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CELL INJURY

(Apoptosis,Necrosis,Gangrene)

Defnition: Cell injury is the effect of stresses due to variety of etiological agents on the cell.

Causes of Cell Injury

1.Hypoxia: It refers to inadequate oxygenation of tissue.

Causes of hypoxia:
•(a) Decreased blood flow is called ischemia.

(b)• Inadequate oxygenation of the blood (hypoxemia)
– Due to pulmonary disease.
– Decreased perfusion of tissues:

– Decreased oxygen-carrying capacity of the blood

– Severe blood loss

Mechanism of injury:

Hypoxia causes cell injury by reducing aerobic oxidative respiration and decreasing the synthesis of adenosine triphosphate (ATP).

2.Physical Agents:

• Mechanical trauma:-

•–  Termal injury: Extremes of temperature (burns and deep cold).

–Radiation (ionizing radiation and non-ionizing radiation).

–• Electric shock

•– Pressure changes

3.Chemical Agents

•– Heavy metals and poisons: For example, arsenic,

• –Strong acids and alkalies

•– Simple chemicals: For example, hypertonic concentrations of glucose or salt.

–• Environmental and air pollutants: For example, insecticides, and herbicides.

–• Terapeutic drugs

4.Infectious Agents: Viruses, bacteria, fungi, rickettsiae and parasites.

5.Immunologic Reactions

•– Autoimmunity: Immune reactions to endogenous self-antigens are responsible for autoimmune diseases.

–• Hypersensitivity reactions and other immune reactions: Heightened immune reactions to many external agents (e.g. microbes and environmental agents).

 6. Genetic Derangements:

Genetic defects may cause cell injury because of:
• –Defciency of functional proteins (e.g. enzyme defects in inborn errors of metabolism).
–• Accumulation of damaged DNA or misfolded proteins
–• Variations in the genetic makeup.

General Principles of Cell Injury

1.Cellular response to injury:

It depends on: (1) type of injury, (2) duration of injury and (3) severity of injury.

2.Consequences of injury:

It depends on:(1) type of cell involved,(2) adaptability of cell,(3) status of cell and(4) genetic makeup of the cell.

3.Targets and biochemical mechanism of cell injury:

These include (1) mitochondrial damage/dysfunction, (2) disturbance of calcium homeostasis, (3) damage to cellular membranes and (4) damage to DNA and misfolding of proteins.

Mechanisms of Cell Injury

Decreased Production of Adenosine Triphosphate

Effects of decreased ATP
– Failure of the cell membrane sodium pump
– Increased anaerobic glycolysis
– Failure of the calcium pump
– Failure of protein synthesis in the ribosomes.

Mitochondrial Damage

Consequences of Mitochondrial Damage

  1. Depletion of ATP:
  2. Formation of reactive oxygen species (ROS)
  3. Formation of mitochondrial permeability transition pore4. Leakage of mitochondrial proteins into cytoplasm

TYPES OF CELL INJURY

–Reversible cell injury

–Irreversible cell injury

 

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Fig.1:- Cellular responses to cell injury

Reversible Cell Injury

If the stimulus is acute and brief or mild, the cell injury produces changes in the cells which are reversible up to a certain point.

Two patterns of reversible cell injury namely cellular swelling and fatty change• Cellular (hydropic) swelling: It is due to changes in ion concentrations and fluid homeostasis.

• Steatosis (fatty change)

Causes:-

• Disorders with hepatocyte damage: Alcoholic abuse, protein malnutrition, starvation, anoxia (anemia, cardiac failure), toxins (carbon tetrachloride, chloroform, etc.) and Reye syndrome. Alcohol is the most common cause of fatty change in the liver.

• Disorders with hyperlipidemia: Obesity, diabetes mellitus or congenital hyperlipidemia. Pathogenesis of Fatty Liver• Excessive entry of free fatty acids (FFA) into the liver

Pathogenesis of Fatty Liver

Fig.2:- Pathogenesis of Fatty Liver

• Defective metabolism of lipids: This may be due to:

– Increased synthesis of fatty acids by liver

– Decreased oxidation of fatty acids into ketone bodies

– Decreased synthesis of apoproteins (e.g. in CCl4 and protein malnutrition) causes decreased formation of lipoproteins from triglycerides•

–Defective excretion of lipoproteins: Fatty liver may also develop due to defect in excretion of lipoproteins from liver into the blood.

