Cellular adaptation is the ability of cells to respond to various types of stimuli and adverse environmental changes. These adaptations include hypertrophy (enlargement of individual cells), hyperplasia (increase in cell number), atrophy (reduction in size and cell number), metaplasia (transformation from one type of epithelium to another), and dysplasia (disordered growth of cells). Tissues adapt differently depending on the replicative characteristics of the cells that make up the tissue. For example, labile tissue such as the skin can rapidly replicate, and therefore can also regenerate after injury, whereas permanent tissue such as neural and cardiac tissue cannot regenerate after injury. If cells are not able to adapt to the adverse environmental changes, cell death occurs physiologically in the form of apoptosis, or pathologically, in the form of necrosis. This article provides an overview of the main cellular adaptive mechanisms and their different consequences in the human body.
- Changes experienced by cells in response to physiological (e.g., increased muscular mass after exercising, increased number of epithelial breast cells during pregnancy) or pathological (e.g., Barett esophagus due to chronic gastric acid exposure) stimuli
- These changes usually make it easier for cells to tolerate adverse environments.
- Persistent stress can lead to cell injury (e.g., critical hypertrophy of the left ventricle → myofibril damage → heart failure).
|Overview of cellular adaptation|
|Definition||Forms and examples|
|Atrophy|| || |
|Anaplasia|| || |
| || |
Early stage: characterized by reversible cellular swelling (e.g., hydropic degeneration)
Tissue hypoxia leads to decreased ATP production:
- Decreased function of Na+/K+ ATPase → diffusion of Na+ and water into the cell → ↓ passive Ca2+ efflux and cellular/mitochondrial swelling (earliest morphologic changes) 
- Disrupted Ca2+ ATPase pump activity → ↓ active Ca2+ removal from the cytoplasm into the extracellular space → Ca2+ accumulation inside the cell → activation of degradative enzymes
- Low oxygen and ATP → anaerobic respiration → ↑ lactate and ↓ intracellular pH → denaturation of proteins and clumping of nuclear chromatin
- Detachment of ribosomes and polysomes → ↓ protein synthesis
- Plasma membrane blebbing
- Aggregation of peroxidized lipids → formation of myelin figures
- Rapid loss of function in affected cells (e.g., loss of myocardial cells contractility 1–2 minutes after the onset of ischemia)
- Tissue hypoxia leads to decreased ATP production:
Late stage: characterized by irreversible membrane damage and cell death
- Degradation of phospholipids in the plasma membrane → rupture of the cell membrane → release of cytosolic enzymes (e.g., troponin, creatinine kinase) into the serum and influx of Ca2+ into the cytoplasm → activation of lysosomal enzymes and proteases (e.g., calpain) → ↑ breakdown of cellular proteins and damage to cytoskeleton → autolysis
- Rupture of lysosomes and release of lysosomal enzymes → autolysis
- Increased mitochondrial membrane permeability → release of cytochrome c from mitochondria → activation of apoptosis → cytoplasmic vacuolization
- Development of amorphous densities/inclusions in the mitochondrial matrix
- Damaged mitochondria → dysfunctional electron transport chain → ↓ ATP
- Nuclear degeneration in form of the following effects:
- Ischemic cell injury
- Reperfusion injury (see “Reperfusion injury” below)
- Metabolic and nutritional causes
- Physical causes
- Autoimmune diseases: immune responses against the body's own cells (e.g., , )
- Genetic defects
- Damage induced by medical therapy and chemicals
- Biological causes
- Decreased arterial perfusion (e.g., due to atherosclerosis, thromboembolism) in solid organs with only a single (end-arterial) blood supply (e.g., kidney, heart) → pale infarct
- Decreased venous drainage (e.g., venous occlusion, testicular torsion, ovarian torsion) in tissues with more than one blood supply (e.g., intestine, lung, liver, testes) or reperfusion (e.g., following angioplasty) → red infarct,
Shock with the following variants:
- hemorrhage) → ↓ intravascular volume → ↓ delivery of oxygen to tissue → ischemia (e.g.,
- cardiac tamponade) → ↓ left ventricular function → ↓ forward flow of blood → ↓ delivery of oxygen to tissue → ischemia (e.g.,
- septic, neurogenic, and ) → systemic vasodilation → peripheral pooling of blood → ↓ delivery of oxygen to tissue → ischemia (e.g.,
- See “Shock” for more specific details.
|Organs most susceptible to ischemia|
|Organ||Specific structure||Clinical significance|
|Kidney|| || |
Ischemic tolerance time: the time after which ischemia causes irreversible tissue damage
- Skin: 12 h
- Musculature: 6–8 h
- Neural tissue: 2–4 h
- A type of cell damage caused by the formation of free radicals within cells and tissues 
- Free radicals form when chemical bonds are broken and each fragment keeps one electron in the outer shell, in redox reactions, and when one radical is cleaved to produce another radical. 
