Cell Injury

Why is it important? Cellular injury appears to be the common denominator in almost all diseases.

The Cell and the Environment Stimuli [ Stimuli [ Causes of Cell Injury] CellAdaptation Cell Injury Reversible Irreversible (cell death) apoptosisnecrosis تكيف

Causes of Cell Injury 1. Hypoxia: 1. Hypoxia: (Oxygen deficiency) Mainly due to: most common  ischemia (impaired blood supply) most common  inadequate oxygenation of blood (cardio-respiratory failure)  loss of oxygen carrying capacity (anaemia)  Carbon monoxide poisoning 2. Physical Agents  Trauma, radiation, extremes of temperatures, electric shock 3. Chemicals and Drugs  Wide variety 4. Microbiologic Agents  Viruses, worms, bacteria ….. 5. Immunologic Reactions  Allergic reactions, autoimmune diseases 6. Genetic Defects  Obvious congenital malformations (Down syndrome)  Subtle single amino acid substitution (hemoglobin S of sickle cell anemia) 7. Nutritional Imbalances  Deficiency of nutrients/ or excess 8. Aging

The Cell and the Environment Stimuli Stimuli [Causes of Cell Injury] CellAdaptation  Achieving a new steady state and preserving viability تكيف

ADAPTATION 1.Atrophy: decrease in size or number of cells leading to reduction in tissue mass 2.Hypertrophy: increase in size of cells leading to increase in size of organ 3.Hyperplasia: increase in number of cells leading to increase size of organ 4.Metaplasia: Is the replacement of one type of cells by another

ADAPTATION  Atrophy: causes  Decreased workload  Loss of innervation  Diminished blood supply  Inadequate nutrition  Loss of endocrine stimulation  Aging

ADAPTATION  Hypertrophy: increase in size of cells leading to increase in size of organ  Increased functional demand  skeletal muscle in exercise  myocardium in hypertension  Specific hormonal stimulation  uterus in pregnancy

Heart, left ventricular hypertrophy Heart, normal

ADAPTATION  Hyperplasia: increase in number of cells leading to increase size of organ  Physiologic  Hormonal (breast during pregnancy)  Compensatory (partial hepatectomy  Pathologic  Excessive hormonal / growth factor  absolute or relative increase in estrogen over progesterone--endometrial hyperplasia

ADAPTATION  Metaplasia: Is the replacement of one type of cells by another  Squamous Metaplasia  Respiratory epithelium  cigarette smoking  vitamin A deficiency  Intestinal Metaplasia  Lower esophageal epithelium  chronic gastric reflux Osseous metaplasia: it is the formation of new bone at sites of tissue injury Myeloid metaplasia (extramedullary hematopoiesis): is the proliferation of hematopoietic tissue in sites other then the bone marrow such as liver or spleen

Aplasia Defective development resulting in the absence of all or part of an organ or tissue Aplasia Cutis Congenita

Hypoplasia Incomplete or arrested development of an organ or a part It may be hereditary or acquired. Enamel hypoplasia

The Cell and the Environment Stimuli CellAdaptation Cell Injury Reversible Atrophy Hypertrophy Hyperplasia metaplasia

Reversible Injury 1.Cellular swelling 2.Fatty change 1.Cellular swelling 2.Fatty change

– Also called hydropic change or vacuolar degeneration – Earliest change – Grossly: organ pallor, increased weight – Microscopy: small, clear cytoplasmic vacuoles Adenosine triphosphate (ATP) depletion water influx ---Cellular swelling Normal kidney tubules Rversible cell injury 1.Cellular swelling Reversible Injury

Lipid vacuoles in the cytoplasm. In cells participating in fat metabolism (e.g., hepatocytes and myocardial cells). 2. Fatty change Normal liver Fatty liver Reversible Injury

The Cell and the Environment Stimuli CellAdaptation Cell Injury Reversible Irreversible (cell death) apoptosisnecrosis Atrophy Hypertrophy Hyperplasia metaplasia Reduced oxidative phosphorylation, adenosine triphosphate (ATP) depletion water influx ---Cellular swelling

Irreversble Cell Injury Necrosis – Definition--sequence of morphologic changes that follow cell death in living tissue. – Enzymatic digestion of cells The enzymes derived from the lysosomes of the dead cells themselves, [autolysis], The enzymes derived from the lysosomes of immigrant leukocytes, [heterolysis].