Irreversible Cell Injury

If the cell is exposed to continuous injurious stimulus or if the injury is severe, the cells undergo cell death.

Two main types of cell death:  Necrosis and apoptosis. •

Necrosis: Always a pathologic process•

Apoptosis: May be physiological or pathological

NECROSIS

Defnition: Morphological changes indicative of cell death in a living tissue following harmful injury. The necrotic cells cannot maintain integrity of membrane and their contents leak out. This bring out acute inflammatory reaction in the surrounding tissue.

MORPHOLOGY

The general changes occurring in a necrotic cell:
•– Cytoplasmic changes: Increased eosinophilia.

–• Nuclear changes: These may take up one of three patterns:

(a)Pyknosis: Shrinkage of nucleus which appears shrunken and deeply basophilic (similar to ink drop).
(b)Karyolysis: Progressive fading of basophilic staining of the nuclei and leads to a ghost nuclei.
(c)Karyorrhexis: Nucleus breaks up into many smaller fragments.

Types of Tissue Necrosis

Coagulative Necrosis

Coagulative necrosis is characteristically seen in infarct of solid organs.

• Causes: Ischemia caused by obstruction in a vessel.

• Mechanism: Ischemia denatures and coagulates structural proteins and enzymes.

• Gross:
– Organs affected: All organs except the brain. More frequent in heart, kidney, spleen and limb (dry gangrene).
– Appearance: Involved region appear dry, pale, yellow and frm. It is wedge-shaped in organs like kidney and spleen.

Liquefactive Necrosis (Colliquative Necrosis)

Liquefactive necrosis: Dead cells are transformed into a liquid viscous mass due to enzymes released from leukocytes accumulated at the site of necrosis. Dead tissue rapidly undergoes softening and transforms into a liquid viscous mass.

• 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).

• Gross:

Organs affected are:
– Brain: Necrotic area is soft and center show liquefaction.
– Abscess anywhere: Localized collection of pus.
– It is also seen in wet gangrene and pancreatic necrosis

Caseous Necrosis

Cheese-like appearance of the necrotic material. 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.

• Gross:
– 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, hence the name caseous (cheese-like) necrosis.

Fat Necrosis

It refers to focal areas of fat destruction, which affects adipose tissue.

Types:

1.Enzymatic fat necrosis:Occurs in adipose tissue around acutely inflamed pancreas (in acute pancreatitis)

2.Traumatic fat necrosis: Occurs in tissues with high fat content (like in breast and thigh) following severe trauma.

Fibrinoid Necrosis

Seen in immune-mediated diseases
1. Polyarteritis nodosa
2. Malignant hypertension
3. Autoimmune disorder
4. Aschoff bodies in rheumatic fever

Gangrene (Gangrenous Necrosis)

It is massive necrosis with superadded putrefaction.

Types:

Two types, namely dry and wet gangrene. A variant of wet gangrene known as gas gangrene is caused by clostridia (Gram-positive anaerobic bacteria).

Dry Gangrene
• Causes: Arterial occlusion (e.g. atherosclerosis).
• Sites: It usually involves a limb, generally the distal part of lower limb (leg, foot, and toe).

• Gross: Affected part is dry, shrunken (shriveled) and dark brown or black resembling the foot of a mummy. The black color is due to the iron sulfde.

Wet Gangrene
• 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.).

• Gross: The affected part is soft, swollen, putrid and dark. No clear line of demarcation.

Differences Between Dry and Wet Gangrene

APOPTOSIS

Apoptosis is a type of (programmed) cell death induced by a tightly regulated suicide program. It is characterized by activation of intrinsic enzymes of the cell that degrade its own nuclear DNA and proteins (nuclear and cytoplasmic).

