Inflammation

• Inflammation is response of living tissue to injury/insult. May be physical/chemical/infective/hypersensitive. It is a protective reaction to dilute, destroy, isolate and initiate repair. It is potentially harmful - components of inflammation can injury bystander normal tissue. Acute and chronic forms.
• Components of the inflammatory process: white blood cells and plasma proteins
• Inflammation is induced by chemical mediators produced by damaged host cells - cytokines and other mediators
• Inflammation is normally controlled and self-limited
• Cardinal signs of inflammation:

  • Heat (calor)
  • Redness (rubor)
  • Swelling (tumor)
  • Pain (dolor)
  • Loss of function
• Acute inflammation is an innate, immediate and stereotyped response in the short term following tissue injury
• Mast cells are a source of mediators including histamine and are found outside blood vessels
• Polymorphonuclear leukocytes are found in blood vessels and eliminate microbes and dead tissue
• Lymphocytes mediate immune response
• Monocytes (in blood vessels) become macrophages (in tissues). They are involved in elimination of microbes and dead tissue, are source of mediators including cytokines and have a role in immune response
• Endothelial cells are sources of mediators including nitric oxide and cytokine
• Extracellular matrix proteins and cells, and fibroblasts, help with repair
• Plasma proteins

  • Complement: mediators of inflammation, elimination of microbes
  • Clotting factors and kininogens: mediators of inflammation
• Acute Inflammation:

  • Fast onset (minutes or hours)
  • Cellular infiltrate is mainly neutrophils
  • Tissue injury/fibrosis is usually mild and self-limiteed
  • Local and systemic signs are prominent
• Chronic inflammation:

  • Slow onset (days)
  • Cellular infiltrate is monocytes/macrophages and lymphocytes
  • Tissue injury/fibrosis is often severe and progressive
  • Local and systemic signs are less prominent, may be subtle
• Acute Inflammation:

  • Immediate and early response to injury
  • Vascular response
  • Vasodilatation, leaky capillaries
  • Cellular response
  • Margination, adhesion, emigration, activation
  • Neutrophils
  • Complement activation
  • Phagocytosis (neutrophils, macrophages)
  • Short duration
• Vasodilation

  • Change in vessel flow
  • NO, histamine -> vascular smooth muscle -> vasodilation -> increased blood flow (heat and redness)
  • stasis: slowed blood flow, hyperviscosity
  • margination of circulating leukocytes and endothelial activation
  • Followed by increased permeability of the vasculature
  • Formation of an early transudate (protein-poor filtrate of plasma) gives way to exudate (protein-rich filtrate) into extracellular tissues
• Vascular leakage and oedema

  • Change in vessel permeability
  • Histamines, bradykinins, leukotrienes cause endothelial cell contraction that widens intercellular gaps of venules
  • Outpouring of protein-rich fluid (exudate) into the extracellular tissues leads to:
  • Reduction of intravascular osmotic pressure
  • Increase in extravascular/interstitial osmotic pressure
  • Increase of interstitial osmotic pressure leads to oedema (water and ions)
• Leukocyte emigration to extravascular tissue:

  1. margination and rolling
  2. activation and adhesion
  3. transmigration
• Prostaglandins and nitric oxide mediate vasodilation
• Histamine, serotonin, C3a, C5a, bradykinin, leukotrienes C4, D4, and E4, and platelet activating factor mediate increased vascular permeability
• C5a, leukotriene B4, bacterial products and chemokines (IL-8) mediate chemotaxis and leukocyte activation
• IL-1, IL-6, TNF and prostaglandins mediate fever
• Prostaglandins and bradykinin medidate pain
• Neutrophil and macrophage lysosomal enzymes, oxygen metabolites and nitric oxide mediate tissue damage
• Clinical indications of acute inflammation:

  • General malaise
  • Fever
  • Pain, often localised to the inflamed area
  • Rapid pulse rate
• Laboratory investigations for acute inflammation:

  • Increased neutrophil count
  • Increased erythrocyte sedimentation rate (ESR)
  • Increase in the concentration of acute-phase proteins in the blood e.g. C-reactive protein (CRP)
• Factors that impair healing

