Tishk International UniversityScience FacultyMedical Analysis Department

Pathology

Fourth Grade- Spring Semester 2020-2021

Cell injury 3- Mechanisms of cell injury, Intracellular accumulations

Dr. Jalal A. JalalAssistant Professor of Pathology

Objectives

• Mechanisms of cell injury

• Intracellular accumulations

Pigments

Pathologic Calcification

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Mechanisms of Cell Injury

1. ATP depletion: failure of energy-dependentfunctions → reversible injury → necrosis.

2. Mitochondrial damage: ATP depletion → failure ofenergy-dependent cellular functions → ultimately,necrosis.

3. Influx of calcium: activation of enzymes thatdamage cellular components and trigger apoptosis.

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4. Accumulation of reactive oxygen species(ROS).

5. Increased permeability of cellular membranes: mayaffect plasma membrane, lysosomal membranes,mitochondrial membranes; typically culminates innecrosis

6. Accumulation of damaged DNA and proteins:triggers apoptosis

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Reactive Oxygen Species (ROS)• Have unpaired electron in most outer orbital

• Very-to-Extremely reactive

• Non-specific

Referred to as ROS, ROM, free radicals

• Usually damaging

• Major ROS

• Superoxide (O2.-)

• Hydrogen peroxide (H2O2)

• Hydroxyl radical (HO.)

• Nitric oxide (NO.)5

Sources of ROS1. UV light, ionizing radiation

2. Mitochondrial electron transport system (ETS)

3. Enzymes (P450, XO, NADPH oxidase)

4. Metals (Fe, Cu, etc)

• Effects/Targets of ROS

1. Membranes

2. Proteins

3. DNA damage

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Cellular defenses against ROS (Antioxidants)

• Enzymatic

• Superoxide dismutase(SOD),

• catalase,

• Glutathione peroxidase (GPX)

• Non-enzymatic

• Vitamins A, C, E

• Glutathione (GSH)

• Metal binding proteins (transferrin,ceruloplasmin, etc)

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INTRACELLULAR ACCUMULATIONS

• Under some circumstances cells may accumulateabnormal amounts of various substances, whichmay be harmless or associated with varyingdegrees of injury.

• The substance may be located in the cytoplasm,within organelles (typically lysosomes), or in thenucleus, and it may be synthesized by the affectedcells or may be produced elsewhere.

Fatty Change (Steatosis)

• Fatty change refers to any abnormal accumulationof triglycerides within parenchymal cells.

• It is most often seen in the liver, since this is themajor organ involved in fat metabolism, but it mayalso occur in heart, skeletal muscle, kidney, andother organs.

• may be caused by toxins, protein malnutrition,diabetes mellitus, obesity, and hyoxia.

• Alcohol abuse and diabetes associated with obesityare the most common causes of fatty change in theliver (fatty liver).

• The significance of fatty change depends on thecause and severity of the accumulation.

• When mild it may have no effect on cellularfunction.

• More severe fatty change may transiently impaircellular function,

Morphology

• gross appearance: the organ enlarges and becomesprogressively yellow until, in extreme cases, it may weigh 3to 6 kg (1.5-3 times the normal weight) and appear brightyellow, soft, and greasy.

• light microscopy: Early fatty change is seen as small fatvacuoles in the cytoplasm around the nucleus. In laterstages, the vacuoles coalesce to create cleared spaces thatdisplace the nucleus to the cell periphery.

Pigments

• Pigments are colored substances that are either exogenous,coming from outside the body, or endogenous, synthesizedwithin the body itself.

• The most common exogenous pigment is carbon (anexample is coal dust), a common air pollutant of urban life.

• When inhaled, it is phagocytosed by alveolar macrophagesand transported through lymphatic channels to the regionaltracheobronchial lymph nodes.

• Aggregates of the pigment blacken the draininglymph nodes and pulmonary parenchyma(anthracosis).

• Heavy accumulations may induce emphysemaor a fibroblastic reaction that can result in aserious lung disease called coal workers'pneumoconiosis.