Patterns of Acute Cell Injury Necrosis: morphology – Cytoplasmic eosinophilia (pink) – Nuclear changes Pyknosis --karyorrhexis --karyolysis Normal kidney tubulesIrrversible cell injuryRversible cell injury

NECROSIS Morphologic Patterns of Necrosis 1.Coagulative necrosis 2.Liquefactive necrosis 3.Caseous necrosis 4.Fat necrosis 5.Gangerene 6.Fibrinoid necrosis

Patterns of necrosis – Coagulative necrosis Preservation of structural outlines for days Characteristic of hypoxic cell death except in the brain Normal kidney tubules Coagulative necrosis Coagulative necrosis in kidney

Patterns of necrosis – Liquefactive necrosis complete digestion of the dead cells 1.bacterial and some fungal infection, 2.hypoxic cell death in brain

Patterns of necrosis – Caseous necrosis cheesy, white amorphous granular debris in a ring of granulomatous inflammation characteristic of tuberculous infection

Patterns of necrosis – Fat necrosis fatty acids combine with calcium to produce grossly visible chalky white areas On histologic examination, the foci of necrosis contain shadowy outlines of necrotic fat cells with basophilic calcium deposits It occurs in: 1.Breast trauma 2.Acute pancreatitis ---pancreatic lipases

Patterns of necrosis Gangrene Necrosis with putrefaction of the tissues, sometimes as a result of the action of certain bacteria, notably clostridia. The affected tissues appear black Dry gangrene Wet gangrene

Patterns of necrosis Fibrinoid necrosis Necrosis of the smooth muscle wall of arterioles in malignant hypertension. Also seen in immune vasculitis

The Cell and the Environment Stimuli CellAdaptation Cell Injury Reversible Irreversible (cell death) apoptosisnecrosis Atrophy Hypertrophy Hyperplasia metaplasia Reduced oxidative phosphorylation, adenosine triphosphate (ATP) depletion water influx ---Cellular swelling

Patterns of Acute Cell Injury Apoptosis (a falling away from) Apoptosis is programmed cell death. It is a pathway of cell death that is induced by a tightly regulated intracellular program in which cells destined to die activate their own enzymes to degrade their own nuclear DNA, nuclear proteins and cytoplasmic proteins. The cell's plasma membrane remains intact, but its structure is altered in such a way that the apoptotic cell sends signal to macrophages to phagocytose it.

Apoptosis is a complicated process Apoptosis is programmed process

Apoptosis – Involves single cells – Eosinophilia, condensed chromatin with peripheral aggregation – karyorrhexis

Regulation of apoptosis It is mediated by a number of genes and their products : - bcl-2 gene inhibits apoptosis - bax genes facilitates apoptosis - p53 facilitates apoptosis by inhibiting bcl2 and promoting bax genes.

Two types of cell death Necrosis Large No. of cells Invariably (always ) pathologic Disrupted Plasma membrane Inflammation Apoptosis Single cells or small clusters Often physiologic; may be pathologic Intact Plasma membrane No inflammation, phagocytes to eleminate it

The Cell and the Environment Stimuli CellAdaptation Cell Injury Reversible Irreversible (cell death) apoptosisnecrosis Atrophy Hypertrophy Hyperplasia metaplasia

Mechanisms of cell injury Depletion of ATP Damage to Mitochondria Influx of Calcium Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Defects in Membrane Permeability Damage to DNA and Proteins

Free radicals are atoms with an unpaired electron [odd number of electrons in its outer ring] They are highly reactive, chemically unstable, Generally present only at low concentrations, and tend to participate in, or initiate, chain reactions.

Free Radical-Induced Cell Injury Generation of reactive oxygen free radicals SMOKING

Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)

Free Radical-Induced Cell Injury  Free Radicals may be generated  Free Radicals may be generated within the cells by: 1.Hydrolysis of water into hydroxyl (OH. ) and hydrogen (H. ) free radicals by ionizing radiation (e.g. ultraviolet, x-ray) 2.Reduction-oxidation (Redox) reactions in normal cell physiology  Respiration generates  (O. ), (H 2 O 2 ), (OH. )  intracellular oxidases action (xanthine oxidase)  transition metal reactions (Fenton reaction) 3.Metabolism of exogenous chemicals  e.g. carbon tetrachloride 4.Macrophages and inflammatory reactions (e.g. Nitric oxide, & others)

Free Radicals  As Free radicals are produced in radiation and chemical cell injury, they are also generated normally during respiration and cell activities  Therefore cells should have mechanisms to degrade free radicals to minimize the damage  Antioxidant defenses 1.detoxifying enzymes 2.scavengers (vitamins E, C, A).

