Cellular Adaptation

Cell exposed to pathological stimuli » new, steady altered state which allows the cell to survive in abnormal environment

Hypertrophy
Increase in size of tissue or organs due to increase in size of the cells which are incapable of cell division due to inc. workload
Physiological hypertrophy
Hypertrophy Of skeletal muscles → muscles Hypertrophy of smooth muscles → uterus pregnancy estrogen
Pathological hypertrophy
Hypertrophy of cardiac muscle → hypertension /aortic stenosis /mitral incompetence
Hypertrophy of smooth muscle → bladder obstruction ( BPH )
Mechanisms of Cellular Hypertrophy → It happens due to increased synthesis of cellular proteins
Activation of the Signal Transduction Pathways
Physiological hypertrophy → Inc. Workload mechanical stretch hypertrophy
Pathological hypertrophy → growth factors ( TGF-β, IFG-1, FGF) Agonists ( α-adrenergic agonists, endothelin-1,
angiotensin II, nitric oxide (NO), and bradykinin )
Activation of Transcription Factors
Increased synthesis of contractile proteins Induction of embryonic/fetal genes
Increased production of growth factors.
Hyperplasia
Increase in size of tissue or organs due to increase in number of the cells which are capable of cell division
Physiological hyperplasia
Due to hormones → glandular epithelium of female breast at puberty, pregnancy & lactation
Compensatory → after hepatectomy
Pathological hyperplasia
Excessive hormonal stimulation → endometrial hyperplasia (estrogen) & BPH (androgen)
Chronic injury/inflammations
Mechanisms of Cellular Hyperplasia → Proliferation of mature cells due to stimulation by growth factors or hormones
Atrophy
Decrease in size of tissue or organs due to decrease in number or size of the cells
Physiological atrophy
During fetal development→ atrophy of embryonic structures (thyroglossal duct)
During adult life → thymus, brain, gonads & heart (senile atrophy)
Pathological atrophy
Local → disuse, denervation, ischemic, pressure
Generalized → starvation (protein-calorie malnutrition)
Mechanisms of Atrophy → decreased protein synthesis and increased protein degradation

Metaplasia
A reversible change in which one adult cell type is replaced by another adult cell type.
Types of Metaplasia
Epithelial Metaplasia → Squamous metaplasia (respiratory tract ciliated columnar epithelial → squamous)
Columnar metaplasia (Barrett esophagus, (squamous → columnar)
Connective Tissue Metaplasia → Osseous metaplasia: Formation of new bone at sites of tissue injury
Mechanism of metaplasia → reprogramming of precursor cells
 Cell Injury
Hypoxia
Decreased blood flow is called ischemia due to thrombosis, embolism, atherosclerosis or external compression of vessel
Inadequate oxygenation of the blood (hypoxemia) due to pulmonary disease, Decreased perfusion, Decreased oxygen-carrying
capacity of the blood & Severe blood loss
Mechanism → reduces aerobic oxidative respiration and decreasing the synthesis of adenosine triphosphate (ATP)
Mechanisms of Cell Injury
Decreased Production of Adenosine Triphosphate
ATP is required for all processes within the cell decrease in its production causes the following effect
Failure of the cell membrane sodium pump Increased anaerobic glycolysis
Failure of the calcium pump. Failure of protein synthesis in the ribosomes

Mitochondrial Damage
Depletion of ATP Formation of reactive oxygen species (ROS)
Formation of mitochondrial permeability transition pore leading to the loss of mitochondrial membrane potential, pH
changes and progressive depletion of ATP and ultimately necrosis of the cell
Leakage of mitochondrial proteins into cytoplasm such as cytochrome C and proapoptotic proteins (e.g. BAX
and BAK) inducing apoptosis.
 Necrosis
Morphological changes indicative of accidental” and unregulated cell death in a living tissue following harmful injury
Cytoplasmic changes: Increased eosinophilia
Nuclear changes: – Pyknosis: Shrinkage of nucleus which appears shrunken and deeply basophilic (similar to ink drop).
– Karyolysis: Progressive fading of basophilic staining of the nuclei and leads to a ghost nuclei.
– Karyorrhexis: Nucleus breaks up into many smaller fragments.
Coagulative Necrosis
Causes: Ischemia caused by obstruction in a vessel
Mechanism: Ischemia denatures and coagulates structural proteins and enzymes.
Organs affected: All organs except the brain
Appearance: Involved region appear dry, pale, yellow and firm
Indistinct outline of dead tissue. Nucleus may be either absent or show karyolysis.

