UNIT 1 patho

Inflammation

• Definition: protective, coordinated response of the body to an injurious agent; involves a specific sequential reaction to cell injury.

• Primary goal: wall off the area of injury, prevent the spread of the causative agent, and activate body defenses to respond to the area under attack.

• Inflammation vs infection: inflammation is not the same as infection.

• Inflammation disorders typically have the suffix “itis” (e.g., appendicitis).

• 5 Cardinal signs of inflammation: redness, swelling, warmth, pain, and loss of function.

• Inflammation can be acute or chronic; the material provided focuses on acute inflammatory processes and wound healing.

Acute Inflammation: Overview

• Acute inflammation involves 3 main stages:
  1) Vascular permeability
  2) Cellular chemotaxis
  3) Systemic response

• Acute inflammation sequence leads to accumulation of fluids and immune cells at the site of injury and can trigger systemic responses.

• Acute inflammatory reactions are driven by mediators released from damaged cells, mast cells, platelets, leukocytes, and other cells.

Acute Inflammation: Three Main Stages (Details)

• Stage 1: Vascular permeability
  • Inflammatory mediators cause dilation and increased permeability of blood vessels.
  • Fluids, white blood cells (WBCs), and platelets travel to the site of injury.
  • Fluids move into injured tissues and may form exudates:
  • Purulent exudate (pus): contains proteins, WBCs, microbial organisms, and cellular debris.
  • Transudate: more watery, very little protein.
• Stage 2: Cellular chemotaxis
  • Chemical signals attract platelets and WBCs to the site.
  • Leukocytosis: WBC count increases in the bloodstream due to increased release from marrow.
  • The first type of WBC to arrive depends on the infection type:
  • Bacterial infections: neutrophils first, followed by monocytes/macrophages.
  • Neutrophils are produced in large amounts for phagocytosis.
• Stage 3: Systemic response
  • Systemic symptoms move body-wide: fever, pain, lymphadenopathy, anorexia, lethargy, anemia, weight loss.
  • Systemic symptoms are caused by mediators such as prostaglandins, TNF-α, and interleukins.

Inflammatory Response: Mediators and Pathways

• Vascular response (Phase 1)
  • Mast cells release kinins (bradykinin) and other mediators leading to immediate vasoconstriction followed by increased capillary permeability and vasodilation.
  • Kinins stimulate pain receptors.
  • Clotting cascade begins.
  • Key mediators released by mast cells and platelets include:
  • Histamine: increases capillary permeability and vasodilation.
  • Kinins (bradykinin): local vasodilation, pain, chemotaxis.
  • Prostaglandins: vasodilation, pain, fever; potentiate histamine effects and platelet production.
• Capillary permeability (Phase 1) → described above as part of vascular response.
• Cellular response (Phase 2)
  • Damaged cells release chemotactic factors that stimulate and attract leukocytes (chemotaxis).
  • Arrival of neutrophils and macrophages is central to cellular response.
  • Other chemical mediators include cytokines (chemical messengers responsible for chemotaxis and leukocytosis).
  • Two common subtypes of cytokines (arise from macrophages):
  • Interleukins (ILs): induce fever, stimulate platelet production, cause fatigue/anemia/headache.
  • TNF (tumor necrosis factor): induce fever, lack of appetite, hypotension, cachexia (wasting).
• Systemic response (Phase 3) is driven by these mediators and can include fever, leukocytosis, malaise, anorexia, etc.

Cellular Components and Leukocyte Roles

• Leukocyte Response: Phagocytosis is central to clearing debris and pathogens.
• Leukocyte types and roles:
  • Neutrophils: "first responders"; arrive 6–12 hours after onset; short life span (up to ~4 days); bandemia (left shift) indicates increased immature neutrophils.
  • Eosinophils: defend against parasitic infections and participate in allergic reactions; increased in parasitic infections (especially helminths) and allergic responses; help counteract histamine effects.
  • Basophils: convert to mast cells; release histamine and heparin.
  • Monocytes: arrive 3–7 days after onset; migrate into tissues and become macrophages; long-lived; major role in phagocytosis (scavengers).
• Phagocytosis steps:
  • Recognition/opsonization: coating pathogens to enhance recognition by phagocytes.
  • Engulfment: ingestion of the pathogen.
  • Phagosome formation.
  • Lysosomal fusion: formation of phagolysosome.
  • Oxidative burst: production of reactive oxygen species to destroy ingested material.