Cellular Accumulations

Intracellular Accumulations – Endogenous normal substance produced at normal or increased rate/rate of metabolism inadequate for removal (fatty liver) normal or abnormal substance cannot be metabolized (storage diseases) – Exogenous – cell cannot degrade substance (carbon)

Intracellular Accumulations Fatty Change (Steatosis) Any abnormal accumulation of triglycerides within parenchymal cells. It is most often seen in the liver, since this is the major organ involved in fat metabolism, but it may also occur in heart, skeletal muscle, kidney, and other organs. Alcohol abuse and diabetes associated with obesity are the most common causes of fatty change in the liver (fatty liver) in industrialized nations.

Intracellular Accumulations Fatty Change (Steatosis) – Liver increased weight, yellow color

fat vacuoles within cytoplasm of hepatocytes

Intracellular Accumulations Exogenous Pigments – Carbon (anthracosis) When inhaled, it is phagocytosed by alveolar macrophages and transported by lymphatics to lymph nodes mild accumulations usually are of no consequence-- heavy accumulations may induce a fibroblastic response

Intracellular Accumulations Endogenous Pigments – Lipofuscin (“wear and tear pigment) insoluble brownish-yellow granular intracellular material that accumulates in a variety of tissues (particularly the heart, liver, and brain) as a function of age or atrophy. It is not injurious to the cell but is important as a marker of past free-radical injury.

Intracellular Accumulations Endogenous Pigments – Melanin brown-black pigment produced in melanocytes It is synthesized exclusively by melanocytes located in the epidermis and acts as a screen against harmful ultraviolet radiation

Intracellular Accumulations Endogenous Pigments – Hemosiderin iron containing golden-yellow pigmen Local or systemic Local excesses of iron and hemosiderin result from hemorrhages or vascular congestion, eg hemosiderosis is the common bruise. With lysis of the erythrocytes, the hemoglobin eventually undergoes transformation to hemosiderin.

hemosiderin hemosiderosis systemic overload of iron, hemosiderin is deposited in many organs and tissues [ liver, bone marrow, spleen, and lymph nodes occurs in 1. increased absorption of dietary iron, 2. impaired utilization of iron, 3. hemolytic anemias, 4. transfusions hemochromatosis hereditary more extensive accumulations of iron with tissue injury including liver fibrosis, heart failure, and diabetes mellitus.

PATHOLOGIC CALCIFICATION dystrophic calcification deposition occurs in dead or dying tissues, normal serum levels of calcium. metastatic calcification deposition in normal tissues almost always reflects some derangement in calcium metabolism (hypercalcemia).

Match A and B A 1)Increase in size of skeletal muscle in exercise 2)increase in number of hepatocytes after partial hepatectomy 3)The replacement of respiratory epithelium to sequamous epithelium 4)Loss of innervation B a)Atrophy b)Hypertrophy c)Hyperplasia d)Metaplasia

Match A and B A 1.Pyknosis 2.fragmentation of the cell membrane 3.Hydropic change, vacuolar degeneration 4.Necrosis 5.Apoptosis B a.reversible cell injury b.irreversible cell injury

Match A and B A 1.Enzymatic digestion of cell by the dead cells themselves 2.Enzymatic digestion of cell by the inflammatory cells B a.Autolysis b.Heterolysis

Match A and B A 1.The affected tissues appear black 2.hypoxic cell death in brain 3.Autoimmune vasculitis 4.hypoxic cell death but not in brain 5.malignant hypertension 6.Breast trauma 7.Diabetes mellitus 8.tuberculous infection 9.Immune vasculitis B a.Coagulative necrosis b.Liquefactive necrosis c.Caseous necrosis d.Fat necrosis e.Gangerene f.Fibrinoid necrosis

Match A and B A 1.programmed cell death 2.Large no. of cells 3.always pathologic 4.Intact Plasma membrane 5.No inflammation 6.Can be physiological 7.Inhibited by bcl-2 gene 8.Gangrene B a.Necrosis b.Apoptosis

Match A and B A 1.systemic overload of iron 2.abnormal accumulation of triglycerides within parenchymal cells 3.Present in old hemorrhage 4.carbon dust 5.Inactivated by [ antioxidants] vitamin E, C, A B a.Steatosis b.Anthracosis c.Free radicals d.Hemosiderosis

Match A and B A 1.Acts as a screen against harmful ultraviolet radiation 2.vacuoles within cytoplasm of hepatocytes 3.May indicate old hemorrhage 4.wear and tear pigment and a sign of free radical injury B a.Fatty Change b.Lipofuscin c.Iron [ hemosidren ] d.Melanin

Match A and B A 1.deposition of calcium salts in dead or dying tissues 2.deposition of calcium salts in normal tissues 3.normal serum levels of calcium 4.hypercalcemia B a.dystrophic calcification b.metastatic calcification