Injury, Inflammation, and Healing Vocabulary

Cellular Injury, Inflammation & Healing

Learning Objectives

• Identify different types of cellular injury.
• Differentiate between cellular adaptations and reversible/irreversible injury.
• Understand and apply the four phases of healing in a clinical setting.

Cellular Injury

• All functional and structural changes are caused by cellular injury.

Reversible vs. Irreversible Cell Injury

Reversible Injury

• Blebs.
• Lipid vacuoles.
• Generalized swelling.
• Autophagy by lysosomes.
• Clumping of nuclear chromatin.
• Aggregation of intramembranous particles.
• Dispersion of ribosomes.
• Small densities.
• Mitochondrial swelling.

Irreversible Injury

• Rupture of lysosomes and autolysis.
• Mitochondrial swelling.
• Nuclear changes:
  • Pyknosis: Nuclear shrinkage.
  • Karyolysis: Nuclear dissolution.
  • Karyorrhexis: Nuclear fragmentation.
• Lysis of the endoplasmic reticulum (ER).
• Defects in the cell membrane.

Causes of Cellular Injury

1. Physical

• Mechanical stress
• Exposure to electricity
• Radiation
• Barotrauma
• Excessive temperature

2. Genetic Factors

• Alterations in chromosome structure or number.
• Single gene mutations affecting protein amount/function.
• Multiple gene mutations interacting with environmental factors (multifactorial disorders).

3. Oxygenation

• Hypoxia: Decreased oxygen supply.
• Anoxia: Complete absence of oxygen.
• Decreased delivery of nutrients.
• Decreased removal of waste products.
• Reduction of ATP.
• Intracellular accumulation of ions and fluids.
• Oxygen Toxicity

4. Chemical Factors

• Toxic substances
• Free radical formation (excessive superoxide $(O<em>2^-)$, hydrogen peroxide $(H</em>2O_2)$, and hydroxyl radical $(^-OH$).

5. Nutritional Factors

• Deficiency or excess of vitamins, minerals, or proteins.
  • Osteoporosis
  • Kwashiorkor
  • Rickets

6. Infectious Agents (IA)

• Bacteria, viruses, fungi, protozoa, prions, and helminthes.
  • Bacterial IA exotoxin production leads to cell injury or death.
  • Bacterial IA endotoxin production leads to septic shock.
  • Viral IA cause direct cellular death
  • Prion IA cause direct cellular death
  • Examples: Tetanus, Chicken Pox, Mad Cow

7. Immune Reactions

• Reaction to antigens (non-self entities).
  • Hypersensitivity reactions (mild allergy to anaphylactic shock).
  • Autoimmunity (cross-reactivity).

Cellular Adaptations

• Hypertrophy
• Hyperplasia
• Metaplasia
• Dysplasia
• Atrophy

Hypertrophy

• Enlargement of tissue/organ due to an increase in the size of cells.
  • Example: Hypertrophic Cardiomyopathy

Hyperplasia

• Enlargement of tissue/organ due to an increase in the NUMBER of cells.
  • Examples: Endometrial hyperplasia, Prostate with benign prostatic hyperplasia

Metaplasia

• Change from one type of fully mature cell to a different type of mature cell not normally found in the tissue involved.

Dysplasia

• Change from one type of fully mature cell to a cell with maturation and differentiation abnormalities.

Atrophy

• Decrease in cell number or size.
  • Effects: decreased size, decreased strength, decreased mobility
  • Hemodynamic unloading leads to:
    • Decrease in myocardial mass
    • Protein synthesis decreases while degradation increases
    • Total metabolic shift
    • Fatal myocardial gene expression

Cell Death

• Apoptosis: Programmed/premeditated cell death.
• Necrosis: Unplanned cell death.
• Changes: Pyknosis, Karyorrhexis, Karyolysis

Phases of Healing

• Hemostasis and Degeneration
• Inflammation
• Proliferation and Migration Phase
• Remodeling and Maturation Phase

1. Hemostasis and Degeneration

• Stop Damage/Bleeding
  • Hematoma formation (blood coagulation, platelets).
  • Necrosis of irreversibly injured cells.
  • Proliferation and migration of epithelial cells, fibroblasts, and vascular endothelial cells, expression of ECM.