Causes of Apoptosis

Physiological Situations

–• Removal of excess cells during embryogenesis and developmental processes

–• Elimination of cells after withdrawal of hormonal stimuli

–• Elimination of potentially harmful cells

Pathological Conditions

–• Elimination of cells with damaged DNA: DNA may be damaged by many injurious agents like radiation, cytotoxic anticancer drugs and hypoxia.

— Destroying cells with dangerous mutations or with DNA damage beyond repair by apoptosis prevents the development of cancer

•— Elimination of cells with excessively accumulated misfolded proteins

•– Killing of viral infected cells

•–Elimination of neoplastic cells/rejection of transplant

–• Elimination of parenchymal cells in pathologic atrophy

Mechanisms of Apoptosis

Phases of Apoptosis
Divided into (A) initiation phase and (B) execution phase

(A)Initiation phase

Apoptosis is initiated by signals derived from two distinct pathways activated by distinct stimuli, namely(1) intrinsic or mitochondrial pathway and (2) extrinsic or death receptor pathway.

1.Intrinsic (mitochondrial) pathway of apoptosis

• (a)Role of mitochondria in apoptosis:

– Mitochondrial damage is the major mechanism in a variety of physiological and pathological apoptosis.

– Mitochondria contain proteins capable of inducing apoptosis.

– Survival or apoptosis of cell is determined by permeability of mitochondria.

• Causes of mitochondrial injury: The proapoptotic signals include:

– Deprivation/withdrawal of growth factor or survival signals.

– DNA damage by radiation, cytotoxic anticancer drugs, hypoxia either directly or through free radical.

– Accumulation of excessive amount of misfolded proteins (endoplasmic reticulum stress).

– Increased intracellular free calcium.

2.Extrinsic (death receptor–initiated) pathway of apoptosis

–• This pathway is initiated by extracellular signals.

–• Many cells express “death-receptors” molecules on the surface of plasma membrane that trigger apoptosis.

–• In the extrinsic (death receptor) pathway, apoptosis is initiated when the death receptors present gets activated.

–• The well-known death receptors are the type 1 TNF receptor (TNFR1) and a related protein called Fas (CD95).

• Functions of extrinsic pathway: This pathway is involved in eliminating:

– Self-reactive lymphocytes thereby avoiding autoimmunity.

– Virus infected cells through cytotoxic T lymphocytes.

– Tumor cells through cytotoxic T lymphocytes. B.

(B)Execution Phase of Apoptosis

–• Te above mentioned two initiating pathways produce initiator caspases namely:(1)the mitochondrial pathway activates initiator caspase-9, and (2) the death receptor pathway activates the initiator caspase-8

–• The initiator caspases activate another series of caspases called executioner caspases (such as caspase-3 and -6) that mediates the fnal phase of apoptosis.

•– Caspases also degrade components of nuclear matrix and cytoskeleton resulting in fragmentation of involved cells.

Diagnosis/Detection of Apoptosis

1.DNA fragmentation assay is carried out by electrophoresis of genomic DNA. Apoptosis produces “step ladder pattern” in contrast to smeared pattern seen in necrosis.

2.Chromatin condensation seen by hematoxylin and eosin, Feulgen and acridine orange staining.

Disorders Associated with Dysregulated Apoptosis

 • Disorders with reduced apoptosis: It may allow the survival of abnormal cells.
– Cancer
– Autoimmune disease.

• Disorders with increased apoptosis: This will cause an excessive loss of cells.

– Neurodegenerative diseases (Alzheimer, Huntigton, Parkinson disease)

– Ischemic injury:

– Death of virus-infected cells:

 Clinical Significance of Apoptosis in Cancers

• Normally, cells with damaged (mutated) DNA are cleared in the body by undergoing apoptosis.

Differece between apoptosis and necrosis

PATHOLOGIC CALCIFICATION

Types of pathologic calcifcation are: (1) dystrophic and(2) metastatic

HYALINE CHANGE

Hyaline refers to an alteration within cells or in the extracellular space, which gives a homogeneous, glassy, pink
appearance in routine histological sections.

Examples of hyaline change

PIGMENTS

Causes of hyper and hypopigmentation

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