lec slides on gen pathology

• Atrophy –

• A decrease in individual cell size due to lower rates of metabolism and decreased protein synthesis.
Causes of atrophy
• (1) Decreased workload
• (2) Loss of innervation
• (3) Diminished blood supply
• (4) Inadequate nutrition
• (5) Loss of endocrine stimulation
• (6) Aging
• Hypertrophy –

• An increase in tissue mass resulting from an increase in cell size rather than cell numbers.
Hypertrophy may be caused by
• (1) Increased functional demand
• (2) Hormonal stimulation
• Hyperplasia –
• Increase in tissue mass due to an increased rate of cell division and cellular proliferation.
•
• Hyperplasia may be physiologic or pathologic.

• (1) Physiologic hyperplasia -as a result of
normal hormonal stimulation
e.g., female breast enlargement during puberty and
pregnancy

• (2) Pathologic hyperplasia is the result of a noxious
stimulus
callous formation on the hands of a manual laborer
or excessive hormonal stimulation
• Pathologic hyperplasia
is probably a step in the development of cancer (neoplasia).

• Thus hyperplastic changes in some tissues may be considered premalignant.
• Metaplasia –
• A reversible change in cell structure from one fully differentiated form to another in response to a noxious stimulus.

• represents an attempt by tissue to replace a susceptible cell type with a more resistant one.
metaplasia
• In smokers -columnar cells cells are replaced by stratified squamous epithelium

• Smokers who quit may regain normal mucous secreting bronchial epithelium.

• Persistent stimulus producing metaplasia -it may induce malignant transformation.

• Thus, like hyperplasia, metaplasia is considered a
pre-malignant change.
• Dysplasia –
• Disordered cellular morphology, organization, and function
– Dysplastic tissues display abnormal variation in overall cell size and shape as well as nuclear structure.

– Dysplasia is strongly implicated as a precursor to cancer.

– Dysplasia is distinguished from cancer by the important fact that dysplastic changes can be reversed if the abnormal stimulus is removed.
CELLULAR INJURY
LIMITS OF ADAPTIVE CAPACITY IS EXCEEDED
CAUSE OF REVERSIBLE CELL INJURY AND CELL DEATH
EXTERNAL GROSS PHYSICAL VIOLENCE
INTERNAL ENDOGENOUS CAUSE
CAUSES OF CELLULAR INJURY
• HYPOXIA
• PHYSICAL AGENTS
• CHEMICAL AGENTS AND DRUGS
• INFECTIOUS AGENTS
• IMMUNOLOGICAL REACTIONS
• GENETIC DERANGEMENTS
• NUTRITIONAL IMBALANCES
HYPOXIA
IMPINGES ON AEROBIC OXIDATIVE RESPIRATION
CAUSES OF HYPOXIA
1. LOSS OF BLOOD SUPPLY (ISCHEMIA)
–MOST COMMON CAUSE

2. INADEQUATE OXYGENATION OF BLOOD
- DUE TO CARDIORESPIRATORY FAILURE

3. LOSS OF OXYGEN CARRYING CAPACITY OF
BLOOD
• DEPENDING ON THE SEVERITY OF HYPOXIA THE CEL MAY

ADAPT
UNDERGO INJURY
DIE
MECHANISMS OF CELL INJURY
• 4 INTRACELLULAR SYSTEMS THAT ARE VULNERABLE TO INJURY

• 1. INTEGRITY OF THE CELL MEMBRANE
• 2. AEROBIC RESPIRATION
• 3. PRODUCTION OF ENZYMES AND STRUCTURAL
PROTEIN
• 4. GENETIC APPARATUS

• Injury at one locus can lead to wide ranging secondary effects…


• Impairment of aerobic respiration—lead to disruption of energy dependent sodium pump--- disrupts cellular ionic and fluid balance
Ischemic and hypoxic injury
• Sequence of events and ultrastructural changes

• Occlusion of coronary artery and examination of the muscle supplied by the artery.
Reversible cell injury
• First point of attack in hypoxia
• Aerobic respiration

