Pathology Basics: Inflammation (multiple choice)

Inflammation Overview

• Vital host defense mechanism that helps eliminate infections and heal injuries.
• Defined as the response of vascularized tissues to infection and damage, facilitating the movement of defense cells and molecules to affected areas.
• Balances beneficial effects (healing) and detrimental effects (potential tissue injury).

Cardinal Signs of Inflammation

• Four classic signs:
  • Rubor (redness)
  • Tumor (swelling)
  • Calor (heat)
  • Dolor (pain)
• Functionality: Reflects early vascular changes during inflammation, with loss of function identified as an additional sign.

Causes of Inflammation

• Stimuli triggering inflammation include infections, tissue necrosis, hypoxia, foreign bodies, and immune reactions (hypersensitivity).

Classification of Inflammation

• Duration:

  • Acute: Rapid onset, lasting minutes to hours.
  • Subacute: Transitional phase between acute and chronic inflammation.
  • Chronic: Prolonged duration, often resulting from unresolved acute inflammation or slow responses to low-grade injuries.

• Morphology: Patterns indicate underlying causes of inflammation and include:

  • Serous: Thin, clear fluid, seen in conditions like skin blisters.
  • Fibrinous: Thick exudate with fibrin, found in peritonitis and pleuritis.
  • Suppurative/Purulent: Pus production indicative of abscesses and infections.
  • Catarrhal: Mucus-rich exudate, typical in mucous membranes.
  • Granulomatous: Chronic inflammation characterized by granulomas, seen in tuberculosis and fungal infections.

Key Cells in Inflammatory Response

• Neutrophils: First responders, short-lived (~24-48 hours), release enzymes, form traps for pathogens.
• Macrophages: Long-lived, crucial for phagocytosis, cytokine production, and tissue repair.
• Mast Cells: Involved in acute and chronic phases, release histamine and other mediators.
• Eosinophils: Active in allergic reactions and parasitic infections, contain toxic granules.
• Lymphocytes: Role in both antibody-mediated and cell-mediated immunity, influence macrophage activity.

Vascular Events in Acute Inflammation

• Vasodilation: Increases blood flow, induced by mediators like histamine.
• Increased Vascular Permeability: Allows plasma proteins and leukocytes to exit circulation, leading to edema.
• Exudate vs. Transudate:
  • Exudate: High protein concentration and cellular debris, indicative of inflammation.
  • Transudate: Low protein fluid, usually non-inflammatory.

Leukocyte Recruitment Processes

• Recruitment involves:
  • Margination: Leukocytes move closer to vessel walls as blood flow slows.
  • Rolling: Leukocytes interact loosely with endothelial cells.
  • Firm Adhesion: Strong attachment to endothelium via adhesion molecules.
  • Emigration: Movement across endothelial cell layers into tissues.

Phagocytosis

• Process whereby leukocytes engulf and digest pathogens or debris, crucial for resolving inflammation.

Termination of Acute Inflammatory Response

• Involves removal of stimuli, apoptosis of leukocytes, and restoration of tissue homeostasis.

Mediators of Inflammation

• Numerous cellular and plasma-derived mediators, such as cytokines and chemokines, play critical roles in both promoting and regulating the inflammatory response.

Differences Between Acute and Chronic Inflammation

• Acute: Short duration, primarily neutrophilic infiltration, rapid onset.
• Chronic: Long-lasting, characterized by macrophages, lymphocytes, and plasma cells, involves ongoing tissue repair and often results in fibrosis.

Systemic Effects of Inflammation

• Inflammation can have systemic responses, including fever, increased white blood cells, and altered metabolic processes.

Terminology

• Inflammation names often use the suffix “-itis” indicating affected tissues (e.g., Hepatitis, Dermatitis). Exceptions exist (e.g., pneumonia for lung inflammation).### Inflammation Process
• Hemodynamic changes during inflammation lead to leukocyte margination.
• Rolling and adhesion of leukocytes to endothelial cells depend on adhesion molecules augmented by cytokines.
• Adhesion molecules include selectins (L-selectin, E-selectin, P-selectin) and integrins, facilitating leukocyte-endothelial interactions.

Cytokines and Chemokines

• Macrophages, mast cells, and endothelial cells produce cytokines (e.g., TNF, IL-1) in response to injury or infection.
• TNF and IL-1 enhance the expression of adhesion molecules on endothelial cells.
• Chemokines attract leukocytes through a chemical gradient, guiding them to sites of infection.

