Cellular Adaptation & Injury

Cellular adaptation

• Cells capabilities to change their structure (size, number & phenotype)

• Purpose: to escape & protect from injury

• Adapted cell: neither normal/injured

Type of cellular Adaptation

Hyperplasia

Hypertrophy

Atrophy

Metaplasia

Hyperplasia

• Increase in size of an organ/tissue caused by increase in number of cells

• Cells capable of synthesizing DNA-undergo mitosis

1. Physiologic :

• Hormonal (endometrium/breast/uterus in pregnancy)

• Compensatory (partial hepatectomy, erythrocytosis)

2. Pathologic

• Excessive hormone/growth factor stimulation of target tissue

• Endometrial hyperplasia (excess oestrogen) - lead to malignancy

• Benign prostatic hyperplasia (excess androgens)

• Connective tissue cells in wound healing

Mechanism:

• Result from growth factor-driven proliferation of mature cells

• Increased output of new cells from tissue stem cells

• E.g.: after partial hepatectomy, growth factors are produced in liver - active signalling pathways that stimulate cell proliferation

Hypertrophy

Bigger cells

• Increase in size of organ/tissue due to increase in size of cell

1. Physiologic

• Hypertrophy of skeletal muscle in muscle builder

2. Pathologic

• Hypertrophy of cardiac heart in hypertension

Mechanism :

• Increase in protein synthesis & increase in size/number of intracellular organelles

• End result: larger organ

• Increase in functional capacity

• May occur with hyperplasia

Atrophy

Smaller cells

• Atrophy decrease in size of organ/tissue due to decrease in mass of cells

1. Physiological:

• Uterus after delivery

2. Pathological:

• Local, generalised

• Denervation

• Endocrine stimulation - loss

• Aging

• Disuse atrophy

• Pressure - tumor compression

• Ischemia - decrease in blood supply to organ

• Inadequate nutrition

Mechanism :

• Reduction - cell structural components

• Main event is degradation of proteins

• 2 major system:

1. Lysosomes

2. The ubiquitin-proteasome pathway

• Atrophic cell - diminished function but NOT DEAD

Metaplasia

• Replacement of one differentiated (adult) cell type by other

1. Fully reversible:

• Reprogramming: STEM cell in epthelia/mesenchymal cell in connective tissue

• Signals from cytokine, growth factors & Extracellular matrix

• Loss of normal function/protection

• If persistent, cause malignancy

2. Squamous Metaplasia

• Cervix: squamocolumnar junction - replacement of columnar epithelium by squamous epithelium (physiologic)

• Occur in respiratory epithelium of bronchus (smoking), endometrium (chronic irritation)& pancreatic ducts (stones)

• Associated with long term irritation (smoking) & Vit A deficiency

• Often reversible

Causes of cellular injury

• Ischemia/hypoxia

• Chemical injury : from drugs to poisons

• Infectious agents : from viruses to parasites

• Immune effector proteins & cells : autoimmune disease

• Growth factor stimulation/removal

• Nutritient imbalances, specific metabolic inhibitors: protein to vitamin deficiencies, excess cholesterol

• Mechanical/physical - trauma, wound, temperature (hot/cold) ionizing radiation

Ischaemic/hypoxic cell injury

Causes - cellular anoxia/hypoxia due to various mechanisms:

• Ischemia - obstruction of arterial blood flow, most common

• Anaemia - reduction in oxygen carrying RBC

• Carbon-monoxide poisoning - altered Hb.

• Decreased perfusion of tissues by oxygen carrying blood - cardiac failure, hypotension & shock

• Poor oxygenation of blood - pulmunary disease

Mechanism of cell injury

• ATP depletion

• Mitochondrial damage

• Infux of intracellular calcium & loss of calcium homeostasis

• Accumulation of oxygen derived free-radicals (oxidative stress)

• Defect in membrane permeability

• Damage to DNA & proteins

ATP Depletion

• ATP is needed for synthetic & degradative processes in cell

• Functional & morphologic consequences of decreased intracellular ATP during cell injury

Mitochondrial dysfunction in cell injury

Loss of Calcium homeostasis

Free radical/Reactive oxygen species (ROS) injury

• Free radical: molecules with single unpaired electron in outer orbital

• E.g.: activated products of oxygen reduction (superoxide & hydroxyl radicals)

• Production of ROS increases/scavenging systems are ineffective, result in excess of free radicals - oxidative stress

• Mechanism that generates free radicals:

1. Normal metabolism: aging

2. Oxygen toxicity: alveolar damage (ARDS)

3. Ionizing radiation: UV light

4. Inflammatory process

5. Drugs & chemicals : introduction of P-450 system

6. Reperfusion after ischaemic injury

Accumulation of oxygen derived Free-radicals (oxidative stress)

