بسم الله الرحمن الرحيم
Cell Injury, Cellular Adaptation & Cell Death
Dr. Wahda M.T. Al-Nueimy
Professor
Department of Pathology
University of Mosul
4th October 2015
Factors that determine fate of cells1-Type of injury (chemical or physical….2-Severity of injury( Mild or moderate or sever).3-Duration of exposure ( short or long).4-Type of cells.5-State of cell.6-Adaptability of the cell.
According to capacity of cell to division it divided into High capacity (labile cell) Nil capacity(permanent cell Epidermis Neurons Gastrointestinal epithelium Cardiac muscle Respiratory epithelium Skeletal muscle Bone marrow Low capacity (stable cell) Hepatocytes Pancreas Kidney Smooth muscle Bone cartilage
Acute Cell Injury Reversible cell injury: indicates that the cellular changes will regress and disappear when the injurious agent is removed; the cell will return to normal both morphologically and functionally Irreversible cell injury: occurs when the injury persist or when it is severe from the start. Here the cell reaches the point of no return and progression to cell death is inevitable.
Causes of cell injury1-HypoxiaIschemia ( decrease blood supply)Cardiac & respiratory diseasesLow O2 carrying capacity2-Physical injury (temp, radiation, electrical shock, trauma, change in atmospheric pressure)3-Chemical agents & drugs.4-Microbial agents (virus, bacterial, …..etc)5-Immunologic reactions (hypersensitivity reaction , anaphylactic shock & autoimmune diseases) 6-Genetic derangement (Down’s syndrome & sickle cell anemia)7-Nutritional imbalance (vitamin deficiency, protein deficiency, increase fat, Obesity, alcoholism)8-Aging
Mechanism of cell injury (pathogenesis) The susceptible targets in cell are 1-Cell membrane destructed by phospholipase which secreted for example by certain bacteria. Cell membrane damage play the Key factor in the pathogenesis of irreversible cell injury mediated by excessive influx of calcium into the cell. 2-ATP production lost by e.g., cyanide which inactivate cytochrome oxidase in mitochondria causing decrease ATP production 3-Protein synthesis 4-Genetic apparatus
Free radical induced injury FR are chemical species with unpaired electron in the outer shell These are highly reactive & autocatalytic Source of free radicals 1-endogenous (leukocytes, macrophages & endothelial cells) 2-metabolites of drugs & chemicals 3-Absorption of radiant energy Types of free radicals Superoxide, nitroxide, hydroxyl, hydrogen peroxide, carbontrichloride
Example of FR induced injury Inflammation as a part of defense mechanism Reperfusion injury to a partially ischemic cells reperfusion cause release of FR from leukocytes Aging process decrease ability to handle FR O2 toxicity e.g., diffuse alveolar damage in lung Radiation Chemical & drug injury e.g., CCL3 cause severe injury in the liver
Targets of FR injury in the cells Membrane damage through the process of lipid peroxidation Cross linking proteins forming disulfide bonds DNA: Single strand break in DNA & induction of mutation that interfere with cell growth
Chemical injury There are 2 general classes of chemical injury 1- Direct interaction with cellular component e.g., mercuric chloride cause membrane damage by binding to sulfhydryl group of cell membrane 2-Indirect by converted in cell into toxic metabolite e.g., carbon tetrachloride change to carbon trichloride free radical result in either fatty change or lipid peroxidation
Microbial injury 1-Direct induced injury e.g., poliovirus cause direct destruction of cell membrane of the host cell by insertion of the virus to the cell membrane 2-Indirect induced injury e.g., hepatitis B virus cause destruction of cell membrane of the cell by stimulation of the immune system against the viral protein that exposed on the cell membrane
Morphology of reversible cell injury: By Light Microscope Cellular swelling result in large pale cytoplasm Hydropic vacuolation Fatty change Clumping of chromatin
Morphological changes in irreversible cell injury By LM: Nuclear changes including Pyknosis (nuclear shrinkage + increase basophilia of the nucleus) Karyorrhexis (fragmentation with nuclear dust) Karyolysis (nuclear loss) A nucleated cells: have intensely eosinophilic cytoplasm due to Loss of RNA Glycogen depletion Denatured intra-cytoplasmic protein
Liver cell necrosis: Nuclear changes
normalpyknosis
karyorrhexis
karyolysis
Necrosis: Morphologic changes that follow cell death in the living tissue or organs due to action of degradative enzymes or protein denaturation on irreversibly injured cells Mechanism of necrosis: Denaturation of proteins Enzymatic digestion by Autolysis by lysosomal enzyme of the cell itself Heterolysis by surrounding inflammatory cells (Neutrophils & Monocytes) It is passive process Associated with inflammation Randomly occurs
Involve a group of cells Always pathologicCauses : ischemia (cell death due to decrease blood supply), chemical injury or infarction ( cell death due to cut of blood supply), nutritional….etcTypes of necrosis:Coagulative necrosisLiquefactive necrosisCaseous necrosisGangrenous necrosis (Gangrene)Fat necrosisFibrinoid necrosisGummatous necrosis (Gumma)
1- Coagulative necrosis The commonest type of necrosis Infarcts occur in all solid organs except the brain & spinal cord result in liquefactive necrosis Grossly: Whitish-gray or red-hemorrhagic firm wedge shape area of infarction Histology: Preservation of the tissue architecture & cellular outline for sometime with loss of internal details including nuclei Result from denaturation of all proteins including enzyme as a result of ischemia & acidosis Fate: after several days fragmentation & phagocytosis then healing .
