heat and pain
  • Cloudy, white-yellow, inflammatory exudate (pus) containing neutrophils
  • Non-cloudy, red, early fluid-based exudate with some blood present
• Septic (Suppurative) arthritis


  • Suppurative arthritis of the joint with the main causative agent associated with age and sex
  • Acute onset of monoarticular joint pain, erythema, heat and immobility with a restricted range of motion
  • Susceptibility factors include deficiencies in complement components, immunodeficiencies, debilitating illness, joint trauma, chronic arthritis, and intravenous drug use
• Routes by which bacteria can reach the joint

  1. Through capillaries of vascular synovium

  2. Directly access the joint space (stasis)
• Pathophysiology of septic arthritis

  1. Bacterial adherence and proliferation

  2. Acute inflammatory response: Heat/redness + Swelling, Blood flow, vasodilation, Vascular permeability

  3. Activation, Phagocytosis, Degranulation, Diapedesis, Chemotaxis

  4. Joint: Increased intra-articular pressure, Necrosis of synovium, cartilage & bone by leukocytes and bacteria

  
• Septic arthritis: Diagnosis and treatment

  • Joint aspiration (arthrocentesis) is diagnostic if it yields purulent fluid in which the infectious organism can be identified
  • Prompt recognition, drainage and effective (empiric) IV antimicrobial therapy can prevent joint destruction
• Lab findings in septic arthritis: Leukocytosis (neutrophilia) & left shift, Increased CRP & erythrocyte sedimentation rate (ESR), Purulent synovial fluid, Gram stain and culture on aspirate
• Sepsis


  Systemic inflammatory state with multiorgan dysfunction caused by a bacterial infection - life-threatening!

  
• Pathophysiological cascade of sepsis

  1. Inadequate source control or host immunity results in excessive cytokine signalling

  2. Involves endothelial damage, vascular permeability, microvascular dysfunction, and coagulopathies

  3. Neutrophil activation results in endothelial damage

  4. Activation of coagulation in microvasculature can lead to thrombosis of vessels and end-organ damage

  5. Immune dysfunction can lead to susceptibility to secondary infections

  
• Sepsis definition


  Presence of two or more signs (hypotension, altered mental state, tachypnea) in conjunction with a bacterial infection
• Common infections associated with progression to sepsis: Pneumonia, urinary tract infections, skin and gut infections
• Common bacterial culprits in sepsis: Staphylococcus aureus, E.coli and Streptococcal strains
• In advanced stages of sepsis: extensive intravascular coagulation may develop, a condition known as Disseminated Intravascular Coagulation (DIC), often signalling the initiation of multi-organ failure
• Septic shock


  Progression to circulatory dysfunction driven by excessive pro-inflammatory cytokine resulting in hypotension, hypovolemia and oedema leading to multi-organ failure
• Sepsis Definition


  Presence of two or more of the following signs in conjunction with a bacterial infection: Hypotension, Altered mental state, Tachypnea (≥22 breaths/min)

  
• Common infections associated with progression to sepsis

  • Pneumonia (lung infection)
  • Urinary tract infections (UTIs)
  • Skin and gut infections

  
• Common bacterial culprits


  • Staphylococcus aureus
  • E.coli
  • Streptococcal strains
• Disseminated Intravascular Coagulation (DIC)


  Extensive intravascular coagulation that may develop in advanced stages of sepsis, often signalling the initiation of multi-organ failure
• DIC Pathogenesis


  • ↑ Bleeding
  • ↑ Thrombosis
• Components involved in DIC Pathogenesis

  • Vascular wall
  • Cellular components of the blood
  • Chemical mediators
  • Clotting (coagulation) system
  • "Un-clotting" (fibrinolysis) system
  • Complement system
  • Kinin system

  
• Acute Inflammation


  • Abscess - via liquefactive necrosis
  • Persistent inflammation – (chronic inflammation) – due to a failure to completely eliminate the pathological insult
  • Healing
• Acute Inflammation-Outcomes


  1. oedema neutrophils

  2. monocytes/macrophages

  3. activity

  
• Repair of damage may occur through regeneration or scarring
• Regeneration


  Requires labile or stable cells which can proliferate; either uninjured differentiated cells e.g. hepatocytes of the liver, or stem cells or progenitors e.g. epithelium and bone
• Scarring


  Deposition of connective tissue (mainly collagen) to provide a permanent patch, in tissues incapable of regeneration e.g. neurons, myocardium, or if structures of ECM (extracellular matrix= the tissue's scaffold) are lost e.g. by liquefactive necrosis

  
• Cell types by capacity to regenerate

  • Labile – continuously dividing
  • Stable – quiescent but can respond
  • Permanent – terminally differentiated, non-proliferative
• Examples of cell types by capacity to regenerate


  • Haematopoietic cells
  • Parenchyma of liver, kidney (limited), pancreas (limited)
  • Neurons & myocardial cells – possibility that there may be minimal stem cell regeneration but not sufficient to repair
  • Surface epithelia- skin, ducts
  • Endothelial cells, fibroblasts, smooth muscle cells
  • Skeletal cells –possibility of some stem cells in the endomysium but not significant to repair