Ischemic cell injury
Ischemia is a decrease or complete cessation of blood circulation in organs. This process consistently develops in coronary artery disease (CAD), cerebrovascular diseases, systemic atherosclerosis, hypertension, and vasculitis.
The morphological outcome depends on the degree and duration of oxygen deprivation:
- Mild degree or chronic course lead to tissue atrophy or the triggering of programmed cell death — apoptosis.
- Acute, severe ischemia causes necrosis. Clinically, this manifests as infarction (coagulative or liquefactive) or gangrene (dry or wet).
Pathogenesis (morphogenesis): The destruction of ultrastructures begins with a state of anoxia, which triggers a lethal cascade:
- Mitochondrial damage $\rightarrow$ energy deficit.
- Activation of anaerobic glycolysis.
- Impairment of membrane ion pumps.
- Accumulation of $Ca^{2+}$ ions inside cells.
- Activation of $Ca^{2+}$-dependent phospholipases and proteases.
- Irreversible destruction of cell membranes.
Free-radical cell death
Free radicals are unstable and highly reactive ions or molecules possessing an unpaired electron in their outer electron shell. Once formed, they act as catalysts for chain reactions, generating new radicals.
Normally, they are produced in small quantities as a byproduct of cellular respiration and are immediately neutralized by natural antioxidants. Leukocytes purposefully use these reactive molecules to destroy bacteria. Pathology begins when defense mechanisms fail and radicals accumulate to toxic concentrations.
Main oxygen derivatives and enzymatic defense:
- Superoxide anion radical ($O_2^{-\bullet}$) $\rightarrow$ inactivated by the enzyme superoxide dismutase.
- Hydrogen peroxide ($H_2O_2$) $\rightarrow$ detoxified by catalase and glutathione peroxidase.
- Hydroxyl radical ($OH^{\bullet}$).
Mechanisms of cell injury:
- Lipid peroxidation (LPO): leads to fatal damage to cell membranes.
- Protein cross-linking: leads to the inactivation of vital enzymes.
- DNA strand breaks: lead to impaired transcription processes and the occurrence of mutations.
Cell death induced by ionizing radiation
Radiation injury is divided into two types. Direct injury causes immediate destruction of DNA and cellular structures. Indirect injury is associated with the production of reactive oxygen species. This gives rise to the "bystander effect," where radicals damage not only the irradiated cell itself but also neighboring intact tissues.
High-energy irradiation is lethal and causes necrosis or apoptosis. Low-energy damage provokes mutations, increasing the risk of malignant transformation (carcinogenesis).
Internal irradiation is the most dangerous. Radionuclides can enter through the respiratory tract, gastrointestinal tract, wounds, and even intact skin.
Pathogenesis using the lungs as an example: Radionuclides entering the tissue cause DNA breaks and the release of free radicals, which initiates an inflammatory syndrome. Neutrophils, macrophages, and lymphocytes rush into the interstitium and alveoli, becoming an additional source of tissue injury. Blood vessels are damaged, plasma leaks into extravascular zones (transudate), initiating fibrosis.
Small particles damage the mucosa of the bronchi, bronchioles, and alveoli, causing bronchitis, bronchiolitis, and idiopathic pulmonary fibrosis (IPF). A vicious circle is formed: developing pneumosclerosis disrupts lymph and blood circulation, which prevents the elimination of radioactive material and promotes its further accumulation.
Briefly: answers to topical questions
Which enzymes are activated upon intracellular calcium accumulation during ischemia?
During intracellular calcium accumulation in ischemia and hypoxia, a cascade of enzymatic reactions is triggered, leading to cell injury and death. Various intracellular enzymes are involved in this process.
- ATPases — accelerate ATP breakdown, exacerbating the energy deficit and impairing the function of cation pumps.
- Phospholipases (phospholipases) — break down phospholipids of cytoplasmic and mitochondrial membranes, leading to their lysis.
- Proteases (proteases) — destroy the proteins of the cytoskeleton and membranes.
- Endonucleases (endonucleases) — cause the hydrolysis of DNA and RNA, destroying the genetic material of the cell.
What non-enzymatic endogenous antioxidants exist?
Non-enzymatic endogenous antioxidants include tocopherols (vitamin E) and glutathione-containing substances.
To memorize the enzymatic defense: Superoxide anion radical is detoxified by superoxide dismutase, and hydrogen peroxide by glutathione peroxidase.
Class and exam questions
How exactly does a cell die in acute ischemia?
Anoxia results in energy depletion and impaired ion pump function. Calcium accumulates within the cell, activating $Ca^{2+}$-dependent proteases and phospholipases that destroy membranes. The outcome is necrosis (infarction or gangrene).
What role do free radicals play in a healthy organism?
They are produced in small quantities as a natural byproduct of cellular respiration. In addition, leukocytes use these reactive molecules as a weapon to destroy captured bacteria.
Why does internal lung irradiation lead to progressive pneumosclerosis?
Radionuclides cause chronic inflammation and transudate leakage, which triggers fibrosis. The proliferating connective tissue disrupts lymph and blood circulation, causing radioactive particles to be retained in the lungs even longer, completing the vicious circle.
What else to study on this topic
- Morphological differences between coagulative and liquefactive infarction
- Types of gangrene: dry and wet in acute ischemia
- Mechanisms of lipid peroxidation (LPO) of cell membranes
- The role of macrophages and neutrophils in radiation lung injury
- Idiopathic pulmonary fibrosis: stages of pathological development
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