  • Poor nutrition
  • Immunosuppression
  • Persisting tissue damage infection
  • Retained foreign material
  • Sequestered dead tissue
  • Poor blood supply
• Factors that aid healing

  • Appropriate antibiotics
  • Surgical removal of foreign material/sequestered dead tissue
  • Attempt to improve nutrition/vitamins
• Chronic inflammation conditions:

  • Cancer
  • Diabetes
  • Neurological Diseases
  • Autoimmune diseases
  • Arthritis
  • Pulmonary disease
  • Alzheimer's disease
  • Cardiovascular
• Chronic inflammation:

  • Long duration
  • Inflammatory response of prolonged duration - persistent causative stimulus
  • Inevitably causes tissue damage - simultaneous attempts at healing and repair
  • May develop in the following ways:
  • progression from acute inflammation
  • repeated episodes of acute inflammation
  • de novo if the causative agent produces only a mild acute response
• Components of chronic inflammation:

  • Lymphocyte, plasma cell, macrophage (mononuclear cell) infiltration
  • Tissue destruction by inflammatory cells
  • Repair with fibrosis and angiogenesis (new vessel formation)
• Inflammation describes the tissue response to injury and is a series of processes initiated to limit tissue damage. Acute inflammation is an innate, immediate and stereotyped response in the short term following tissue injury.
• Acute inflammation occurs in response to a variety of situations where there may be tissue damage. Common causes include infection, hypersensitivity reactions, physical or chemical agents and tissue necrosis.
• Immediately following injury, there is transient arteriolar vasoconstriction to control blood loss followed by arteriolar vasodilation to enhance blood flow in nearby capillaries and tissues. Provides blood components for managing primary injury and initiating repair. Causes rubor and calor.

  Mast cells, basophils, and platelets at the injury site release histamine. Blood vessels become more permeable and exudate forms within tissues. Circulation slows which increases concentration of red blood cells near injury site. This leads to swelling.
• Exudation of fluid occurs due to Starling’s Law. Vasodilation of arterioles leads to increased hydrostatic pressure and, as a result, higher fluid movement out of vessels.  In addition to this, increased vessel permeability allows proteins to move into the interstitium, leading to increased colloid pressure and further increasing fluid movement out of vessels.

  This increase in tissue fluid also leads to increased lymphatic drainage, which can help remove damaging substances and causative microbes.

  This fluid allows plasma proteins, such as fibrin, to be delivered directly to the injury site.
• Exudation occurs as a result of several mechanisms:

  • Endothelial contraction, mediated by histamine and leukotrienes
  • Cytoskeletal reorganisation, mediated by cytokines, IL-1 and TNF-α.
  • Direct injury, from toxic burns or chemicals.
  • Leukocyte-dependent injury, due to toxic oxygen species or enzymes from leukocytes.
  • Increased transcytosis (channels across endothelial cytoplasm), mediated by VEGF.
• Stasis of circulation allows neutrophils to line-up along endothelium near injury site (margination). They roll along the endothelium, sticking intermittently, then attach more avidly (adhesion). Finally, neutrophils migrate through blood vessel walls via relaxation of inter-endothelial cell junctions and digestion of vascular basement membrane.

  Neutrophils move to areas of damage via chemotaxis, following concentration gradient of chemotaxins, including  C5a, LTB4, and bacterial peptides.

  Neutrophils phagocytose pathogens and cellular debris to remove them, facilitated by opsonins.
• The changes that occur in acute inflammation help with controlling the infection and restoring tissues to their normal state:

  • Exudation of fluid helps deliver plasma proteins to injury sites. It, furthermore, dilutes toxins and increases lymphatic drainage.
  • Infiltration of neutrophils leads to the removal of pathogens and cellular debris.
  • Vasodilation, much like exudation, helps to increase the delivery of necessary proteins and cells and to increase tissue temperature.
  • Pain and loss of function help to enforce rest and lower the risk of further tissue damage.
• Chronic inflammation also arises as a response to injury but takes place over a longer period of time than acute inflammation. The process is less stereotyped than acute inflammation and has an overlap with host immunity.