Complement System and Lymphatics

• Complement system and opsonization:
  • Opsonization: pathogens are marked by the complement system to enhance engulfment by phagocytes.
  • Complement system releases histamine and coats/alter cell surfaces to facilitate phagocytosis.
• Lymphatic network:
  • Parallels blood circulation; acts as a drainage system (duct-work) that filters and drains certain body areas.
  • Returns lymph containing WBCs (lymphocytes) to systemic circulation via the subclavian veins.
  • Responsible for removal of cellular debris, waste, and excess fluids.

Local and Systemic Manifestations of Inflammation

• Local symptoms: heat (vasodilation), erythema (redness), pain, edema, loss of function.
• Systemic symptoms: fever, leukocytosis, nonspecific malaise, headache, anorexia.
• Relationship of local signs to cellular response:
  • Heat and erythema: vasodilation and increased blood flow.
  • Pain: prostaglandins and kinins stimulate nociceptors.
  • Edema: increased capillary permeability leads to fluid exudation.
  • Loss of function: due to edema and tissue damage.
• Exudate types (in relation to tissue injury):
  • Serous: watery; contains fluid, some proteins, and WBCs.
  • Fibrinous: thick, sticky; high cell and fibrin content.
  • Purulent: thick, yellow-green; contains leukocytes, cell debris, and microorganisms.

Systemic Inflammation and Diagnostics

• Systemic inflammatory symptoms: fever is produced by pyrogens that activate prostaglandins to reset the hypothalamic temperature-regulating center.
  • Pyrogens include microbes, bacterial products, and cytokines (TNF/ILs).
  • Fever is beneficial up to a point as it increases WBC efficiency.
• Leukocytosis: increased WBC count due to chemotactic factors; bandemia/left shift can occur.
• Chronic inflammation can result from:
  • Ongoing exposure to irritants/toxic agents.
  • Persistent infection.
  • Abnormal immune response.
• Diagnostic laboratory indicators of inflammation/infection:
  • WBC elevation: $WBC > 10{,}000$
  • Differential WBC: elevated neutrophils; bandemia increased with left shift.
  • ESR (erythrocyte sedimentation rate) elevation.
  • CRP (C-reactive protein) elevation.
  • Fibrinogen elevation.
  • Isoenzyme elevation (organ-specific): e.g., $AST,\, SGOT,\, CK{-}MB,\, Trop$.

Inflammation and Wound Healing: Stages and Methods

• Inflammation is part of the broader wound healing process which has stages:
  1) Hemostasis
  2) Inflammation
  3) Proliferation
  4) Remodeling
• Methods of wound healing:
  • Primary intention
  • Secondary intention
  • Tertiary (delayed primary) intention

Factors Affecting Healing

• Positive factors:
  • Youth
  • Adequate nutrition (protein, vitamins, especially Vitamin A and Vitamin C)
  • Adequate hemoglobin
  • Good circulation
  • Strong immune system
  • Clean, protected wound
  • No complications
• Negative factors:
  • Advanced age
  • Poor nutrition, dehydration
  • Anemia
  • Poor circulation
  • Other diseases (e.g., diabetes, renal failure, obesity)
  • Infection
  • Steroids
  • Radiation
  • Hematoma

Potential Complications of Healing

• Impaired function
• Contractures
• Adhesions/obstructions
• Hyperplasia (keloid) formation
• Fistula
• Specific note: Keloid scar formation can occur when excessive scar tissue develops at wound site.

Connections to Foundational Principles and Practical Implications

• Inflammation is a protective mechanism that, when well-regulated, promotes healing and defense against infection, but if uncontrolled can cause tissue damage and chronic disease.
• The balance of mediators (histamine, kinins, prostaglandins, cytokines) determines the intensity and duration of the inflammatory response and its local versus systemic manifestations.
• Understanding leukocyte kinetics (neutrophil-dominant early response; macrophage-dominant later response) helps interpret clinical presentations and interpret lab results (e.g., left shift in bacterial infections).
• Wound healing is context-dependent and influenced by systemic factors (nutrition, comorbidities) and local factors (infection, movement, wound care).