- Both endogenous and exogenous sources can lead to the generation of free radicals. 
- Endogenous sources
- Exogenous sources
Free radicals can cause damage to a variety of structures:
- DNA: induce breakage
- Cell membranes: direct damage and lipid peroxidation → ↑ permeability
- Mitochondrial membranes: lipid peroxidation and formation of transition pores → ↑ permeability
- Cellular proteins: modification
- Microvasculature: microvascular injury → ↑ permeability of capillaries and arterioles → ↑ diffusion and fluid filtration → tissue swelling
- Furthermore, free radicals induce a number of reactions:
- Recruit and activate platelets → ↑ coagulation
- Recruit and activate WBCs → worsening of immune response started by ischemia
- Elimination of free radicals can occur via numerous mechanisms:
Oxygen toxicity 
- Definition: reintroduction of oxygen into a previously ischemic environment → activation of endothelial cells → generation of free radicals by leukocytes → damage (e.g., a )
- Complications (depending on the location of ischemia/reperfusion injury)
- Monitoring and symptomatic treatment
- Amputation if the affecting limb that is beyond recovery
Metal storage diseases
Overview of cell death
|Overview of apoptosis and necrosis|
|Pathophysiology|| || |
- Definition: programmed cell death (physiological cell turnover)
- DNA damage
- Hypoxia; and other types of exogenous damage to the cell (free radicals, irradiation, toxins)
- Growth factor withdrawal
- Specific signals such as TNF-alpha and ligands (TRAIL, FasL) activate the apoptotic program of the cells via binding to death receptors (DR 4/5, Fas, TNF-R).
- Cytotoxic T cells, which recognize a pathogen on the target cell
- Shrunken and irregularly shaped cells with condensed chromatin and membrane blebbing
- The cell detaches from other cells or the extracellular matrix.
- The basophilic nucleus undergoes the following changes:
- The eosinophilic cytoplasm and cell organelles form small bubbles and the endonucleases degrade the chromatin in the nucleus, resulting in nuclear fragmentation and apoptotic bodies that are phagocytized by macrophages.
- DNA laddering (fragments in multiples of 180 base pairs) is seen on gel electrophoresis; and can be used as a sensitive marker for apoptosis.
- Apoptosis can be initiated via two different pathways: the extrinsic pathway (through external stimuli) or the intrinsic pathway (through internal stimuli).
- General sequence of events: stimulus → activation of initiator caspases → activation of executioner caspases → apoptosis
- Caspases: enzymes from the group “Cysteine-ASpartic ProteASES” that cleave proteins and peptides and attack the cell membrane, nucleus, and cytoplasm
- Caspase 8 is not only a part of the extrinsic pathway but also stimulates the intrinsic pathway by altering the permeability of the inner mitochondrial membrane.
Extrinsic pathway (death receptor pathway)
Can be activated via 2 mechanisms:
Ligand receptor interaction
Extracellular ligands (e.g., TNF-α, TRAIL, or FasL) bind to a death receptor on the cell surface.
- Interaction between Fas (CD95) and Fas ligand (FasL) is crucial for thymic medullary negative selection. Defective interactions may cause autoimmune lymphoproliferative syndrome, lymphadenopathy, hepatosplenomegaly, and autoimmune cytopenias.
- In general, Fas mutations produce an increased number of circulating self-reacting lymphocytes due to defective clonal selection.
- The receptor-ligand complex activates initiator caspases such as caspase 8.
- Initiator caspase activates executioner caspases such as caspase 3.
- Extracellular ligands (e.g., TNF-α, TRAIL, or FasL) bind to a death receptor on the cell surface.
- Immune cell activation: The release of perforin and granzyme B from cytotoxic T cells activates executioner caspases.
