Abstract

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 learning card provides an overview of the main cellular adaptive mechanisms and their different consequences in the human body.

Cellular adaptation

Definition: Changes experienced by cells in response to physiological or pathological stimuli. These changes usually make cells more tolerable an adverse environment to which they are exposed.

	Definition	Forms and examples
Atrophy	Hypotrophy (simple atrophy): tissue degeneration caused by a decrease in protein synthesis and cell content (e.g., organelles, cytoskeleton) Numerical atrophy: reduction in cell number Degradation of cytoskeletal proteins occurs via the ubiquitin-proteasome pathway Electron microscopic examination shows the presence of autophagosomes	Involution: organs are temporarily enlarged followed by degradation via atrophic processes (e.g., thymus, breast) Senile atrophy: due to the physiological aging of cells Affects all organs; includes the formation of lipofuscin deposits (especially in the heart and liver) Pathological atrophy Generalized atrophy: catabolism, malnutrition, cancer anorexia-cachexia syndrome Localized atrophy: inactivity, pressure induced atrophy, hormonal (e.g., osteoporosis), ischemia (oxygen/substrate shortage), chronic inflammation Neurogenic atrophy: muscular atrophy via degeneration of neuromuscular transmission
Hypertrophy	Increased tissue size via enlargement of cells caused by an increase in organelles, and structural proteins.	Physiological hypertrophy Increased muscle mass through sport Uterus enlargement due to hormonal changes Pathological hypertrophy: hypertrophic cardiomyopathy due to arterial hypertension
Hyperplasia	Increased tissue size via an increase in cell numbers	Physiological hyperplasia Estrogenic stimulation of the endometrium during the menstrual cycle Reactive bone marrow hyperplasia in hemolytic anemias Pathological hyperplasia Endometrial hyperplasia due to excess estrogen stimulation → can progress to dysplasia and cancer
Anaplasia	Loss of morphological features of malignant cells → Resemblance to normal cells of a particular tissue where tumor cell originated from is lost.	Malignant transformation
Metaplasia	Tissue transformation from one type of epithelium to another (e.g., squamous metaplasia)	Physiological metaplasia: cervical ectopy Pathological metaplasia Occurs as a response to chronic chemical or physical stimuli May completely regress or lead to malignant transformation (considered precancerous) Examples Intestinal metaplasia (Barrett metaplasia) Squamous metaplasia of the bronchi due to smoking → ciliated pseudostratified columnar epithelium is replaced by stratified squamous epithelium Squamous metaplasia of the bladder due to Schistosoma infection, urinary calculi, or indwelling catheters
Dysplasia	Disordered growth of epithelium (abnormally frequent mitotic figures, loss of cell orientation, size, and shape) Precancerous: can progress to carcinoma in situ	Congenital dysplasia Acquired dysplasia
Proliferation	Rapid division and increase in the number of cells	Labile tissue: short-lived, rapidly dividable cells with constant cell division or renewal. Primarily established by replication of stem cells in e.g., mucous membranes in gastrointestinal and respiratory tract, skin, hematopoietic tissue Permanent tissue: cells with little to no replication throughout life. Examples: cardiac muscle, neurons Stable tissue: expandable tissue Examples: exocrine and endocrine glands, connective tissue. liver and renal parenchyma, bones
Regeneration	Complete regeneration: Tissue loss is both homogeneously functionally and structurally replaced.	Complete recovery/healing: only possible in labile and minimally damaged stable tissue (e.g., regeneration of skin without scarring).
Regeneration	Incomplete regeneration: Tissue loss is replaced by tissue of an inferior quality.	Partial recovery/repair: occurs in permanent tissue and stable tissue with pronounced damage (e.g., healing of skin with scar formation)

Causes of cell damage

Ischemic cell injury: Injury due to a lack of oxygen
- Atherosclerosis
- Decreased venous drainage (see ischemia for details)
- Variable vulnerability: organs have different oxygen demand, oxygen expenditure, and susceptibility to hypoxic damage.
Metabolic and nutritional causes
- Malnutrition
  - Marasmus → decreased intake of calories
  - Kwashiorkor → decreased intake of protein
- Excess calories: obesity → atherosclerosis → ischemic cell injury
- Vitamin deficiencies: see the learning card vitamins for more information.
- Impaired metabolism of glucose or ATP synthesis
Physical causes
- Mechanical
  - Abrasion, laceration, contusion
  - Stab or gunshot wound
  - Fracture
- Thermal
  - Hypothermia (e.g., frostbite)
  - Hyperthermia (e.g., burns)
- Electrical: electrical injury
- Radiation
  - Ionizing radiation, e.g., radiation
  - UV radiation, e.g., sunburn, basal cell carcinoma
- Air pressure: from explosions
Autoimmune diseases: immune responses against the body's own cells (e.g., SLE, RA)
Genetic defects: misdirect cell metabolism (e.g., cystic fibrosis (CFTR gene), hemophilia A (Xq28 gene), α1-antitrypsin deficiency)
Damage induced by medical therapy and chemicals
Biological causes

