Cellular injury

ACEM Primary

Table of Contents

Cellular Adaptation

Hypertrophy = increase in size of cells thus increase in size of organ
- Caused by increased functional demand or stimulation by hormones/ growth factors
- Synthesis of more cellular proteins
- Adaptation to stress can progress to functionally significant cell injury if stress not relieved
- Eg. striated muscle with exercise, cardiac muscle with chronic haemodynamic overload or uterus in pregnancy
- 2 main biochemical pathways for muscle: phosphoinositide 3- kinase/ Akt pathway and G protein coupled receptors
- Can also apply to organelles eg. Hypertrophy of SER in hepatocytes of patients on barbiturates -> increased number of enzymes to metabolise the drug -> reduced response over time

Hyperplasia = increase in number of cells
- Takes place in cell population capable of dividing, growth factor driven
- Physiological
  - Hormonal hyperplasia = increases functional tissue when needed. Eg: Proliferation of glandular epithelium of female breast at puberty and pregnancy
  - Compensatory hyperplasia = increases tissue mass after damage or resection. Eg: Regeneration of liver after resection
- Pathological
  - Excess hormones or growth factors Eg: Endometrial hyperplasia due to imbalance in estrogen and progesterone or prostatic hypertrophy due to increased androgen -> remain controlled as nil gene mutations, but is a “fertile soil” for these to arise and cause cancer
  - Viral infections Eg: HPV causing mucosal lesions

Atrophy = reduced size of an organ or tissue resulting from decrease in cell number and size
- Decreased protein synthesis and increased degradation via ubiquitin- proteasome pathway
- Increased autophagy (self eating)
- Early atrophic cells have diminished function -> may progress to apoptosis
- Physiologic:
  - Embryonic structures such as notochord/ thyroglossal duct or post partum uterus
- Pathologic:
  - Decreased workload – muscle following fractured bone being immobilised
  - Loss of innervation – damaged nerves to skeletal fibers
  - Loss of blood supply – brain “senile atrophy” due to atherosclerosis
  - Inadequate nutrition – marasmus
  - Loss of endocrine stimulation – menopause, atrophy of breast/ vaginal epithelium/ endometrium
  - Pressure – enlarging benign tumour compressing on surrounds

Metaplasia = reversible change where one differentiated cell type is replaced by another -> adaptive substitution for survival
- Reprogramming stem cell to new pathway via cytokines/ growth factors/ ECM components
- Most common epithelial metaplasia is columnar to squamous
  - Eg. Respiratory tract: Chronic irritation by cigarettes -> metaplasia from columnar to squamous epithelium -> loss of mucous secretory function -> increased risk of infection
  - Eg. Oesophagus: Gastric acid irritation -> metaplasia from squamous to intestinal like columnar cells
- Factors that predispose to metaplasia -> malignant transformation if persistent

Reversible cell injury
- Reduced oxidative phosphorylation -> depletion in ATP -> change in ion concentration + water influx = cell swelling
- 2 features: cellular swelling (loss of ionic/ fluid homeostasis) and fatty change (lipid vascuoles)
Irreversible cell injury
- Lysosomal membrane damage and leakage of proteolytic enzymes into cytoplasm
- Nuclear fragmentation
- Necrosis
Cell death
- Necrosis = severe membrane damage -> lysosomal enzymes enter and digest cell -> cellular components leak out.
  - Pathologic process
  - Increased eosinophilia (H&E stains) due to loss of RNA and increase in denatured cytoplasmic proteins (bind red dye)
  - Whorled phospholipid masses ‘myelin figures’
  - Nuclear changes = loss of DNA: karyolysis (enzymatic degradation) + pyknosis (nuclear shrinkage and basophilia) + karyorphexis (fragmentation)
  - Patterns:
    - Coagulative (firm texture eg. Kidney infarct)/ Gangrenous (limb)
    - Liquefactive (liquid viscous mass eg. Cerebral infarct)
    - Caseous (cheese- like eg. TB lung infection)
    - Fat necrosis (acute pancreatitis)
    - Fibrinoid necrosis (immunologic reactions)
- Apoptosis = cellular proteins beyond repair -> nuclear dissolution (fragmentation of cell WITHOUT loss of membrane integrity) + removal of cellular debris
  - Physiologic process
- Autophagy

Depletion of ATP
- ATP produced in 2 ways:
  1. Oxidative phosphorylation of adenosine and diphosphate -> reduction of oxygen by electron transfer system of mitochondria
  1. Glycolytic pathway using glucose to generate ATP
- Reduced supply of oxygen/ nutrients + Mitochondrial damage + toxins (cyanide) -> ATP depletion
- Tissues with greater glycolytic capacity (liver) are able to survive loss of oxygen/ decreased oxidative phosphorylation better than tissues with limited glycolytic capacity (brain)
- Irreversible damage to mitochondrial and lysosomal membranes = necrosis

Mitochondrial damage
- Sensitive to cytosolic Ca2+, reactive oxygen species and hypoxia
- 2 consequences of damage:
  - Formation of mitochondrial permeability transition pore -> loss of membrane potential -> cannot make ATP
  - Sequester cytokines and cytochrome C within membranes -> indirectly activate apoptosis

Influx of calcium and loss of calcium homeostasis
- Cytosolic Ca2+ usually maintained at low levels compared to extracellular levels
- Ischaemia/ toxins -> release Ca2+ from intracellular stores + influx across damaged membrane:
- Oxidative stress due to accumulation of ROS
  - Oxygen derived free radicals = chemical species which have unpaired electron in an outer orbit -> unstable configuration -> release energy through reactions with adjacent molecules -> damage to cell membranes and nuclei
  - ROS are produced normally in cells at low concentrations during mitochondrial respiration and energy generation, removed by cellular defense systems
- Generation of free radicals:
  - Reduction- oxidation reactions during normal metabolic processes
  - Absorption of radiant energy (UV light, XR)
  - Inflammation: Rapid bursts of ROS produced by activated leukocytes
  - Enzymatic metabolism of exogenous chemicals/ drugs
  - Transition metals (iron and copper) reduced to participate in Fenton reaction
  - Nitric oxide
- Removal of free radicals:
  - Decay spontaneously
  - Antioxidants can block initiation or inactivate
  - Minimise levels of reactive transition metals
  - Enzymes:
    - Catalase
    - Superoxide dismutase (SODs)
    - Glutathione peroxidase
- Pathologic effects:
  - Lipid peroxidation in membranes
  - Oxidative modification of proteins
  - Lesions in DNA
- Free radicals can trigger necrosis OR apoptosis

Defects in membrane permeability
- Mechanisms of membrane damage:
  - Free radicals
  - Decreased phospholipid synthesis
  - Increased phospholipid breakdown
  - Cytoskeletal abnormalities
- Lead to mitochondrial/ plasma membrane damage -> apoptosis + lysosomal leakage/ activation of enzymes which digest proteins -> necrosis

Damage to DNA and proteins
- Drugs, Radiation, Oxidative stress -> severe DNA damage -> apoptosis

Last Updated on August 19, 2021 by Andrew Crofton