Anthracosis, pleural surface of the lung

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Pigments

• Endogenous pigments include lipofuscin, melanin,and Hemosiderin.

• Lipofuscin, or "wear-and-tear pigment," is aninsoluble brownish-yellow granular intracellularmaterial that accumulates in a variety of tissues(particularly the heart, liver, and brain) as a functionof age or atrophy.

• Lipofuscin represents complexes of lipid andprotein that derive from the free radical- injury.

• The brown pigment when present in largeamounts, imparts an appearance to the tissue thatis called brown atrophy.

• By electron microscopy, the pigment appears asperinuclear electron-dense granules.

• Melanin

• is an endogenous, brown-black pigment.

• It is synthesized exclusively by melanocyteslocated in the epidermis and acts as a screenagainst harmful ultraviolet radiation.

Hemosiderin

• is a hemoglobin-derived granular pigment that is goldenyellow to brown and accumulates in tissues when there is alocal or systemic excess of iron.

• Iron is normally stored within cells in association with theprotein apoferritin, forming ferritin.

• Hemosiderin pigment represents large aggregates offerritin, readily visualized by light and electron microscopy;the iron can be identified by the Prussian blue histochemicalreaction.

Hemosiderosis

• A condition when there is systemic overload of iron,hemosiderin is deposited in many organs and tissues.

• It is found at first in the mononuclear phagocytes of theliver, bone marrow, spleen, and lymph nodes and inscattered macrophages throughout other organs.

• With progressive accumulation, parenchymal cellsthroughout the body (but principally the liver, pancreas,heart) become "bronzed" with accumulating pigment.

Hemosiderosis

• Hemosiderosis occurs in the setting of:

(1) increased absorption of dietary iron.

(2) hemolytic anemias.

(3) Repeated blood transfusions (the transfused red cellsconstitute an exogenous load of iron).

• In most instances of systemic hemosiderosis, theiron pigment does not damage the parenchymalcells or impair organ function despite an impressiveaccumulation.

• However, more extensive accumulations of iron areseen in hereditary hemochromatosis, with tissueinjury including liver fibrosis, heart failure, anddiabetes mellitus.

PATHOLOGIC CALCIFICATION

• Pathologic calcification is a common process in a wide variety of disease states;

• it implies the abnormal deposition of calcium salts, together with smaller amounts of iron, magnesium, and other minerals.

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• When the deposition occurs in dead or dyingtissues, it is called dystrophic calcification; it occursin the absence of calcium metabolic derangements(i.e., with normal serum levels of calcium).

• In contrast, the deposition of calcium salts innormal tissues is known as metastatic calcificationand almost always reflects some derangement incalcium metabolism (hypercalcemia).

Dystrophic calcification

• Dystrophic calcification is encountered in areas of necrosisof any type.

• It is virtually inevitable in the atheromas of advancedatherosclerosis, associated with intimal injury in the aortaand large arteries and characterized by accumulation oflipids.

• Dystrophic calcification of the aortic valves is an importantcause of aortic stenosis in the elderly.

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Metastatic Calcification• Metastatic calcification can occur in normal tissues

whenever there is hypercalcemia.

• The four major causes of hypercalcemia are

(1) increased secretion of parathyroid hormone, due to eitherprimary parathyroid tumors or production of parathyroidhormone-related protein by other malignant tumors;

(2) destruction of bone due to immobilization, or tumors(increased bone catabolism associated with multiplemyeloma, leukemia, or diffuse skeletal metastases);

(3) vitamin D-related disorders including vitamin Dintoxication and sarcoidosis

(4) renal failure, in which phosphate retention leads tosecondary hyperparathyroidism.

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Summary

• Variety of mechanisms may produce cell injury.

• Abnormal deposits of materials in cells and tissues result from excessive intake or defective transport or catabolism.

• Pigments are colored substances of endogenous( as melanin) or exogenous origin ( as carbon particles).

• Calcification is excess deposition of Ca+2 salts.

• Dystrophic & metastasizing calcification are types of calcification.

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