• Decrease in production of ATP

• In heart muscle occlusion of 60sec. Resulted in cessation of contraction
Anaerobic glycolysis
• Consequence of decrease ATP
• 1. Increase in lactic acid
• 2. Decrease intracellular ph
• 3. Clumping of nuclear material
Acute cellular swelling
• Earliest and most common manifestation of cellular hypoxia

• Impairment of cellular volume regulation

• Failure of active transport by sodium pump
• Accumulation of sodium intracellularly

• Net gain of solute accompanied by isosmotic gain of water
Detachment of ribosome
• Ribosomes detached from E.R.
• Maybe due to disruption of energy-dependent reaction between ribosome and E.R. membrane

• Blebs start to form

• All changes are still reversible
Irreversible cellular injury
• If hypoxia continues irreversible changes occur
• Vacuolization of mitochondria
• Extensive damage to plasma membrane
• Swelling of lysosomes
• Release of lysosomal enzymes
• Digestion of cellular components
• Cell death
Cell death
• Progressive degradation of cell components
• Leakage of cellular enzymes into ECF

• In cardiac muscle after 30-40mins of hypoxia
• SGOT, LDH, CK– criteria for MI
Mechanisms of irreversible injury
• What is the critical biochemical event responsible for the “point of no return”?

• Duration of hypoxia differs in type of tissue
• liver—1 to 2 hrs
• brain ----2 to 3 mins
Cell systems most vulnerable to injuries that induce necrosis include
1. Cell membranes
2. Aerobic respiration
3. Synthetic apparatus (proteins, enzymes)
4. Genetic apparatus
Four common mechanisms associated with injuries that induce necrosis
1. ATP DEPLETION
2. FREE RADICALS
3. MEMBRANE DAMAGE
4. CALCIUM INFLUX
• caspases

• are a family of proteins that are one of the main executors of the apoptotic process.

• They belong to a group of enzymes known as cysteine proteases and exist within the cell as inactive pro-forms or zymogens
Free radicals and cell injury
• Chemical species that has a single unpaired electron in an outer orbital

• Extremely reactive and unstable

• Reacts with inorganic and organic chemicals—key molecules in membranes

• Initiates autocatalyctic reactions
molecules they react to becomes free
radicals themselves thus propagating damage
FREE RADICALS
• MAYBE INITATED WITHIN CELLS BY

1. radiant energy
2. oxidative reactions within normal
metabolism
3.metabolism by exogenous chemicals
The Role of Oxygen-derived Free Radicals
• While oxygen is vital for normal energy metabolism, it also plays a special role in cell injury.
• mitochondria generates
Superoxide
hydrogen peroxide
hydroxyl radicals

• These are short-lived molecules unstable and highly reactive.
MORPHOLOGIC TYPES OF NECROSIS
1. COAGULATION NECROSIS
2. LIQUEFACTION NECROSIS
3. FAT NECROSIS
4. CASEOUS NECROSIS
5. GANGRENOUS NECROSIS
COAGULATION NECROSIS
• most common pattern of necrosis
• lost of nucleus
• preservation of basic cell outline and architecture
• sudden severe ischemia
• denaturation of protein and enzymes
LIQUEFACTION NECROSIS
• Ischemic destruction of brain tissue
• Autolysis and heterolysis by hydrolytic enzymes
• Necrotic tissue is converted to cystic structure
• Filled with fluid and debris
FAT NECROSIS
• Opaque, chalky white deposits
• Fatty acids forming complex with calcium
• Lipases catalyze decomposition of triglycerides
• Acute pancreatic necrosis
CASEOUS NECROSIS
• Combination of coagulative and liquefactive necrosis
• Tuberculous infections
• Friable whitish-gray debris– cheesy material
• Encountered within granulomatous wall
GANGRENOUS NECROSIS
• Usually applied to a limb
• Lost of blood supply in lower limb
• Ischemic cell death and coagulative necrosis modified by liquifactive necrosis