• Role of reactive oxygen species in cell injury

• O2 is converted to superoxide (O2) by oxidative enzymes in endoplasmic reticulum (ER), mitochondria, plasma membrane, peroxisomes & cytosol

• O2 converted to H202 by dismutation & then to OH by Cu2+/Fe2+ (catalyzed Fenton reaction)

• H2O2 also derived directly from oxidase in peroxisomes

• Another potential injurious radical, singlet oxygen, resultant free radical damage to lipid (peroxidation), proteins & DNA leads to various forms of cell injury

• Superoxide catalyzes reduction of Fe3+ to Fe2+, enhancing OH generation by Fenton reaction

• Major antioxidant enzymes are superoxide dismutase (SOD), catalase & glutathione peroxidase

• GSH reduced glutathione

• GSSG oxidized glutathione

• NADPH reduced form of nicotinamide adenine dinucleotide phosphate

Mechanism of cell injury by ROS

• Not adequately neutralized, free radicals can damage cells by 3 basic mechanism:

1. Lipid peroxidation of membranes:

• Double bonds in polyunsaturated membrane lipids are vulnerable to attack by oxygen free radicals

2. DNA fragmentation

• Free radicals react with thymine in nuclear & mitochondrial DNA to produce single strand breaks

3. Protein cross-linking:

• Free radicals promote sulfhydryl-mediated protein cross-linking, resulting in increased degradation/loss of activity

Defect in membrane permeability

Mechanism of membrane damage in cell injury:

• Decreased O2 & increased cytoslic Ca2+ are typically seen in ischemia but may accompany other forms of cell injury

• Reactive oxygen species, often produced on reperfusion of ischemic tissue cause membrane damage (not shown)

Damage to DNA

• Cells have mechanism that repair damage to DNA

• If the damage to severe

• E.g.: after exposure to DNA damaging drugs, radiation/ oxidative stress

• Cell initiates suicide program - death by apoptosis

Cellular response to injury

Ischaemic/hypoxic cell injury

• Early stage - first mitochondria is affected leading to decreased oxidative phosphorylation and ATP synthesis

Hypoxic injury becomes irreversible after:

• 3-5 min for neurons

• 1-2 hrs for myocardial & liver cells

• Many hours for skeletal muscle cells

Consequences of decreased ATP availability

1. Failure of cell membrane pump

• Intracellular Na+H20 accumulation, cellular swelling & swelling of organelles : Ca2+ influx

• Hydropic change - large vacuoles in cytoplasm

• Swelling of endoplasmic reticulum (reversible)

• Swelling of mitochondria (reversible to irreversible)

2. Disaggregation of ribosomes - failure of protein synthesis

• Stimulation of phosphofructokinase activity - increased glycolysis, accumulation of lactate & decreased intracellular pH

• Acid causes reversible clumping of nuclear material

3. Late stage

• Hypoxic injury causes membrane damage; plasma membrane, lysosomal & organelle with loss of phospholipids

• Reversible morphologic signs : myelin figures damage cell membrane & cellular blebbing

4. Cell death - severe/prolonged injury

• Irreversible membrane damage - massive Ca influx, mitochondrial damage & cell death

• Release of intracellular enzymes & proteins from necrotic cells into circulation (lab test, indicators of necrosis ; myocardial & liver enzymes)

• Vulnerability of cells to hypoxic injury varies - depending on cell type

Ischaemia reperfusion injury

“Reperfusion” Damage

• If cells are reversible injured due to ischaemic, restoration of blood flow can paradoxically results in accelerated injury

• Clinically important: contribute to myocardial & cerebral infarctions

• Exact mechanism: unclear; restoration of flow may expose compromise cells to high concentration of calcium

• Reperfusion: increase free radical production from compromised mitochondria & circulating inflammatory cells

Reversible & irreversible cellular injury

Reversible:

• Characterized by generalized swelling of cell and it's organelles

• Blebbing of plasma membrane, detachment of ribosomes from endoplasmic reticulum & clumping of nuclear chromatin

• Hallmark include:-l

• Reduced oxidative phosphorylation with reduced ATP

• Cellular swelling caused by changes in ion concentration & water influx

• Changes in mitochondria & other organelles

Irreversible :

• Characterized by increasing swelling of cell; swelling & disruption of lysosomes, presence of large amorphous densities in swollen mitochondria, disruption of cellular membranes & profund nuclear changes

• Latter include nuclear condensation (pyknosis), followed by fragmentation (karyorrhexis)& dissolution of nucleus (karyolysis)

