Central Concepts of Pathophysiology: Inflammation

Physiologic Mechanisms of Defense

  • First line: Physical, mechanical, and biochemical barriers, along with the normal microbiome.
  • Second line: Innate immunity, also known as the inflammatory response to injury or infection.
  • Third line: Adaptive immunity, also known as the immune response.

First Line of Defense: Natural Barriers

  • Physical and mechanical barriers: Skin, epithelial layers, gastrointestinal peristalsis, and broncho-pulmonary cilia.
  • Biochemical barriers: Sweat, tears, saliva, and nasal secretions.

Human Microbiome (Normal Flora)

  • Body sites colonized with bacteria and fungi specific to an individual and/or location.
  • Microorganisms exist in a mutualistic relationship with the individual.
  • Example: Bacteria in the gastrointestinal tract aid digestion and prevent infection from harmful microorganisms.
  • Normal flora usually do not cause disease but can become opportunistic infections in immunocompromised individuals.

Second Line of Defense: Inflammation

  • The body’s immediate response to injury, infection, or allergy.
  • Purposes:
    • Limit the extent of tissue damage.
    • Protect against infection.
    • Initiate repair of damaged tissue.

Inflammation vs. Immunity

  • Inflammation and immunity are not the same.
  • Inflammation follows a predictable stepwise physiological response.
  • Inflammation is activated before adaptive immunity.

Third Line of Defense: Adaptive (Acquired) Immunity

  • Activated by inflammation.
  • Includes humoral and cell-mediated immune reactions.

Acute Inflammatory Response

  • Initiated by cellular injury or pathogenic invasion.
  • Initial response involves:
    • Mast cell degranulation.
    • Activation of the complement system.
    • Clotting and kinin systems.
    • Release of end products from damaged cells.
  • Visible signs of inflammation:
    • Vasodilation (redness, heat).
    • Increased vascular permeability (edema or swelling).
    • Thrombosis (clotting).
    • Stimulation of nerve endings (pain).
    • Cellular infiltration (pus).

Forms of Exudate

  • Serous: Watery fluid containing proteins and a few white blood cells (e.g., blister).
  • Fibrous: Thick and clotted fluid with white blood cells (e.g., from the lungs).
  • Purulent: Pus containing a large deposit of white blood cells at the injury site.
  • Hemorrhagic: Containing blood (red blood cells).

Initiation of Inflammatory Response

  • Initiated by various types of cellular damage:
    • Infection, mechanical damage, ischemia, nutrient deprivation, temperature extremes, radiation exposure.
  • Occurs in vascularized tissue.
  • Cardinal localized signs and symptoms:
    • Redness (rubor).
    • Heat (calor).
    • Swelling (tumor).
    • Pain (dolor).

Mechanisms of Inflammatory Response

  • Two major mechanisms:
    • Vascular response.
    • Cellular response.
  • Vascular Response:
    • Local vasodilation.
    • Increased vascular permeability causing leakage of fluid from the vascular space.
    • Diapedesis: White blood cells adhere to vessel walls and migrate through the vessels to the site of injury.

Plasma Protein Systems

  • Contribute to the acute inflammatory response.
    • Complement system.
    • Clotting system.
    • Kinin system.

Complement System

  • Contains several plasma proteins (about 10% of circulating proteins).
  • Directly destroy pathogens and work with other components of the immune system.
  • Pathways to destroy pathogenic microorganisms:
    • Classical pathway: Activation of proteins from acquired immunity through the antigen/antibody complex.
    • Lectin pathway: Activated by bacterial carbohydrates.
    • Alternative pathway: Activated by gram-negative bacteria or fungal cell wall polysaccharides.
  • All three pathways converge in the Complement System.

Clotting System (Coagulation System)

  • A group of plasma proteins that initiate a coagulation cascade.
  • The final step is the formation of a fibrinous mesh at the inflamed site.
  • Benefits of the fibrin mesh:
    • Prevents the spread of infection to adjacent tissues.
    • Traps microorganisms and foreign bodies at the inflammatory site for removal by infiltrating cells.
    • Forms a clot that stops bleeding.
    • Provides a framework for tissue repair and healing.
  • The coagulation cascade is activated through convergent pathways:
    • Intrinsic pathway: Initiated by enzymatic release.
    • Extrinsic pathway: Activated by tissue damage.
  • The end product is a fibrin mesh created from insoluble protein.

Kinin System

  • Contributes to the inflammatory process with the production of bradykinin.
  • Effects of bradykinin:
    • Dilation of blood vessels (redness, heat).
    • Stimulates nerve endings and produces pain (pain).
    • Contraction of smooth muscle cells.
    • Increased vascular permeability (swelling).
    • Increased leukocyte chemotaxis.
    • Chemotaxis: Biologic process by which cells direct their movement according to chemicals in their environment; bradykinin directs leukocytes to the area of injury.