• Dry gangrene – if coagulative predominates
• Wet gangrene – if liquefaction predominates
Chemical injury
• 1. Act directly by combining with some molecular
component or organelle
• 2. Some are converted to reactive toxic
metabolite

May result to
1. membrane injury or
2. generation of free radical

Virus induced cell injury
• 2 types
• 1. cytolytic/cytopathic viruses
• 2. oncogenic tumors
CYTOPATHIC EFFECTS OF VIRUSES
• 1. Rapidly replicating virus particles interfere with host cell metabolism

• 2. Induction of immunologic response
- destruction of cell by antibody or cell mediated reaction
Hepatitis B
• Damage to the hepatocytes
- caused by cytolysis mediated by T lymphocytes
INFLAMMATION
• Inflammation is the process in which healthy tissue responds to an injury

• Purpose of inflammation
1. To destroy and remove substances recognized as being foreign to the body
2. to prevent minor infections from becoming overwhelming
3. To prepare any damaged tissue for repair
INFLAMMATION AND REPAIR
• Reaction of vascularized living tissue to injury

• Destroy, dilute wall off injurious agents

• Heal and repair damaged tissue:
• 1. Regeneration of native parenchymal cell

• 2. filling of defects with fibroblastic tissue(scar)
Causes of Inflammation
• Infection
• Physical trauma
• Chemical trauma
• Irradiation
• Thermal injury (hot or cold)
• Immunity (hypersensitivity)
• Ischemia
• Nutrient deprivation
Acute/Chronic Inflammation
• Short term inflammatory process that complete resolves
– mostly PMN’s

• Chronic Inflammation
long term that may or may not completely
resolve

inflammation
• Acute
-short duration
- exudation of fluid and plasma protein
- emigration of leukocytes
Chronic inflammation
• Longer duration
• Presence of lymphocytes and macrophages
• Proliferation of blood vessels and connective tissue

Systemic Manifestations
• Fever
– endogenous pyrogens are produced by the macrophages and possibly by the eosinophils
• Mechanism
– act on hypothalamus to reset thermostat
– body generates arachidonic acid
– vasoconstriction
– piloerection
– shivering
Changes in vascular flow
• 1.transient vasoconstriction
• 2. vasodilatation – increase blood flow
• 3. slowing of circulation – brought about by
increased in permeability resulting in
hemoconcentration – stasis
• 4. leukocytic margination - emigration
Changes in vascular compartment
• Increase in hydrostatic pressure and vasodilatation - transudation
Cellular events
• Most important feature of inflammation
– -accumulation of leukocytes
– Engulf and degrade bacteria, immune complexes

Margination
Adhesion
Emigration toward chemotactic stimulus
phagocytosis

Systemic Manifestations
• Lymphadenopathy
– enlarged lymph node
• Lymphangiitis
– inflammation of lymphatic vessel
• Lymphadenitis
– inflammation of lymph nodes
Vascular Response
• Momentary vasoconstriction which decreases blood flow

• Vasodilation of the arterioles and venules which increases blood flow
– fluid flows from the capillaries into the interstitial spaces to dilute the injurious agent
– fluid brings complement and antibodies to the area
Cellular Response
• Polymorphonuclear Neutrophils
– first to arrive at the injury
– secrete powerful chemotactic chemicals
Cellular ResponseMargination
• Movement of neutrophils toward the endothelial lining
• Causes of margination
– electrical charge on the endothelial cells changes
– blood viscosity increases
– blood flow slows
– chemical mediators
Cellular Response Diapedesis
• When activated, neutrophils squeeze through the endothelial gaps into the tissues by a process known as Diapedesis
• Diapedesis means “cell-walking
Cellular ResponseChemotaxis
• Chemotaxis
• --is the directional and purposeful movement of cells by ameboid movement toward an area of injury in response to a chemical mediator.
Cellular ResponsePhagocytosis
• The plasma membrane of the neutrophil flows around the foreign particle and engulfs it.
• Lysosomes release chemicals which digest the foreign particle.
• The phagocyte often dies.Cellular debris is removed by monocytes and macrophages