• Laminated structure (myelin figures) derived from damaged membranes of organelles & plasma membrane first appear during reversible stage & become more pronounced in irreversible damaged cells

• Necrosis & apoptosis

Reversible injury into irreversible injury

• With continuing damage, injury becomes irreversible & cells can't recover

• Irreversibly injured cell undergoes morphologic change: death cell

• 2 type of death cell : different in morphology, mechanism, role in disease & physiology

1. Necrosis: always pathologic process with different morphologic types

2. Apoptosis

Causes of reversible injury

• Decreased ATP levels

• Ion imbalances

• Decreased pH

• Hydropic swelling

• Fatty change

Cause of irreversible cellular injury

• Severe membrane damage

• Influx of extracellular Ca++& release of intracellular Ca++

• Lysosomal swelling

• Lysosomal rupture

• Extensive DNA damage

• Mitochondrial vacuolization

• Pyknosis, karyolysis/karyorrhexis of nucleus

Mechanism of irreversible cellular injury

• Mitochondrial dysfunction

• Membrane function disorders - most central factor in pathogenesis of irreversible cell injury

Necrosis

• Death of group of cells/tissues in living person

• Sequence of morphologic change that follow cell death

• Types:

1. Coagulative necrosis (ischemia)

2. Liquetactive necrosis (hydrolases)

3. Fat necrosis (enzymatic/non enzymatic)

4. Caseous necrosis

5. Gangrenous (ischemia+ bacterial liquefaction)

6. Fibrinoid necrosis (immune reactions)

Coagulative necrosis

Cause - ischaemic hypoxic injury

• Infraction: tissue death by local lack of oxygen; obstruction of tissue’s blood supply

• Coagulation; protein denaturation due to increased acidosis

• Seen in most organ : heart, muscle, spleen & gut

Liquetactive necrosis

• Seen in brain & bacterial infection

• In brain cells:

1. Brain cells are rich in hydrolytic enzymes & lipids; very little connective tissue

2. Cells are digested by their own hydrolases

3. Tissue become soft, lique8, walled off from healthy tissue : forming cysts

• In bacterial infection:

1. Caused by Staphylococcus, streptococcus & etc..

2. Neutrophils release enzymes to destroy bacteria

3. Enzymes also destroy tissue causing liquefaction

Fat necrosis

• Seen in breast (traumatic fat necrosis) & pancreas (enzymatic fat necrosis)

• Traumatic fat necrosis

1. After trauma to breast, haemorrhage occurs

2. Cause swelling of breast tissue, with considerable ischaemia & pressure necrosis: necrosis of fat cells

• Enzymatic fat necrosis:

1. Cellular dissolution caused by lipases

2. Lipases breakdown triglycerides releasing fatty acids - combine with calcium, magnesium & sodium ions making soap: saponification

3. Necrotic tissue appears opaque and chalky white

Caseous necrosis

• Characteristics of tuberculous infection, can involve any organ

• Mycobacterium tuberculosis cell wall contains complex wax (peptidoglycolipids) cause toxic effect

• Dead cells disintegrated but not completely digested by hydrolases

• On gross it has cheese like consistency, soft gray friable

• Microscopically there is granuloma/tubercle with central area of caseous necrosis

Gangrenous necrosis

• Mostly seen in lower extremities & bowel

• Death of tissue due to hypoxia

• Dry gangrene: coagulative necrosis without liquefaction skin become dry, wrinkled & dark brown(dusky) in colour

• Wet gangrene: complicated by infection & invasion of neutrophils causing liquefaction necrosis

Fibrinoid necrosis

• Necrosis associated with immune complex deposition involving blood vessels

• Seen when complexes of antigens & antibodies are deposited in walls of arteries

• These complexes will activate complacent system & neutrophilic activity

• Immune complex deposits caused bright pink amorphous appearance

Apoptosis

• Programmed cell death

• Important mechanism for removal of cells : cell with irreparable DNA damage(from free radical, viruses, cytoxic immune mechanism)

• Protecting against malignant transformation

• Occur in normal tissue for regulating number of cell/cell removal during embryogenesis

Physiological Apoptosis

• Embryogenesis: formation of digit from limb buds, formation of lumen in gut

• Menstrual cycle: endometrial cell loss

• Ovulation

• Breast: after cessation of lactation

• Immune cell development: deletion of immune cells that may react with body’s own tissue

Pathological Apoptosis

• Tumors: apoptosis is major cancer killer mechanism. When tumor forms, balance between apoptosis & cell proliferation is disturbed

• Viral infection: viral hepatitis, infected hepatocyte can be seen in apoptosis form

• AIDS: loss of CD4 T lymphocytes by apoptosis