Cell Injury, Adaptation & Death

Dr. Nabila Hamdi

MD, PhD

B5.114 nabila.hamdi@guc.edu.eg

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Course Structure

Assessment

Methods Weight

Quizzes (best 2 out of 3) 20%

Assignments 5%

Mid-term exam 30%

Final exam 45%

The midterm and final exams are computer based - case oriented

problems

6th semester

Dr. Ahmed Ihab PL1

Dr. Hend EL Tayebi PL2

Dr. Nabila Hamdi PL3

Pathology & Histology PHTX 621

Cell Injury Inflammation Tissue Healing & Repair Immune Disorders Neoplasia

Course content

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How to study?

Lectures

Tutorials

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evelivesey.deviantart.com

Basic Science Cell, molecule

Clinical Practice Symptoms

Etiology

Pathogenesis

Pathology is the study of suffering

pathos logos

Why Pathology?

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ILOs

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

• Understand the examples of cell injury stated in this lecture

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

• Compare the pathogenesis of dystrophic and metastatic calcifications

• Define intracellular accumulations and cite examples

• Understand the process of aging 6

Outline I. Causes of Cell Injury

II. 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

III. Cellular Adaptation to Injury 1. Atrophy

2. Hypertrophy

3. Hyperplasia

4. Metaplasia

5. Subcellular Responses to Injury

6. Intracellular Accumulations

7. Pathologic Calcification

III. Reversible/Irreversible Injury

IV. Apoptosis/Necrosis

V. Ageing

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http://ww2.odu.edu/~czemlin/heartattacks.html

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Causes of Cell Injury

Cell Injury

Oxygen Deprivation Hypoxia: low O2 cc Ischemia: reduced blood supply

Chemical Agents poisons, air pollutants, insecticides, CO, ethanol, therapeutic drugs…

Infectious Agents

Immunologic Reactions autoimmune reactions, allergic reactions…

Genetic Defects Hb S Sickle cell anemia Enzyme metabolic diseases

Nutritional Imbalances Protein-calorie insufficiency Vitamin deficiencies Obesity, animal fat…

Physical Agents Trauma, radiation, electric shock, extremes of temperatures…

Aging Cellular senescence

Viruses, rickettsiae, bacteria, fungi, protozoans and worms

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Mechanisms of Cell Injury General Biochemical Mechanisms

Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components. The most important targets of injurious stimuli are (1) mitochondria, the sites of ATP generation; (2) cell membranes, on which the ionic and osmotic homeostasis of the cell and its organelles depends; (3) protein synthesis;

(4) the cytoskeleton; and (5) the genetic apparatus of the cell.

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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 12

Mechanisms of Cell Injury Oxygen in Cell Injury

The critical role of oxygen in cell injury Ischemia causes cell injury by reducing cellular oxygen supplies,

whereas other stimuli, such as radiation, induce damage by toxic activated oxygen species

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Mechanisms of Cell Injury Mitochondrial Damage

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Mechanisms of Cell Injury Calcium Influx

ATP-dependent calcium transporters (Ischemia/Toxins)

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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. 16

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

If oxygen is restored, all of these disturbances are reversible. If ischemia persists, irreversible injury and necrosis ensue.

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Free Radical-Induced Injury

The Stance of Antioxidants in Brain Tumors By Pinar Atukeren and M. Ramazan Yigitoglu

Sources of reactive oxygen species in the human body

Antioxidant defense mechanisms (II): enzymatic mechanisms José A. Hernández Cortés. Research Scientist (CEBAS-CSIC)

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Free Radical-Induced Injury

Cu2+/Fe2+

Endogenous or exogenous antioxidants (e.g., vitamins E, A, and C, and β-carotene)

Cell Injury. David S. Strayer Emanuel Rubin Copyright ©2009 Lippincott Williams & Wilkins

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Ischemia/Reperfusion Injury

Oxygen paradox

ROS generation

Inflammation

Calcium Influx

Medicine, Mediators of Lethal Reperfusion Injury: the Oxygen Paradox, by Ernst

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Chemical Injury

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

Other chemicals must be first converted to reactive toxic metabolites • 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

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