Lecture 3 Cell Adaptation, Injury & Death

Dr. Nabila Hamdi

MD, PhD

ILOs

• Describe the major mechanisms whereby most injurious agents exert their effects

• Understand the examples of cell injury stated in this lecture, including their causes

and mechanisms

• Describe cell changes that occur with atrophy, hypertrophy, hyperplasia and

metaplasia, and state general conditions under which these changes occur

• State and discuss patterns of reversible/irreversible cell injury

• Differentiate cell death associated with apoptosis and necrosis

• Recognize the different patterns of necrosis

• Compare the pathogenesis of dystrophic and metastatic calcifications

• Understand subcellular responses and autophagy

• Define intracellular accumulations and cite examples

• Understand the process of aging 2

Outline I. Overview

II. Cellular Adaptation to Injury

III. Causes of Cell Injury

IV. Morphology of Cell & Tissue Injury 1. Reversible injury

2. Necrosis/Apoptosis

3. Patterns of Tissue Necrosis

V. Mechanisms of Cell Injury 1. General Biochemical Mechanisms

2. Ischemic & Hypoxic Injury

3. Ischemia/Reperfusion Injury

4. Free Radical-Induced Cell Injury

5. Chemical Injury

VI. Autophagy

VII. Intracellular Accumulations

VIII. Pathologic Calcifications

IV. Aging

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Mechanisms of Cell Injury General Biochemical Mechanisms

The principal biochemical mechanisms and sites of damage in cell injury ATP: adenosine triphosphate; ROS: reactive oxygen species

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Mechanisms of Cell Injury ATP Depletion

Depletion of ATP to less than 5% to 10% of normal levels has widespread effects

on many critical cellular systems

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Membrane damage

Mechanisms of Cell Injury Mitochondria in cell injury and death

Mitochondrial permeability transition pores

(high-conductance channels)

Failure of oxidative phosphorylation

Abnormal oxidative phosphorylation

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Cytochrome C

Mechanisms of Cell Injury Calcium Influx

ATP-dependent calcium

transporters (Ischemia/Toxins)

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Activation of caspases

Apoptosis

Necrosis

Mechanisms of Cell Injury Oxidative Stress

Oxygen-derived free radicals

In all cells, superoxide (O2•) is generated during mitochondrial respiration by the electron transport chain and may be converted to H2O2 and the hydroxyl (•OH) free radical or to peroxynitrite (ONOO−)

(Superoxide dismutase)

Pathways of production of reactive oxygen species (ROS) Oxygen-derived free radicals 8

(metals) Acute iron toxicity

Mechanisms of Cell Injury Oxidative Stress

The generation, removal, and role of reactive oxygen species (ROS) in cell injury

• Superoxide dismutase: O2•→H2O2 • Glutathione peroxidase: 2 GSH (glutathione) + H2O2 → GS-SG + 2 H2O • Catalase: 2H2O2 → O2 + 2H2O

• Endogenous or exogenous antioxidants (vitamins E, A, and C and β-carotene) may either block the formation of free radicals or scavenge them once they have formed.

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Mechanisms of Cell Injury Defects in Membrane Permeability

The most important sites of membrane damage during cell injury are the mitochondrial membrane, the plasma membrane, and membranes of lysosomes. 10

Ischemic and Hypoxic Injury

Ischemia is the most common cause of cell injury in clinical medicine

Ischemia injures tissues faster than does hypoxia !

Why?

Anaerobic glycolysis (less efficient)

Anaerobic glycolysis No delivery of substrates

ATP depletion

Loss of function (60 sec) + Reversible changes

Coronary occlusion

If ischemia persists

Irreversible injury and necrosis

• Severe swelling of mitochondria • Damage to plasma membranes • ROS accumulation • Influx of calcium

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Ischemia/Reperfusion Injury

Oxygen paradox

1. ROS generation : • mitochondrial damage leads to incomplete reduction of oxygen • action of oxidases in leukocytes, endothelial cells, or parenchymal cells • antioxidant defense mechanisms are compromised by ischemia

2. Inflammation : • increased influx of leukocytes and plasma proteins • The products of activated leukocytes and complement system

Under certain circumstances, the restoration of blood flow to ischemic but viable tissues (myocardial and cerebral ischemia) results, paradoxically, in the death of cells that are

not otherwise irreversibly injured.

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Chemical/Toxic Injury

Some chemicals act directly • Mercuric chloride poisoning • Antineoplastic chemotherapeutic agents

Other chemicals must be first converted to reactive toxic metabolites (P-450 in SER) • Carbon tetrachloride CCl4 CCl3

• Liver toxicity "fatty liver“ within 2 hours!

• Acetaminophen overdose Acute liver failure

Direct binding to critical molecular component or cellular organelle (membrane proteins, DNA…)

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Chemical/Toxic Injury

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Intracellular Accumulations

Fatty liver (Steatosis)

A, The possible mechanisms leading to accumulation of triglycerides in fatty liver. Defects in any of the steps of uptake, catabolism, or secretion can lead to lipid accumulation. B, High-power detail of fatty change of the liver. In most cells the well-preserved nucleus is squeezed into the displaced rim of cytoplasm about the fat vacuole. (Courtesy of Dr. James Crawford, Department of Pathology, University of Florida School of Medicine, Gainesville, Florida.)

Alcohol

CCl4

Malnutrition

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Autophagy (“self-eating”)

Lysosomal Catabolism

• Autophagy refers to lysosomal digestion of the cell’s own components.

• It is a survival mechanism in times of

nutrient deprivation.

• With time, starved cell eventually can no longer cope by devouring itself; at this stage, autophagy may also signal cell death by apoptosis.

• Autophagy is also involved in the clearance of misfolded proteins, for instance, in neurons and hepatocytes

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Lipofuscine

Pathologic Calcification Dystrophic

Calcification of the aortic valve (important cause of aortic stenosis in the elderly)

A view looking down onto the unopened aortic valve in a heart with calcific aortic stenosis

Dystrophic calcification is the abnormal deposition of calcium salts in dead or dying tissues, in the absence of calcium metabolic derangements

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Normocalcemia

Pathologic Calcification Metastatic

Increased secretion of PTH (primary parathyroid tumors or production by

other malignant tumors)

Destruction of bone (immobilization, tumors)

Vitamin D-related disorders (vitamin D intoxication)

Renal failure (phosphate retention leads to secondary hyperparathyroidism)

Hypercalcemia

deposition in normal tissues

Metastatic calcification is the deposition of calcium salts in normal tissues and almost always reflects some derangement in calcium metabolism

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Aging

Telomeres are short repeated sequences of DNA present at the linear ends of chromosomes that are important for ensuring the complete replication of chromosome ends and for protecting the ends from fusion and degradation. When somatic cells replicate, a small section of the telomere is not duplicated, and telomeres become progressively shortened. The ends of chromosomes cannot be protected and are seen as broken DNA, which signals cell cycle arrest. The lengths of the telomeres are normally maintained by nucleotide addition mediated by an enzyme called telomerase.

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References

ROBBINS Basic Pathology 8th Edition Basic Pathology 7th Edition, by Kumar, Cotran and Robbins Source of the cover cell image http://timothyjoseph.net/kill-or-be-killed/

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