Ischemia

Definition: Decreased blood supply that cannot meet the oxygen demands of an organ or tissue.
Pathophysiology
- Decreased arterial perfusion → e.g., atherosclerosis, thromboembolism
- Decreased venous drainage → e.g., Budd-Chiari syndrome, testicular torsion, ovarian torsion
- Shock
  - Hypovolemic shock (e.g., hemorrhage) → decreased intravascular volume → decreased delivery of oxygen to tissue → ischemia
  - Cardiogenic shock (e.g., cardiac tamponade) → decreased left ventricular function → decreased forward flow of blood → decreased delivery of oxygen to tissue → ischemia
  - Distributive shock (e.g., septic, neurogenic, and anaphylactic shock) → systemic vasodilation → peripheral pooling of blood → decreased delivery of oxygen to tissue → ischemia
  - For more specific details see the learning card on shock.

Organs most susceptible to ischemia
Organ	Specific structure	Clinical significance
Brain	Watershed areas Anterior cerebral artery Middle cerebral artery Posterior cerebral artery Purkinje cells (cerebellum) Pyramidal cells (hippocampus and neocortex)	Ischemic stroke
Heart	Subendocardial tissue of the left ventricle	Stable angina CAD Unstable angina NSTEMI STEMI
Kidney	Proximal tubule (straight segment in the medulla) Thick ascending limb (in the medulla)	Acute kidney injury
Liver	Region around the central vein (zone III)	Centrilobular necrosis (e.g., Budd-Chiari syndrome, shock liver in trauma)
Bowel	Watershed areas Splenic flexure → confluence of blood supply between the SMA and IMA Rectum → confluence of blood supply between the superior rectal artery (branch of the IMA) and the middle and inferior rectal artery	Ischemic colitis (colonic ischemia) Acute mesenteric ischemia Chronic mesenteric ischemia

References:^[1]

Overview of cell death

Cell injury: cellular damage due to internal and external environmental changes
- Early stage (reversible)
  - Swelling of the cell; (e.g., hydropic degeneration; ): tissue ischemia → decreased ATP production → decreased Na⁺/K⁺ ATPase and Ca²⁺ pump activity → diffusion of Na⁺ and water into the cell → cellular swelling
  - Clumping of nuclear chromatin
  - Detachment of ribosomes and polysomes → decreased protein synthesis
- Late stage (irreversible) → results in cell death
  - Degradation of phospholipids in the plasma membrane → rupture of the cell membrane → release of cytosolic enzymes into the serum and influx of Ca²⁺into the cytoplasm → activation of lysosomal enzymes → autolysis
  - Rupture of lysosomes and release of lysosomal enzymes → autolysis
  - Increased mitochondrial membrane permeability
  - Nuclear changes
    - Pyknosis: shrinkage of the nucleus due to chromatin condensation
    - Karyorrhexis: fragmentation of the nucleus (mediated by endonucleases)
    - Karyolysis: disintegration or dissolution of the nucleus
Cell death: irreversible damage that renders cells unable to carry their function. It results in either apoptosis or necrosis.

Apoptosis vs. necrosis

Characteristics	Apoptosis	Necrosis
Definition	Programmed cell death (ATP-dependent process)	Nonphysiologic cell death
Pathophysiology	Extrinsic signaling pathways Fas (CD95) → Fas ligand (FasL) TNF-alpha → TNF receptor 1 (TNFR1) Immune-mediated → cytotoxic T cells release granzyme B and perforin Intrinsic signaling pathways DNA injury → p53 activation → arrest of cell cycle → unrepairable DNA damage → p53 activates apoptosis → ↑ BAX and BAK, ↓ Bcl-2 → cytochrome c release from mitochondria → ↑ Apaf-1 signaling → activation of caspases (execution) and endonucleases → apoptosis Does not result in an inflammatory response	Membrane damage → influx of calcium Organelle swelling (e.g., mitochondria, endoplasmic reticulum) → inability of cells to produce ATP, release of ribosomes into the cytoplasm (release digestive enzymes), loss of RNA → nuclear shrinkage (pyknosis), fragmentation (karyorrhexis), disintegration (karyolysis) of the nucleus → autolysis Results in an inflammatory response
Microscopy	Single cell or small group of cells Cell shrinkage Eosinophilic cytoplasm Nuclear changes Cytoplasmic blebs Apoptotic bodies → phagocytized by macrophages	Large group of cells, tissues, or organs Cell swelling, cell blebbing, cell organelle destruction, nuclear changes → cell bursts → inflammation → degradation of the necrotic tissue by leukocytes → organization of granulation tissue

