Cell Injury and Repair - PHIDG 1501

Cell Injury, Inflammation, and Repair (3 lecture hours)

• Course: PHIDG 1501 - Integrated Sequence 1
• Recommended Reading: Robbins Basic Pathology, 10th Edition (2018)
• Learning Objectives:
  • Describe the general principles of cell injury.
  • Detail cell injury concepts: homeostasis, adaptation, hypertrophy, hyperplasia, atrophy, and metaplasia.
  • Describe all possible mechanisms of cell injury.
  • Detail morphological changes associated with cell injury.

Homeostasis

• The intracellular milieu of cells is tightly regulated to remain fairly constant.
• This state of cellular stability is called homeostasis.
• Intracellular milieu components include anion and cation concentrations, enzyme concentration and activity, protein concentrations, and the pH of the cytosol and organelles.

Cellular Adaptation

• Cells adapt to physiological stress (increased workload) or pathological stress (nutrient deprivation, injury).
• The goal of cellular adaptation is to preserve cell viability and function.
• Cellular injury develops if the adaptive capacity is exceeded.

Cell Injury Progression

• Normal cell (homeostasis) → Injurious stimulus → Reversible injury → Severe, progressive injury → Irreversible injury → Cell death (necrosis or apoptosis)

Principal Adaptive Responses

• Hypertrophy: Increased cell size (e.g., striated muscle cells). No new cells, only bigger cells enlarged by increased structural proteins and organelles. Could be physiological or pathological (e.g., in the heart due to hypertension).
  • Physiological stimuli: chronic exercise, pregnancy
  • Pathological stimuli: hypertension, myocardial infarction, endocrine disorders.
• Hyperplasia: Increased cell number (e.g., smooth muscle cells). A response to hormones or other growth factors; occurs in tissue capable of cell division.
  • Physiological hyperplasia: hormonal hyperplasia (e.g., female breast during puberty and pregnancy) and compensatory hyperplasia (e.g., growth of residual tissue after removal of part of liver).
  • Pathological hyperplasia: excess hormones or growth factors (e.g., endometrial hyperplasia, papillomavirus wart).
• Atrophy: Decreased cell/organ size due to loss of cell substance. Diminished function, but not dead. Possible causes include loss of innervation, decreased workload, reduced blood supply, inadequate nutrition, or loss of endocrine stimulation (e.g., menopause) and aging.
• Metaplasia: Reversible change where one adult cell type is replaced by another. Cells sensitive to a stress are replaced by cells better able to withstand adverse environments. Example: squamous change in respiratory epithelium of smokers.

Overview of Cell Death

• Necrosis: "chaotic," death of many cells, inflammation, lysosome breakdown, and cell swelling.
• Apoptosis: "programmed," death of single cells, no inflammation, lysosomes intact.

Causes of Cell Injury

• Oxygen deprivation: Interferes with oxidative phosphorylation (e.g., ischemia, commonly caused by reduced blood supply).
• Chemical agents: Reactive oxygen species (ROS), O2, OH, other free radicals, various toxins.
• Infectious agents: Viruses, bacteria, fungi, etc.
• Immunologic reactions: Autoimmune and allergic reactions.
• Genetic defects: Deficiency of functional proteins.
• Physical agents: Trauma, radiation, extreme temperatures.

Morphology of Reversible Injury

• Cellular swelling: ATP depletion leads to failure of ion pumps, loss of ionic and fluid homeostasis.
• Fatty change (steatosis): Accumulation of lipids in cytoplasm, impairment of lipid metabolism.

Morphology of Necrosis

• Increased eosinophilia (pink staining due to less RNA and increased denatured protein).
• Myelin figures.
• Calcification.
• Nuclear changes:
  • Karyolysis: DNA degradation
  • Pyknosis: Shrinkage of nucleus
  • Karyorrhexis: Fragmentation of the nucleus

Subcellular Responses to Injury

• Autophagy: Lysosomal digestion of the cell's own components (survival mechanism during nutrient deprivation).
• Residual bodies can contain undigested debris (e.g., pigments from tattoos)

Induction of Smooth ER

• Drugs metabolized by the P450 enzyme system in the liver.
• Protracted drug use leads to adaptive increase of SER (smooth endoplasmic reticulum).
• Consequence: Need to increase drug dose.

Mitochondrial Alterations

• Changes in size, shape, and number (e.g., exercise increases the number of mitochondria for energy production).

Cytoskeletal Abnormalities

• Cytoskeleton: Elaborate array of protein fibers maintaining cell shape, strength, and chromosome separation.
• 3 types: Microtubules, actin filaments, and intermediate filaments.
  • Cells constantly remodel their intracellular scaffolding in response to environmental stress.
  • Membrane stability depends on cytoskeleton.
  • Drugs binding to microtubules can prevent proliferation (e.g., anticancer drugs).

Mechanism of Cell Injury Overview

• Injurious stimulus causes:
  • Membrane damage
  • Cytoskeletal damage
  • DNA damage and accumulation of misfolded proteins.
• These events lead to cell death (primarily by apoptosis).

ATP Depletion

• Lack of oxygen and nutrients, direct mitochondrial damage, or toxins (e.g., cyanide) are the causes of ATP depletion.
• Ichemia is a common cause of ATP depletion (e.g., reduced blood supply to the brain).
• Consequences of ATP depletion include sodium pump dysfunction, osmotic gain of water, and subsequent cellular swelling.

Increased Cytosolic Calcium

• When ATP-dependent calcium transporters fail in cells, cytosolic calcium increases significantly.
• Increased cytosolic calcium leads to activation of enzymes.

Cellular Injury by Oxidative Stress

• Oxidative stress occurs through the production of reactive oxygen species (ROS).
• ROS damage cellular components, leading to cell injury and death.
• ROS damage may include lipid peroxidation of fatty acids in cell membranes, protein oxidation, or DNA damage, producing mutations.
• Cells have antioxidant mechanisms (e.g., superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase) for the removal of free radicals. However, prolonged oxidative stress will overwhelm cellular antioxidant mechanisms and result in injury.

Sources of ROS

• NO synthase, NADPH oxidases, and xanthine oxidase are sources of ROS (reactive oxygen species).

ROS Paradigm Shift

• Hydrogen peroxide and other ROS act as physiological second messengers for many biochemical pathways.
• Excessive ROS production can damage cells.
• Elevated ROS levels can cause cellular damage or dysregulation of cellular function.