Cellular Response of Acute Inflammation

  • Involves actions of granulocytes and monocytes.
  • Granulocytes (neutrophils, eosinophils, and basophils) are recruited and activated by the Plasma Protein System and biochemicals released during cell destruction.
  • Monocytes derived from the monocyte/macrophage complex circulate in the blood and are also found at the injured site.

Cell-Mediated Inflammatory Responses

  • Cellular receptors.
  • Mast cells.
  • Phagocytosis.
  • Neutrophils.
  • Monocytes and macrophages.
  • Basophils.
  • Natural killer cells.
  • Thrombocytes.

Cellular Reception

  • A complex biologic process that allows cells and tissues to respond selectively.
  • Cells have receptors on the cell surface that bind to soluble substances produced during tissue damage or infection.
  • Receptor binding results in activation of intracellular signaling pathways which further trigger the inflammatory response.

Mast Cells

  • Cellular bags of granules located in loose connective tissue close to blood vessels.
  • Found in abundance in areas that frequently interact with the environment (skin, respiratory tract, and GI tract).
  • Activated by physical injury, chemical agents, anaphylactic immune response, or toll-like cell receptors specific to bacteria and fungi.
  • Act by releasing soluble and potent chemicals by:
    • Degranulation (release of microbial toxic molecules from cell granules).
    • Synthesis of inflammatory mediators.

Chemical Mediators from Mast Cells

  • Stimulate production of chemical mediators from lipids in cell membranes with clinically significant effects.
  • Leukotrienes:
    • Produced from arachidonic acid.
    • Effects similar to histamine but released later and have longer effects.
    • Airway constriction.
    • Increased vascular permeability.
  • Prostaglandins:
    • Also produced from arachidonic acid with different groups.
  • Platelet-Activating Factor:
    • Produced by mast cells, neutrophils, monocytes, endothelial cells, and platelets (thrombocytes).
    • Effects considered identical to leukotrienes.

Phagocytosis

  • The process by which cells engulf or ingest cellular debris or foreign material.
  • Most phagocytes are circulating in the blood, so they must leave the bloodstream and advance to the injured site.
  • At the site of injury, they engulf the undesired material and fuse with lysosome granules to destroy the material.
  • When the phagocytic cell fulfills its purpose, it begins to break apart.
  • Enzymes liberated from the dead phagocytic cell contribute to increased inflammation, restarting the cycle.

Neutrophils

  • An important component of the Inflammatory Process.
  • Phagocytosis by neutrophils begins 6-12 hours after the initial injury.
  • Sensitive to the acidic environment and are very short-lived.
  • Once they begin to die, they become a component of the purulent exudate.

Monocytes and Macrophages

  • Slower and larger than neutrophils.
  • Do not arrive at the inflammatory site for at least 24 hours.
  • Usually present within 3-7 days and function for a longer period of time.
  • Not as sensitive to the acidic environment, so divide and replicate to continue to challenge the inflammation.

Basophils

  • Similar to mast cells.
  • Usually associated with inflammatory processes related to allergies or asthma.

Natural Killer Cells

  • Generally present when the inflammatory process is viral in origin.
  • Recognize and eliminate viral-infected cells.
  • Work best in the circulatory system rather than at the tissue level.
  • Differentiate infected cells and tumor cells from normal cells.

Platelets (Thrombocytes)

  • Part of the inflammatory process.
  • Stimulate both the coagulation cascade and degranulation.

Cellular Products in Inflammation

  • Elevated levels of these products are commonly found in the blood when inflammation from many different causes is present.
  • Soluble factors that contribute to the inflammatory process.
    • Pro-inflammatory (contributing to the inflammatory response).
    • Anti-inflammatory (helping resolve inflammation).
  • Two main biologic products:
    • Cytokines (e.g., interleukins, interferons, tumor necrosis factor).
    • Chemokines.

Classic Signs/Symptoms of Acute Inflammation

  • Redness.
  • Heat.
  • Swelling.
  • Pain.

Systemic Signs and Symptoms of Inflammation

  • Acute Inflammation:
    • Fever.
    • Leukocytosis (elevated white blood count).
    • Increased plasma proteins (e.g., Interleukin-1, interleukin-6, fibrinogen, and C-reactive protein).
  • Chronic Inflammatory States:
    • May not see the same acute inflammatory pattern.
    • May see elevated plasma proteins, lymphocytes, and macrophages.