Apoptosis

Description: programmed cell death (physiological cell turnover)
Causes
- DNA damage
- Hypoxia and other types of exogenous damage to the cell (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
- Denervation
Characteristics
- ATP-dependent physiological process
  - Occurs e.g., during the involution of the thymus
- Usually affects individual cells and not groups of cells (in contrast to necrosis)
- No inflammatory response or cellular swelling (in contrast to necrosis)
Signaling cascade: 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
  - Extrinsic pathway (death receptor pathway): extracellular ligands (e.g., TNF-α, TRAIL, or FasL) bind to a death receptor on the cell surface.
    1. The death receptor is activated by binding to the ligand.
    2. The receptor-ligand complex activates initiator caspases such as caspase 8.
    3. Caspase 8 activates executioner caspases such as caspase 3.
  - Intrinsic pathway (mitochondrial pathway): intracellular stimuli activate the mitochondrial pathway.
    1. p53 is activated through DNA damage (e.g., chemical toxins, radiation).
    2. p53 leads to an intracellular increase of proapoptotic proteins (e.g., Bax or Bad).
    3. These proteins increase the permeability of the mitochondrial outer membrane, e.g., through the formation of a membrane channel by the heterodimer Bax/Bad.
    4. Cytochrome c enters the cytosol from mitochondria through the membrane.
    5. Cytochrome c binds to APAF-1 (apoptotic protease activating factor-1) in the cytosol.
    6. The complex of cytochrome c and APAF-1 converts procaspase 9 into active caspase 9.
    7. Caspase 9 activates executioner caspases such as caspase 3.
  - Association: 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.
Histopathological findings
1. Shrunken and irregularly shaped cells with membrane blebbing
2. The cell detaches from other cells or the extracellular matrix.
3. Nuclear changes (pyknosis, karyorrhexis, karyolysis)
4. Degradation of the cell into apoptotic bodies
5. Phagocytosis by macrophages

Proteins of the Bcl-2 family can have opposite effects, e.g., Bad and Bax have a proapoptotic effect, whereas Bcl-2 and Bcl-xL have an antiapoptotic effect!

Abnormal regulation of apoptosis

Tumor suppressor genes that regulate the cell cycle and cell death can mutate and allow cells to remain alive even if they have abnormal genes that can cause cancer. Some examples include:

Follicular lymphoma → translocation t(14;18) → Blc-2 (regulator of apoptosis) on chromosome 18 is translocated to the immunoglobulin heavy chain locus on chromosome 14 → overexpression of Bcl-2 → abnormal lymphocytes never died and produce cancer.
Burkitt lymphoma → translocation t (8;14) → c-myc (nuclear regulator protein) on chromosome 8 is translocated to the immunoglobulin heavy chain locus on chromosome 14 → overexpression of c-myc → associates with Bcl-2 → overexpression of c-myc and Bcl-2 → lymphoma
Cervical cancer
- Infection with high-risk strains of HPV (e.g., HPV-16 and HPV-18)
  - → HPV encodes for protein E6 → E6 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
  - → HPV encodes for protein E7 → E7 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

Necrosis

Short description: collective term for unprogrammed cell death and tissue destruction
Characteristics
- Never physiologically induced
- Always associated with an inflammatory reaction
Process: : cell damage → nuclear changes (pyknosis, karyorrhexis, karyolysis) → cell swelling, cell wall protrusions, cell organelle destruction → cell bursts → inflammation → degradation of the necrotic tissue by leukocytes → organization of granulation tissue