Liquefactive Necrosis
Dead cells are transformed into a liquid viscous mass due to enzymes released from leukocytes accumulated at the site
of necrosis.
Causes: Ischemic injury to central nervous system (CNS)
Suppurative infections: Infections by bacteria which stimulate the accumulation of leukocytes.
Mechanism: Liquefaction is due to digestive action of the hydrolytic enzymes released from dead cells (autolysis) and
leukocytes (heterolysis).
Organs affected: Brain & Localized collection of pus.
Pus consists of liquefied necrotic cell debris, dead leukocytes and macrophages (scavenger cells).

Caseous Necrosis
Distinctive type of necrosis which shows combined features of both coagulative and liquefactive necrosis.
Cause: Characteristic of tuberculosis and is due to the hypersensitivity reaction.
Organs affected: Tuberculosis may involve any organ, most common in lung and lymph node.
Appearance: Necrotic area appears yellowish-white, soft, granular and resembles dry, clumpy cheese (cheese-like)
Focal lesion of tuberculosis is a granuloma which may be caseating (soft granuloma) or noncaseating (hard granuloma).
Caseous necrotic material may undergo dystrophic calcification.
Appears as eosinophilic, coarsely granular material. It is surrounded by epithelioid cells; Langhans type giant cells.
lymphocytes and fibroblasts
Fat Necrosis
Focal areas of fat destruction, which affects adipose tissue.
Enzymatic fat necrosis: in adipose tissue around acutely inflamed pancreas
Mechanism: In pancreatitis, the enzymes leak from acinar cells and causes tissue damage. Lipase destroys fat cells
and liberates free fatty acids which combine with calcium and form calcium soaps (fat saponification)
Appears as chalky-white areas
Necrotic fat cells appear pale with shadowy outlines surrounded by an inflammatory reaction
Traumatic fat necrosis: Occurs in tissues with high fat content (like in breast and thigh) following severe trauma.

Fibrinoid Necrosis
Causes: immune-mediated vascular injury/vasculitis (e.g. polyarteritis nodosa), malignant hypertension, Aschoff bodies in
rheumatic heart disease, placenta in preeclampsia, or hyperacute transplant rejection.
Deposition of pink-staining proteinaceous material in the tissue matrix with a staining pattern reminiscent of fibrin

Gangrenous Necrosis
Massive necrosis with superadded putrefaction.
Dry Gangrene Coagulative type
Causes: Arterial occlusion (e.g. atherosclerosis).
Sites: It usually involves a limb, generally the distal part of lower limb (leg, foot, and toe).
Affected part is dry, shrunken and dark brown or black resembling the foot of a mummy due to the iron sulfide.
A line of demarcation is seen between gangrenous and adjacent normal area
Wet Gangrene Liquefactive type
Causes: Due to the venous blockage (e.g. strangulated hernia, intussusception or volvulus).
Sites: Occurs in moist tissues or organs (e.g. bowel, lung, mouth, etc.).
Affected part is soft, swollen, putrid and dark. No clear line of demarcation.
Gas gangrene
Special type of wet gangrene caused by infection with a gas forming anaerobic clostridia.
Toxins produced by them cause local necrosis and edema and also severe systemic manifestations.

Gummatous Necrosis
The necrotic tissue is firm and rubbery and is usually found in syphilis.
 Apoptosis
Apoptosis is a type of (programmed) cell death induced by a tightly regulated suicide program characterized by activation of
intrinsic enzymes of the cell that degrade its own nuclear DNA and proteins (nuclear and cytoplasmic)

Physiological Causes of Apoptosis

Removal of excess cells during embryogenesis and developmental processes → web tissues between fingers and toes
Elimination of cells after withdrawal of hormonal stimuli → endometrial cell breakdown during the menstrual cycle
Elimination of cells after withdrawal of tropic stimuli → neutrophils in an acute inflammatory response
Elimination of potentially harmful cells → self-reactive lymphocytes are deleted by apoptosis

Pathological Causes of Apoptosis

Elimination of cells with damaged DNA → tumor-suppressor gene p53 recognizes cells with damaged DNA and assesses
whether it can berepaired. If the damage is too severe to be repaired, p53 triggers apoptosis.
Elimination of cells with excessively accumulated misfolded proteins → Excessive intracellular accumulation of these
abnormally folded proteins in the ER is known as ER stress, which results in apoptotic cell death.
Killing of viral infected cells → infected cells are lost mainly due to apoptosis induced either by the virus or by host human
response by cytotoxic T lymphocytes
Elimination of parenchymal cells in pathologic atrophy→ Obstruction of duct in the parenchymal organs like pancreas,
parotid gland and kidney can lead to apoptosis of the parenchymal cells.