2. Inflammation

• Body responds to cellular injury with inflammation.
• S.H.A.R.P (Swelling, Heat, Altered function, Redness, Pain)

Functions of Inflammation

• Inactivate injurious agent (e.g., bacteria).
• Break down and remove dead cells.
• Initiate healing of the tissue.

Inflammation Affects

• Blood vessels.
• Circulating blood cells.
• Connective/interstitial tissues (fibroblasts, mast cells, macrophages).
• Chemical mediators.

Steps in Inflammatory Response

1. Histamine release (Mainly from mast cells): Vasodilation/vasopermeability
2. Lipid Inflammatory Mediators: injured lipid membranes are broken down into
   • Cyclooxygenase pathway:
     • Prostaglandins; vasodilation/vasopermeability, neutrophil chemotaxis
     • Thromboxanes; platelets aggregation
   • Lipooxygenase pathway
     • Leukotrienes; neutrophil chemotaxis
3. Migration of Plasma factors
   • Kinin cascade: vasodilation/vasopermeability
   • Clotting cascade: vasopermeability, neutrophil chemotaxis, clotting
   • Fibrinolytic cascade: immune activation, tissue remodeling
4. Phagocytosis by phagocytes (mainly neutrophils, macrophages and dendritic cells)
   • Destruction of microbial contaminants
   • Removal of dead cells
   • Release of Prostaglandins, Leukotrienes and other chemotactic factors
   • Release of cytokines
     • Interleukin -1
     • Interleukin-6
     • Tumor necrosis factor-alpha
       • Local effects
       • Systemic effects:

3. Proliferation and Migration

• Priorities:
  • Angiogenesis (endothelial cell proliferation).
  • Reduce tissue gaps by repairing matrix.
• Result: Formation of Granulation tissue.

4. Remodeling and Maturation

• Reduction and remodeling of scar tissue, decreased density of fibroblasts and capillaries, contraction of ECM.
• Result: Tissue regeneration, restoring structure and function!

Timeline

• Hemostasis and Degeneration: Begins immediately, lasts hours to days.
• Inflammation: Begins days post-injury, lasts weeks to months.
• Proliferation and Migration: Begins days post-injury, lasts weeks to months.
• Remodeling and Maturation: Begins weeks post-injury, lasts weeks to months.

PT Intervention Guide

Terms to Know

• Inflammation: The body’s complex biological response to injury to initiate the healing process, characterized by SHARP.
• -itis (suffix): Inflammation
• Edema: An abnormal accumulation of fluid in the cavities and intercellular spaces of the body.
• Vasoactive factors: Substances that affect the blood vessels especially in respect to the degree of their relaxation or contraction
• Chemotactic factors: Substances involving, inducing, or exhibiting chemotaxis
• Pro-inflammatory cytokines: Small cell-signaling protein molecules released during inflammation to promote both a localized and systemic response.
• Hypoxia: A pathologic condition where there is a decrease in blood/oxygen supply to a tissue (or entire body), below physiological levels.
• Anoxia: A pathologic condition where there is an absence of oxygen supply to a tissue
• Ischemia: A local deficiency of blood/ oxygen due in part to functional constriction or actual mechanical obstruction of a blood vessel. Frequently caused by an embolus or thrombus.
• Embolus: An abnormal particle or mass circulating in the blood
• Embolism: The sudden obstruction of a blood vessel by an embolus
• Thrombus: A clot of blood formed within a blood vessel and remaining attached to its place of origin
• Pathogenic Agent/ Infectious Agent: Any microorganism that causes tissue damage and/ or disease
• Toxin: Substances created by plants, animals or bacteria that are poisonous to humans.
• Bacterial Exotoxin: A soluble harmful substance produced during growth of a microorganism and released into the surrounding area
• Bacterial Endotoxin: A harmful substance present in bacteria but separable from the bacteria only on its disintegration/death
• Antigen: Any substance recognized as foreign by the immune system, provoking an immune response
• Allergy: A reaction of your immune system to something called an allergen, that does not bother most other people.
• Anaphylactic Shock: An often severe and sometimes fatal systemic reaction in a susceptible individual upon a second exposure to a specific allergen (E.g. wasp venom or penicillin) after previous sensitization that is characterized especially by respiratory symptoms, fainting, itching, and hives
• Karyolysis: Dissolution of the cell nucleus.