Types of necrosis

	Coagulative necrosis	Liquefactive necrosis	Fibrinoid necrosis	Caseous necrosis	Fat necrosis	Gangrenous necrosis
Definition	A type of necrosis caused by tissue ischemia that occurs in most tissues except the brain	A type of necrosis with liquefaction/softening of the affected tissue	A type of necrosis characterized by vessel wall damage due to immune complexes that combine with fibrin (type III hypersensitivity reaction)	A type of necrosis characterized by granular debris that results from macrophages walling off a pathogen	A type of necrosis in which adipose cells die off prematurely	A subtype of coagulative necrosis most commonly seen in the limbs
Pathophysiology	Decreased oxygen delivery → decreased ATP anaerobic metabolism → increased lactic acid production → decreased pH → denaturation of proteins (including proteolytic enzymes) → cell death impaired Na⁺/K⁺-ATPase → ↑ intracellular Na⁺ → ↑ intracellular H₂ → cell swelling	Release of hydrolytic enzymes from neutrophilic lysosomes that digest the affected tissue Especially occurs in damaged tissue that contains fat, such as the brain and pancreas	Vessel wall damage by immune complexes → fragmentation of collagenous and elastic fibers	Macrophages, epitheloid cells and multinucleated giant cells (Langhans giant cell) surround a foci of infection	Release of lipase and triglycerides from the cytoplasm of damaged cells → lipase breaks down triglycerides → fatty acids bind calcium → saponification (esp. in acute pancreatitis)	Dry gangrene: caused by ischemia Wet gangrene: caused by superinfection of dry gangrene
Microscopic appearance	Preserved, anuclear, eosinophilic cellular architecture. H&E staining: eosinophilia	Macrophages and cellular debris (early) followed by cystic spaces or cavitations (late) In bacterial infections → cellular debris and neutrophils	Vessel wall damage with fragments of embedded cellular debris, serum, and fibrin Necrotic areas stain intense red	Cellular debris in a granular pattern, epitheloid cells and multinucleated giant cells that form granulomas	Adipocytes with no nuclei Saponification: dark blue appearance on H&E staining	Dry gangrene: shows coagulative necrosis Wet gangrene: shows coagulative and liquefactive necrosis
Example	Myocardial, splenic, hepatic, and renal infarction Gangrene Organ damage caused by acidic solutions	Bacterial abscesses (purulent infection) Stroke Pancreatitis Organ damage caused by alkaline solutions	Polyarteritis nodosa Rheumatoid arthritis Preeclampsia Hypertensive emergency	Tuberculosis Histoplasmosis Nocardiosis	Mechanical trauma: Traumatic breast injury Enzymatic damage: Acute pancreatitis	Peripheral arterial disease Acute limb ischemia Sepsis Clostridium perfringens: gas gangrene

Cellular inclusions

Steatosis

Short description: 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
Examples:
- Alcoholic liver disease
  - Appears as swollen hepatocytes with necrosis, fatty changes, neutrophilic infiltration, and the presence of Mallory bodies
  - Early changes: centrilobular macrovesicular steatosis → can be reversible with alcohol cessation
  - Late changes: fibrosis around the central vein → irreversible
- Reye syndrome
  - Microvesicular steatosis
  - Cytoplasmic fatty vacuoles within hepatocytes

Calcification

Metastatic calcification: diffuse calcification of normal tissue
- Etiology: hypercalcemia due to
  - Multiple myeloma → bone metastases and increase bone resorption
  - Nephrocalcinosis → leads to renal failure and/or diabetes insipidus
  - Hyperparathyroidism, vitamin D overdose, bone demineralization in long-term immobility, ESRD,
- Serum: increased calcium levels.
Dystrophic calcification: localized calcification of degenerated inflammatory sites or necrotic tissues
- Etiology: tuberculosis, chronic granulomatous disease, schistosomiasis, arteriosclerosis, heart valve disease, CREST syndrome, fat necrosis, psammoma bodies
- Serum: normal calcium levels.

Hyalinization

Hyaline: : descriptive term used for proteins that appear homogeneously transparent under light microscopy and are eosinophilic in H&E staining (also stain red in the van Gieson's stain). It can be used to differentiate between intracellular and extracellular hyaline.
Hyalinization: replacement of normal tissue by proteins that have an eosinophilic, homogenous, translucent appearance on H&E staining.

Intracellular hyaline

Intracellular hyaline	Morphology	Occurrence
Mallory bodies	Inclusion bodies within the cytoplasm of the hepatocytes that contain intermediate filaments and appear pink on H&E stain.	Most common in alcoholic liver disease
Councilman bodies	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
Russel bodies	Accumulation of immunoglobulins	Plasma cells in plasmacytoma or chronic inflammation

Extracellular hyaline

Hyaline arteriosclerosis
- Occurrence: vascular changes in diabetes mellitus and hypertension → vascular fragility → may lead to cerebral hemorrhage
Fibrin
- Occurrence: in thromboses and hyaline membranes
Amyloid
- Occurrence: e.g., amyloidosis, Alzheimer's disease