Intrinsic pathway (mitochondrial pathway)
- Involved in tissue remodeling (e.g., during embryogenesis)
- p53 is activated through DNA damage (e.g., hypoxia, chemical toxins, radiation) or the withdrawal of regulating factors from a proliferating cell population (e.g., IL-2 after completion of an immunologic reaction → apoptosis of effector cells).
p53 causes an intracellular increase of proapoptotic proteins of the Bcl-2 family (e.g., Bax, Bad, Bak).
- The Bcl-2 family is composed of numerous proteins that can have a proapoptotic (e.g., Bad, Bax, and Bak) or antiapoptotic (e.g., Bcl-2; , Bcl-xL) effect.
- Bcl-2 can prevent apoptosis by keeping the mitochondrial membrane intact, thereby preventing cytochrome c release.
- On the other hand, Bcl-2 overexpression (e.g., in follicular lymphoma) promotes tumorigenesis since it decreases caspase activation.
- Proapoptotic proteins increase the permeability of the mitochondrial outer membrane (e.g., via the formation of a membrane channel by the heterodimer Bax/Bad).
- Cytochrome c is released from the inner mitochondrial membrane and enters the cytosol.
- Cytochrome c binds to APAF-1 ( ) in the cytosol, forming a wheel-like structure known as an apoptosome.
- The complex of cytochrome c and APAF-1 converts procaspase 9 into active caspase 9.
- Caspase 9 activates executioner caspases such as caspase 3.
Abnormal regulation of apoptosis
- Follicular lymphoma: Bcl-2 (regulator of apoptosis) on chromosome 18 is translocated to the immunoglobulin heavy chain locus on chromosome 14 → overexpression of Bcl-2 → dysfunctional apoptosis of abnormal lymphocytes → tumorigenesis
- Burkitt lymphoma: translocation t(8;14) → c-myc (nuclear regulator protein) on chromosome 8 translocation to the immunoglobulin heavy chain locus on chromosome 14 → overexpression of c-myc and Bcl-2 → lymphoma
Cervical cancer: precipitated by infection with high-risk strains of HPV (e.g., HPV-16 and HPV-18)
- HPV encodes for protein E7 which binds to Rb → inability of Rb to bind to E2F and arrest the cell cycle → proliferation of abnormal cells → low-grade dysplasia → high-grade dysplasia → carcinoma in situ → invasive cervical carcinoma
- HPV encodes for protein E6 which binds to p53 → inactivation of p53 → inability of p53 to arrest the cell cycle and to activate DNA repair genes → proliferation of abnormal cells → low-grade dysplasia → high-grade dysplasia → carcinoma in situ → invasive cervical carcinoma
- Definition: : collective term for unprogrammed cell death and tissue destruction
- Not physiologically induced
- Always associated with an inflammatory reaction (in contrast to apoptosis)
- Pathophysiology: injury → cell damage (damaged plasma membranes) → nuclear changes (pyknosis, karyorrhexis, karyolysis) → cell swelling (oncosis), cell wall protrusions, cell organelle degradation, and protein denaturation → cell burst → leak of intracellular components → inflammation → degradation of the necrotic tissue by leukocytes → organization of granulation tissue
Types of necrosis
|Characteristics of necrosis|
|Coagulative necrosis|| || |
|Liquefactive necrosis|| || |
|Caseous necrosis|| |
|Fat necrosis|| |
|Gangrenous necrosis|| |
- Definition: increased storage of triglycerides, cholesterol, and complex lipids in cells
- Occurrence: liver, heart, muscles, kidneys
- Histological staining: Sudan stain or oil red O staining, unfixed or formalin-fixed, frozen sections
|Overview of calcification|
|Metastatic calcification||Dystrophic calcification|
|Involved tissues|| |
|Etiology|| || |
|Serum calcium findings|| || |
- Hyalinization: replacement of normal tissue by proteins that have an eosinophilic, homogenous, translucent appearance on H&E staining
|Characteristics of intracellular hyaline|
|Mallory bodies||Inclusion bodies within the cytoplasm of hepatocytes that contain damaged intermediate filaments and appear eosinophilic (pink) on H&E stain||Most common in alcoholic liver disease|
|An eosinophilic remnant of apoptotic hepatocytes with pyknosis||Particularly in yellow fever and viral hepatitis|
|Schaumann bodies||Round calcium and protein inclusions in the cytoplasm with laminar stratification||Granulomas in sarcoidosis|
|Russell bodies||Accumulation of immunoglobulins||Plasma cells in plasmacytoma or chronic inflammation|