Leukocyte Function

• Phagocytosis occurs in three steps: recognition, engulfment, and killing of pathogens.
• Opsonization facilitates phagocytosis, primarily through IgG antibodies and complement components (e.g., C3b).
• Engulfed materials form phagosomes that merge with lysosomes for degradation of pathogens.

Phagocytosis Mechanism

• Recognition involves attachment of pathogens to leukocyte receptors.
• Engulfment creates a phagosome, which combines with lysosomes for microbial killing.
• Reactive oxygen and nitrogen species, along with lysosomal enzymes, carry out the degradation.

Macrophage Role

• Macrophages contribute to tissue repair and regeneration by releasing growth factors.
• They can both intensify and limit the inflammatory response by secreting various mediators.

Potential for Damage

• Prolonged inflammatory responses can cause additional tissue damage.
• Autoimmune diseases occur when inflammation is misdirected against host tissues.
• Allergic reactions involve excessive responses to non-harmful substances.

Defects in Leukocyte Function

• Inherited defects, such as leukocyte adhesion deficiencies, increase infection risks.
• Bovine Leukocyte Adhesion Deficiency (BLAD) leads to recurrent infections and is caused by a mutation in the CD18 gene.
• Chédiak-Higashi syndrome impairs phagocytic function due to defective phagosome-lysosome fusion.

Resolution of Inflammation

• Inflammation subsides as mediators have short half-lives and are actively degraded.
• Active termination mechanisms include a shift from pro-inflammatory to anti-inflammatory mediators.

Mediators of Inflammation

• Mediators can be cell-derived or plasma-derived and are crucial in regulating inflammation.
• Cell-derived mediators include vasoactive amines (histamine and serotonin) and arachidonic acid metabolites (eicosanoids).

Key Mediators

• Histamine, released by mast cells, causes vasodilation and increased permeability.
• Prostaglandins influence vascular responses; key types include PGE2, PGD2, PGF2α, PGI2, and TxA2.
• Leukotrienes are produced by leukocytes, acting as chemoattractants and mediators in inflammatory responses.

Cytokines and Chemokines

• TNF and IL-1 are pivotal pro-inflammatory cytokines produced by activated macrophages.
• They activate endothelial cells and leukocytes, inducing systemic acute-phase responses.

Other Inflammatory Mediators

• Platelet-activating factor (PAF) initiates platelet aggregation and has wide inflammatory effects.
• Reactive oxygen species amplify inflammatory responses by increasing chemokine and cytokine production.

Plasma Protein-Derived Mediators

• The complement system, kinin system, and coagulation system play distinct roles in inflammation and immune responses.
• Complement proteins (C3a, C5a) are crucial for increasing permeability and chemotaxis.

Outcomes of Acute Inflammation

• Complete resolution restores normal tissue after mild or limited injury.
• Healing occurs through fibrosis when substantial tissue damage prevents regeneration.
• Chronic inflammation arises from persistent injury or ineffectiveness of healing processes.

Chronic Inflammation

• Characterized by prolonged inflammation, chronic inflammation often results from persistent infections or immune-mediated diseases.
• Histological features include infiltration of mononuclear cells and attempts at healing through fibrosis and angiogenesis.

Systemic Effects of Inflammation

• Fever and leukocytosis are common responses during acute inflammation.
• Acute-phase proteins such as C-reactive protein (CRP) increase in concentration and act as opsonins.

Tissue Repair

• Tissue regeneration and repair mechanisms are intertwined with inflammation and occur shortly after injury.
• Regeneration succeeds when damaged tissues can restore normal function without significant scarring.### Tissue Repair and Regeneration
• Injured tissues may develop structural issues like fibrosis if unable to fully restore or regenerate.
• Tissue repair capability is primarily influenced by the proliferative capacity of the cells.
• The cell cycle regulates cell proliferation via growth factors and interactions with the extracellular matrix.
• Labile tissues continuously lose and replace cells.
• Stable tissues exist in resting phases but can proliferate in response to injury.
• Permanent tissues consist of non-proliferative, terminally differentiated cells.

Scar Formation

• Repair involves connective tissue deposition and scar formation if regeneration is not possible.
• Macrophages play a pivotal role in repair by clearing harmful agents and releasing growth factors that promote cell proliferation.
• Key repair processes include inflammation, angiogenesis, granulation tissue formation, and connective tissue remodeling.

