Cellular Injury & Adaptations

Cellular adaptations

Overview. Under stress, cells change their size, number or type. The four adaptations are hypertrophy (bigger cells), hyperplasia (more cells), atrophy (smaller or fewer cells) and metaplasia (one adult cell type replaced by another). Dysplasia, disordered pre-malignant growth, is taught alongside them but is not a true adaptive response.

Hypertrophy. Cell SIZE increases through synthesis of more organelles and structural protein, without new cells. It is the only way permanent tissues, such as cardiac and skeletal muscle, can grow. Example: left ventricular hypertrophy from hypertension or aortic stenosis.

Hyperplasia. Cell NUMBER increases in tissues capable of division. It may be physiologic, as in the pregnant uterus (together with hypertrophy), or pathologic, as in endometrial hyperplasia from unopposed estrogen. Pathologic hyperplasia can progress to dysplasia and cancer; benign prostatic hyperplasia (BPH) is the classic exception that does NOT.

Atrophy. Cell size and/or number decreases. Proteins are degraded by the ubiquitin-proteasome pathway and organelles by autophagy, and apoptosis reduces cell number. Triggers are disuse, denervation, decreased blood supply, loss of hormonal or trophic signals, and aging. Examples are the muscle of an immobilized limb and the brain in Alzheimer disease.

Metaplasia. One adult cell type is replaced by another better suited to the stress, and the change is reversible if the stimulus is removed. In Barrett esophagus, acid reflux converts squamous epithelium to intestinal-type columnar epithelium with goblet cells. In smokers, bronchial pseudostratified columnar epithelium becomes squamous. Vitamin A deficiency drives keratinizing metaplasia. If the insult persists, metaplasia can progress to dysplasia, as when Barrett esophagus leads to adenocarcinoma.

Dysplasia. This is disordered growth with loss of uniformity and tissue architecture plus nuclear changes: hyperchromasia and a high nuclear-to-cytoplasmic ratio. It is pre-malignant, but mild to moderate dysplasia is still REVERSIBLE if the stimulus is removed; severe dysplasia often is not. Unchecked, it progresses to carcinoma in situ (full-thickness dysplasia with an intact basement membrane) and then invasive carcinoma.

Reversible versus irreversible injury

Reversible injury. Ischemia depletes ATP, the Na+/K+ ATPase fails, and sodium and water enter the cell. Cellular (hydropic) swelling is therefore the hallmark. Other features are ribosome and polysome detachment (less protein synthesis), plasma membrane blebbing, mitochondrial swelling and fatty change. All of them reverse if perfusion returns.

Irreversible injury. The point of no return is severe mitochondrial damage (loss of membrane potential, vacuolization, Ca²⁺-rich densities), massive cytosolic Ca²⁺ influx that activates destructive enzymes (phospholipases, proteases, endonucleases), and rupture of the plasma and lysosomal membranes. The nucleus then undergoes pyknosis, karyorrhexis and karyolysis. Ruptured membranes release intracellular proteins into the blood, the basis of serum markers such as troponin after myocardial infarction.

Mechanisms of injury

Free radicals. Reactive oxygen species, including superoxide (O₂•⁻), hydrogen peroxide (H₂O₂) and the hydroxyl radical (•OH), cause lipid peroxidation of membranes, DNA damage and protein cross-linking. Sources include ischemia-reperfusion, radiation, the Fenton reaction (Fe²⁺ converts H₂O₂ into •OH), CCl₄ in the liver, acetaminophen and the oxidative burst of neutrophils. Defenses are superoxide dismutase, catalase, glutathione peroxidase and the antioxidant vitamins A, C and E.

CCl₄ is metabolized to a radical that causes hepatocyte fatty change. Retinopathy of prematurity arises from oxygen free radicals in premature infants given high oxygen.

Reperfusion injury. Restoring blood flow to ischemic tissue can paradoxically increase injury through a burst of oxygen free radicals, calcium overload, and complement- and neutrophil-mediated inflammation. This explains part of the myocardial damage after reperfusion and the CNS damage after resuscitation.

Who dies first. Neurons tolerate ischemia worst, with irreversible injury in 3–5 min; the hippocampus, cerebellar Purkinje cells and neocortex are most vulnerable. Cardiac myocytes and the proximal renal tubule follow (~30 min). In global hypoperfusion, watershed zones and the subendocardium suffer most.

Necrosis

Definition. Necrosis is enzymatic death of groups of cells with membrane rupture and inflammation. The nucleus dies in a fixed order:

The brain is the exception: ischemia there causes liquefactive, not coagulative, necrosis.

Red and pale infarcts

Red (hemorrhagic) infarcts. These occur in loose tissues with a dual or collateral blood supply, or after reperfusion, because blood seeps into the dead zone: lung, intestine, testis, liver and ovary. "REDLIT" covers the classic trio of Lung, Intestine and Testis.

Pale (anemic) infarcts. These occur in solid organs with a single end-arterial supply: heart, kidney and spleen. They are wedge-shaped, with the apex at the occluded vessel, and have sharp margins.