Excessive Activation of Hydrolases
Exposure to various pathogenic factors, such as uncompensated acidosis, triggers the release of aggressive enzymes from lysosomes. This initiates a cascade of self-destruction within the cell.
A key role in this pathogenesis is played by a significant increase in the activity of lipases, phospholipases, and proteases. All of their pools are activated: membrane-bound, free (solubilized), and lysosomal. This leads to the intense hydrolysis of vital cellular substrates:
- Phospholipids of the lipid bilayer;
- Glycoproteins;
- Cytoskeletal proteins;
- The cell's own native enzymes.
The result of this enzymatic aggression is a sharp increase in plasma membrane permeability and a critical decline in the activity of remaining cellular enzymes.
Detergent Effect of Amphiphilic Compounds
Concurrently with hydrolase activation and lipid peroxidation, amphiphiles accumulate within the cell. The primary accumulating compounds include free fatty acids, lipid hydroperoxides, and various glycerophospholipids (phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines).
The pathogenesis of injury relies on their amphiphilicity—a unique ability to insert and rigidly anchor simultaneously into both the hydrophobic and hydrophilic zones of membranes. The process unfolds in several stages:
- Massive insertion of amphiphiles into the membrane.
- Formation of extensive lipid clusters.
- Creation of micro-tears.
- Complete destruction of membrane structures.
Repair Failure and Macromolecular Conformation Changes
Under normal conditions, a cell continuously repairs its structures. However, under the influence of damaging factors, these processes are suppressed. Both the reparative resynthesis of altered molecules (lipids, proteins, glycoproteins) and the de novo synthesis of membrane components are impaired. Defective repair exponentially magnifies the scale of damage to the membrane apparatus.
Physicochemical shifts induce modifications in the normal spatial structure of macromolecules. The tertiary and quaternary structures of proteins, lipoproteins, and glycoproteins are altered. This leads to the distortion or complete loss of their functions, including the suppression of vital biologically active substances such as enzymes, hormones, and cytokines.
Osmotic Overstretching and Rupture
Against the background of metabolic disorders, ions and hydrophilic molecules of organic compounds—such as lactate, pyruvate, glucose, and albumins—accumulate excessively inside the cell.
This causes a sharp rise in intracellular osmotic and oncotic pressure. Hyperhydration ensues, as water rushes inward, causing swelling of the cell and its organelles. The core mechanism of this injury involves the critical overstretching of membranes, inevitably culminating in their mechanical rupture and cell death.
Ion and Fluid Imbalance
Ionic imbalance occurs secondarily to or concurrently with membrane damage in the setting of energy depletion. Transmembrane transport of key ions (K⁺, Na⁺, Ca²⁺, Mg²⁺, Cl⁻) is severely disrupted. Membrane defects and impaired membrane ATPases lead to the following consequences:
- Dysfunction of plasma membrane Na⁺/K⁺-ATPase causes cellular loss of K⁺ and an excessive accumulation of Na⁺ cations in the cytosol.
- Malfunction of the Na⁺/Ca²⁺ exchanger (which normally exchanges two inward Na⁺ for one outward Ca²⁺) and Ca²⁺-ATPases leads to a fatal increase in intracellular Ca²⁺ concentration.
- Disrupted cation distribution inevitably alters intracellular anion content (Cl⁻, OH⁻, HCO₃⁻).
The main consequences of these shifts are hypo- or hyperhydration and severe electrogenesis impairment in excitable tissues (disrupted excitation, action potential propagation, and electromechanical coupling).