Cell Alterations, Injury, & Homeostasis

Cell Alterations

• Cells that are subjected to physiological stress or pathogenic stimuli undergo a series of morphological and physiological adaptations to preserve their viability and modulate their function.
• When adaptation limits are exceeded, a sequence of events known as cellular injury follows.
• Cellular injury is reversible to a certain point.
• Injury can become irreversible after persistent stimuli

Cellular Injury & Homeostasis

• Homeostasis refers to the ability to supply normal physiological demands involving genetic programming that determines metabolism, differentiation, and specialization related to the surrounding environment.

Cellular Injury Factors

• Hypoxia
• Physical agents
• Chemical agents and drugs
• Infectious agents
• Immunological reactions
• Genetic disorders
• Nutritional imbalances

Mechanisms of Cellular Injury

• Four intracellular systems are particularly vulnerable including:
  • Maintenance of cell membrane integrity.
  • Aerobic respiration involving oxidative phosphorylation and ATP production
  • Synthesis of enzymatic and structural proteins.
  • Preservation of the integrity of the genetic content of the cell.
• Repercussions depend on the type, duration, and severity of the harmful stimuli, as well as the cell's type, condition, and adaptability.
• Morphological changes become evident only after critical biochemical systems have been disrupted

The principle biochemical mechanisms and sites of damage in cellular injury include:

• ATP, multiple effects downstream
• mitochondrial damage
• increased reactive oxygen species.
• damage to lipids, proteins and DNA
• entry of Ca2+, increased permeability mitochondrial
• activation of various enzymes
• damage to the membrane
• plasma membrane
• lysosome membrane
• protein misfolding, DNA damage
• activation of pro-apoptotic proteins

Processes important in mediating injury and cell death.

• Oxygen and oxygen-derived free radicals.
• Intracellular calcium and loss of calcium homeostasis
• ATP depletion
• Defects in membrane permeability.

Cell Membrane Injuries

• Reversible injuries include;

• Alteration of villi due to increased intracellular water and changes in the cytoskeleton.

• Formation of myelin sheath figures due to digital impression/alteration of membrane components of lipids and proteins.

• Irreversible injuries consist of;

• Formation of bubbles on the surface.

• Rupture owing to reduced protein synthesis and altered fatty acids in phospholipids

• Loose intercellular junctions, or their disappearance with structural alterations of the membrane.

Mitochondria Injuries

• Mitochondrial matrix condensation is caused by O2 deficiency.
• Mitochondrial swelling of the inner chamber leads to a reduction in the number of crests that flatten out until complete disappearance, or crestolysis.
• Electrodense granules in the matrix are composed of floccular material consisting of lipo-protein material from the disintegration of the inner membrane, or of calcium salt crystals.
• Mitochondrial swelling that preserves the architecture of the crests represents reversible injury.
• The loss of crests including the appearance of non-crystalline structures signifies irreversible injuries.

Endoplasmic Reticulum Injuries

• Dilation of the cisternae, and proliferation induced by substance metabolized in the smooth endoplasmic reticulum of cells experiencing reversible injuries
• Enzyme systems increase activities when overloaded with the substrate.
• An example would be hepatocites of chronic alcoholics

Lysosome Injuries

• Reversible injuries only cause swelling, but no change in permeability to hydrolases.
• Irreversible injury leads to cell death, Lysosomal enzymes are released into cytosol

Nucleus Injuries

• Nuclear membrane injuries occur in two ways:
  • Dilatation of the perinuclear cistern as a consequence of osmotic expansion of the cell.
  • Thickening of the inner membrane.
  • Infolding and tortuosity, inclusions in the perinuclear cistern, and qualitative and quantitative variations in the pores are all signs.
• Injuries involving changes in chromatin is caused when reduced intracellular pH induces the upspiralization of chromatin, which associates with histones as it accumulates along the membrane

Morphology of Reversible Cell Injury

• Fatty alteration
• This can occur for several reasons including alcoholism, diabetes, nutritional deficiency, obesity, and poisoning in organs like the heart, liver, and kidney.
• Hyaline change
• Accumulation is not specific to protein material.
• Accumulation of exogenous pigments takes place in the lung due to carbon, silica, and iron as well as lead arising from plumbism, and silver arising from argyria
• Accumulation of endogenous pigments happens:
• Via Melanin.
• From Bilirubin due to cholestasis and hepatic diseases.
• Through Lipofuscin or pigment deposited in the cell that serves to detect the time of cell life
• Pathological Calcification.
• Metastatic calcification caused by hypercalcemia, hyperparathyroidism, osteolytic tumors.
• Dystrophic calcification from previously injured tissue in areas of trauma, tuberculosis, scars in cardiac valves and atherosclerotic lesions

Necrosis Morphology

• Necrosis is the sum of the degradative changes in the intracellular space after cell death.
• Cell death proceeds autolysis in the living body.
• Autolysis refers to the process of degradation reactions caused by the cell's intracellular enzymes

Types of Necrosis

• Coagulative
• Liquefactive
• Gangrenous
• Caseous
• Fat
• Fibrinoid

Coagulative Necrosis

• Frequently results from an interruption of the blood supply of organs such as the heart and kidney.
• Tissue architecture is usually preserved, except for nuclear alterations, and cytoplasm with a coagulated substance
• (ie. acidophilic/granular gel).

Liquefactive Necrosis

• Enzymatic liquefaction of necrotic tissue.
• Frequently happens in the brain, adrenal glands, gastric mucosa due to blocked blood supply & bacterial infection.
• Necrotic zones become soft, semi-fluid, or liquid due to lysosomal enzymes.

Caseous Necrosis

• Necrotic area assumes a macroscopic texture similar to cheese.
• Shares characteristics between coagulative and liquefactive necrosis.
• Can be attributed to granulomas in tuberculosis.
• Cell contours & structural details are lost without tissue liquefaction.

Gangrenous Necrosis

• Occurs when external agents act upon necrotic tissue.
• Desiccation in contact with air leads to dry gangrene with a parchment-like texture.
• Anaerobic microorganisms invade necrotic tissue and produce foul-smelling gases.
• Gas accumulates in bubbles between dead and healthy tissue, resulting in wet or putrid gangrene.
• Gas gangrene is secondary to contamination from Clostridium bacteria.

Fat Necrosis

• Pancreatic autolysis is caused by digestive enzymes following trauma.
• Necrosis of fat cells associated with acute inflammation will form calcified deposits and histiocytes.

Fibrinoid Necrosis

• Deposition of proteinceous material in artery walls, generally as a result of immune-mediated vasculitis.

Gummatous Necrosis

• Variety of coagulation necrosis in which the necrotic tissue takes on a compact, elastic appearance like rubber (gum), or a viscous fluid like gum arabic.
• Often observed in late or tertiary syphilis (syphilitic gumma).