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• DNA: Physical

  Ionising Radiation e.g. X-Rays
• Toxicity of Ionising Radiation

  • Acute damage to vascular endothelial cells
  • Cells dying and surrounding tissues shrink (atrophy)
  • Ulceration
  • Bleeding
  • Scarring
• Misrepair of Ionising Radiation

  Can lead to chromosome translocations -> blood cancers
• DNA: Physical

  Ultraviolet radiation e.g. Sunlight
• Toxicity of Ultraviolet Radiation

  • Acute damage to keratinocytes on the skin can lead to peeling sunburn
• Misrepair of Ultraviolet Radiation


  Chronic damage can lead to accumulation of mutations and development of skin cancer
• DNA: Chemical

  Alkylation e.g. aflatoxin B1
• Alkylation

  DNA adducts, G to T transversions
• Toxicity of Aflatoxin B1

  • Leads to damage in the liver and acute aflatoxicosis (injury) - at high doses
• Misrepair of Aflatoxin B1

  Chronic low doses can lead to liver cancer (hepatocellular carcinoma)
• Lipids: Physical

  • MSU (monosodium urate)
  • Silica
  • Asbestos
  • Cholesterol
  • Hydroxyapatite (calcium phosphate from bone)
• Lipids: Chemical

  • Oxidants e.g. oxygen therapy
  • Lysosome
  • Inflammasome
• Many forms of radical (atom with unpaired electron)
• In biology, most common are oxygen radicals = Reactive Oxygen Species (ROS)
• Sequential reduction of molecular oxygen

  1. Oxygen

  2. Superoxide Anion

  3. Peroxide

  4. Hydroxyl Radical
• Superoxide dismutase (SOD)


  • Converts superoxide anion radical into O2 and hydrogen peroxide
• Catalase


  • Converts hydrogen peroxide into water and O2
• Hydroxyl radicals react with lipid hydrogens -> lipid peroxidation
• Lipid peroxidation


  Damage to unsaturated fatty acids in membrane phospholipids
• Effects of Lipid Peroxidation: Increased membrane rigidity, Decreased activity of membrane bound enzymes e.g. sodium pumps, Altered activity of membrane receptors, Altered membrane permeability
• ROS injures cells in many ways

  • Oxygen therapy given to premature babies can lead to lung damage
  • Inflammation mediated by macrophages and neutrophils during infection
  • UV radiation excites molecules (photosensitisers) which transfer energy or electrons to oxygen and cause skin damage
  • Radiotherapy (Ionising Radiation) induces hydroxyl radicals
• Lipases


  Enzymes that hydrolyse lipids
• Phospholipases


  Enzymes that hydrolyse phospholipids
• Acute Haemorrhagic Pancreatitis - inflammation of the pancreas causes damage to exocrine, enzyme packed cells. These leak and damage the cells surrounding them.
• Protein denaturation


  Occurs at >42°C, leads to inflammation, ischemia, haemorrhage, oedema
• Heat Shock Proteins (chaperones)

  • Bind to denatured proteins, stop their aggregation, aid in renaturation, promote proteolytic destruction of proteins that are too damaged
• Glycation

  Maillard Reaction - Attaches sugars to proteins
• Advanced Glycation End products (AGE)

  Inhibit protein function, cause proteins to cross-link and become insoluble, generate ROS, bind to cell surface receptors (RAGE) and signal to reduce blood flow and cause inflammation
• AGE accumulate in diabetes (more sugar available), aging and chronic inflammation. Cardiovascular disease (damage to retinas and kidneys), Neurodegeneration in brain e.g. Alzheimer's through insoluble proteins blocking neuronal function, Cataracts in the lens, increased with aging and through protein deposition.
• Proteases


  Enzymes that hydrolyse proteins
• Effects of proteases

  • Arthritis - cleaved collagen in joints
  • Emphysema - cleaved elastin in the lung extracellular matrix
  • Cancer invasion - cleaved laminin allows cancer cells to migrate
• Acute intracellular oedema (hydropic change, cell swelling)


  Due to increased membrane permeability to Na+, damage to Na+/K+ pump ATPase, disrupted ATP synthesis in mitochondria
• Abnormal Storage

  Accumulation of fats and glycogen due to disruption of normal processing
• Causes of abnormal storage

  • Diabetes - increased fatty acids from adipose tissue
  • Alcohol - damages hepatocyte mitochondrial capability to oxidise triglycerides
  • Kwashiorkor severe malnutrition - inability to export triglycerides as VLDL
• Adaptive responses to stress

  DNA damage response, Heat Shock (proteotoxic) response, Hypoxia response, Antioxidant response, Unfolded Protein Response
• DNA Damage Response


  p53 detects DNA breaks, induces DNA repair and cell cycle arrest to allow repair before cell division, failure leads to apoptosis
• Proteotoxic (Heat Shock) Response


  HSF1 transcription factor activates chaperone proteins (Heat Shock Proteins) to refold denatured proteins, prevent aggregation, target damaged proteins for destruction
• Hypoxia Response

  HIF1a transcription factor induces proteins for glucose transport, glycolysis, erythrocyte production, blood vessel development to support oxygen transfer
• Antioxidant Response

  Upregulates antioxidant enzymes to rebalance redox homeostasis in response to oxidative stress and ROS
• Unfolded Protein Response (UPR)

  Induced by unfolded proteins in ER, enhances protein refolding, suppresses protein synthesis, targets damaged proteins for degradation, promotes autophagy