Factors Impairing Tissue Repair

• Local and systemic factors affecting wound healing include:
  • Local infections
  • Metabolic diseases
  • Nutritional deficiencies
  • Glucocorticoids (steroids)
  • Mechanical issues
  • Poor tissue perfusion
  • Presence of foreign bodies
  • Wound characteristics (size, location, type)

Plasma Proteins

• Plasma and serum proteins, primarily albumin and globulins, are maintained within narrow ranges in healthy animals.
• Functions of plasma proteins include:
  • Nutritional support
  • Maintaining colloid osmotic pressure
  • Involvement in immune response, inflammation, and clotting
  • Regulation of acid-base balance

Age-Related Changes

• In mammals, plasma protein levels are low at birth, rise after colostrum absorption, drop within a few weeks, and normalize by six months.

Albumin

• Comprises 35-50% of total serum protein; synthesized by the liver; regulated by cytokines like IL-1.
• Half-life varies: ~8 days in dogs, ~19 days in horses, ~2-3 weeks in cattle.
• Responsible for ~75% of plasma's colloidal osmotic activity.
• Functions include:
  • Colloid osmotic pressure maintenance
  • Transport of small, soluble substances
  • Calcium transport (~40% of serum calcium)
  • Serving as an amino acid source
  • Acts as an antioxidant and buffer
  • Identified as a negative acute phase protein

Globulins

• A diverse protein group, separated into three main categories by serum protein electrophoresis: alpha, beta, gamma.
• Alpha-globulins: liver-produced, function as transport proteins and anti-inflammatory agents.
• Beta-globulins: include transport proteins and immunoglobulins (IgM, IgA); synthesized by liver and plasma cells.
• Gamma-globulins: primarily consist of IgG antibodies produced by B lymphocytes.

Protein Measurement Techniques

• Total Protein Evaluation: Refractometry measures total solids in plasma or serum, affected by glucose, urea, sodium levels, and turbidity.
• Albumin Quantification: Bromcresol green dye-binding method is common but can yield false results; serum protein electrophoresis is an alternative.
• Globulin Measurement: Derived from the total protein minus albumin; electrophoresis separates globulin fractions.

Protein Abnormalities (Dysproteinemias)

• Hyperproteinemia: Increased total protein concentration, commonly due to dehydration or inflammatory disease.
• Hypoproteinemia: Decreased protein levels arising from conditions such as burns, gastrointestinal disease, or excessive fluid dilution.
• Albumin Abnormalities:
  • Hyperalbuminaemia: Often related to dehydration.
  • Hypoalbuminaemia: Associated with malnutrition, chronic disease, or excessive fluid losses.
• Globulin Abnormalities:
  • Hyperglobulinaemia: Frequently linked to dehydration or increased inflammatory activity.
  • Hypoglobulinaemia: Often results from conditions like hemorrhage or protein-losing enteropathies; common in neonates due to passive transfer failure.

Failure of Passive Transfer

• Neonates are born with minimal immunoglobulins; proper colostrum ingestion is essential for protection.
• Serum IgG levels indicate transfer success: >8 g/L is adequate, 2-8 g/L indicates partial failure, and <2 g/L indicates complete failure.
• Various tests are available to assess passive transfer, including glutaraldehyde coagulation, zinc sulfate turbidity, and serum GGT activity.

Acute Phase Proteins (APPs)

• APPs increase in response to inflammation, crucial for immune response and recovery.
• Divided into major and moderate APPs based on their production rate and peak response time.
• Most APPs are derived from liver and respond to cytokines such as IL-1 and TNF.
• Significant in various species, with specific APPs that show characteristic responses.

Gammopathies

• Polyclonal gammopathy: Features broad peaks of diverse immunoglobulin types, indicating chronic inflammation or liver disease.
• Monoclonal gammopathy: Narrow peaks from a single clone of neoplastic cells, reflecting conditions like cancer.
• Hypoglobulinemia often accompanies hypoalbuminemia, indicating potential underlying pathologies.

Explore the key concepts of inflammation and repair in veterinary anatomy and clinical pathology. This quiz is based on foundational texts, including Robbins Basic Pathology and the Pathologic Basis of Veterinary Disease. Test your understanding and deepen your knowledge in this crucial area of veterinary medicine.