Mechanisms of Apoptosis
Initiation phase
Mitochondrial pathway of apoptosis
Mitochondria contain proteins capable of inducing apoptosis. (cytochrome c and several proapoptotic proteins.)
Mitochondrial permeability is controlled by BCL2 family Proapoptotic proteins: BAX and BAK
Antiapoptotic proteins:BCL2,BCL-XL,and MCL1
Survival or apoptosis of cell is determined by permeability of mitochondria. If the balance shifts to proapoptotic proteins,
the apoptotic cascade is activated
Causes of mitochondrial injury – Deprivation/withdrawal of growth factor or survival signals.
– DNA damage by radiation, cytotoxic anticancer drugs, hypoxia
– Endoplasmic reticulum stress
– Increased intracellular free calcium
Mitochondrial injury activate a number of sensors of BCL2 family called BH3-proteins → activate BAX and BAK.
BAX and BAK create channels in the mitochondria → leak of several mitochondrial proteins into the cytosol (cytoplasm).
cytochrome c which binds to a protein called apoptosis-activating factor-1 and forms an important caspase cascade
activator called apoptosome → binds to caspase-9
Sensors of BCL2 family namely BH3-only proteins also bind to and block the function of protective BCL2 and BCL-XL
 Death receptor initiated pathway of apoptosis
Cells express “death-receptors” molecules on the surface of plasma membrane that trigger apoptosis.
Apoptosis is initiated when the death receptors present gets activated.
Death receptors are the type 1 TNF receptor (TNFR1) and a related protein called Fas (CD95)
Self-reactive lymphocytes → FasL is expressed on T-cells that recognize self-antigens and function to eliminate self-
reactive lymphocytes
Virus infected cells & tumor cells → cytotoxic T lymphocytes.
Extrinsic pathway become activated when CD95/Fas binds to its ligand CD95L/FasL → cytoplasmic death domains
binds with an adapter protein contains a death domain and is called Fas-associated death domain (FADD)
FADD in turn binds to pro-caspase-8 → active caspase-8 → mediate the execution phase of apoptosis.

Execution phase
Mitochondria pathway activates initiator caspase-9 Death receptor pathway activates the initiator caspase-8.
Initiator caspases activate another series of caspases called executioner caspases (such as caspase-3 and -6) that
mediates the final phase of apoptosis.
Caspases degrade components of nuclear matrix and cytoskeleton resulting in fragmentation of involved cells.
 Pathological Calcification
Abnormal deposition of calcium salts in tissues other than osteoid or enamel in association with a small amounts of iron,
magnesium and other minerals

Dystrophic Calcification
Deposition of calcium salts in dying or dead tissues with Serum calcium level normal causing organ dysfunction
Causes
Necrotic tissue → caseous, enzymatic fat necrosis, in dead eggs of Schistosoma, cysticercosis and hydatid cysts.
Degenerating tissue → Heart valves, Atherosclerosis, goiter of thyroid, dense old scar, cysts
Monckeberg’s medial calcific sclerosis → Calcification in the media of the muscular arteries in old people.
Psammoma bodies→ Single necrotic cells on which several layers of mineral get deposited progressively to create
lamellated shape called psammoma bodies

Metastatic Calcification
Deposition of calcium salts in normal tissues associated with hypercalcemia secondary to deranged calcium metabolism
Causes
Increased secretion of parathyroid hormone → bone resorption-hyperparathyroidism
Destruction of bone tissue → Secondary to primary tumors of bone marrow (e.g. multiple myeloma, leukemia and
metastatic tumors to bone)
Vitamin D–related disorders Sarcoidosis and milk alkali syndrome.
Renal failure→ Causes retention of phosphate, leading to secondary hyperparathyroidism
Sites
Lungs: Alveolar septa of the lung.
Kidney: Basement membrane of the renal tubules.
Blood vessels: On the internal elastic lamina of systemic arteries and pulmonary veins.
Stomach: Interstitial tissues of the gastric mucosa