Coagulative necrosis (Myocardial infarction in the heart)
infarctionIt is an ischemic necrosis caused by occlusion of either the arterial supply or the venous drainage. Necrosis is of coagulative type (except brain and spinal cord : liquifactive). The necrotic zone is called an infarct.
classification
Infarcts are classified on the basis of their color into: 1-Red(haemorrhagic) infarction. 2-White(anemic) infarction. and on the presence or absence of infection into: 1-Septic infarction. 2-sterile infarction.Red infarct(haemorrhagic)
Venous occlusion(testis , ovary). Loose tissue that allow the blood to collect in the infarcted zone (lungs). Tissues with dual circulation(lungs, small intestine). Previously congested tissues(from sluggish venous flow). Reperfusion of previously ischemic tissue (following angioplasty of an arterial obstruction).LUNG INFARCT
Grossly, red infarcts are sharply circumscribed, firm and dark red to purple. Over a period of several days, acute inflammatory cells infiltrate the necrotic area from the viable border. The cellular debris is phagocytosed and digested by polymorphonuclear leukocytes and later by macrophages. Granulation tissue eventually forms, to be replaced ultimately by a scar.White infarct (anemic)
Occur in the arterial occlusion in solid organs with end-arterial circulation (spleen, kidneys, heart). Most infarcts tend to be wedge-shaped , with the occluded vessel at the apex and the periphery of the organ forming the base. On gross examination, 1 or 2 days after the initial hyperemia, the infarct becomes soft, sharply delineated, and light yellow due to denaturated cellular proteins which resist digestion by proteiolytic enzymes. The border tends to be dark red, reflecting hemorrhage into surrounding viable tissue. Microscopically, a pale infarct exhibits uniform coagulative necrosis.Coagulative necrosis- Kidney
The effects of vascular occlusion can range from no or minimal effect to causing the death of a tissue or person. The major determinants of the eventual outcome are: 1- Nature of the vascular supply ,the availability of an alternative blood supply is the most important determinant of whether vessel occlusion will cause damage, the lungs, liver, hand and forearm, have dual blood supply so they are relatively resistant to infarction. In contrast, renal and splenic circulations are end-arterial, and vascular obstruction generally causes tissue death.
2- Rate of occlusion development. Slowly developing occlusions are less likely to cause infarction, because they provide time to develop alternate perfusion pathways. 3- Vulnerability to hypoxia. Neurons undergo irreversible damage when deprived of their blood supply for only 3 to 4 minutes. Myocardial cells are also quite sensitive and die after only 20 to 30 minutes of ischemia. In contrast, fibroblasts within myocardium remain viable even after many hours of ischemia. 4- Oxygen content of blood. A partial obstruction of a small vessel that would be without effect in an otherwise normal individual , but it might cause infarction in an anemic or cyanotic patient.
2- Liquefactive necrosis Early softening & liquefaction of the necrotic tissue Proteolytsis over protein denaturation Seen in Ischemic necrosis of CNS Abscess formation in pyogenic infection Gross Soft liquid like Histology Loss of original tissue .
Liquefactive necrosis- Brain infarction
3- Caseous necrosisBeing soft & yellow white appears as cheese-like gross appearanceHistology:Tissue architecture is completely loss. Appears as a brightly eosinophilic & amorphous structureless materialCharacteristic of Tuberculosis(TB):It’s coagulative necrosis modified by capsule lip- polysaccharide of TB bacilliIt could be seen in other lesions so it is not pathognomonic of TB .Caseous necrosis- involving hilar lymph node & is elicited grossly as cheesy like material
Fat necrosis4-
Necrosis of adipose tissue, characterized by the formation of small quantities of calcium soaps when fat is hydrolyzed into glycerol and fatty acids. Also called steatonecrosis . A term for necrosis in fat, caused either by release of pancreatic enzymes from pancreas or gut (enzymic fat necrosis) or by trauma to fat, either by a physical blow or by surgery (traumatic fat necrosis) in breast.
Fat necrosis 1-Enzymatic fat necrosis: In acute hemorrhagic pancreatitis cause activated lipase leading to adipose tissue destruction causing releasing of triglycerides & fatty acid Deposition of calcium ending in calcium soap 2-Traumatic fat necrosis: Trauma to the breast causing rupture of fat cells resulting in foreign body reaction Ending in fibrosis & calcification causing stony hard lump which is easily misdiagnosed by carcinoma of breast clinically.
Fat necrosis of the mesentery: chalky white patches on the surface of mesentery due to enzymatic digestion of mesenteric fat secondary to acute pancreatitis
Fatty necrosis-Acute pancreatitis
5- Fibrinoid necrosis Intense eosinophilic staining of involved (necrotic) tissue, like fibrin Example: Fibrinoid necrosis of blood vessels in malignant hypertension & vasculitis Fibrinoid necrosis of collagen tissue in connective tissue disease as in rheumatoid arthritisis caused by immune-mediated vascular damage. It is marked by deposition of fibrin-like proteinaceous material in arterial walls, which appears eosinophilic on light microscopy.
Artery, fibrinoid necrosis
6- Gangrene It is coagulative necrosis plus putrefaction by saprophytes (anaerobic bacteria) Either wet gangrene which has large amounts of fluid as in D.M. Or dry gangrene drying & mummification of dead tissue, seen in distal parts of the lower limbs associated with peripheral vascular diseases (atherosclerosis, vasculitis). Necrosis is separated by a line of demarcation from viable tissue
Gangrene
Gangrene
It can be classified into two types according to the cause of the tissue necrosis: Primary gangrene Secondary gangrene
Primary gangrene
It is brought by infection with pathogenic bacteria which both kill the tissue by secreting exotoxins & then invade & digest the dead tissue.Secondary gangrene
This type of gangrene is characterized by necrosis due to some other causes , usually loss of blood supply from vascular obstruction or tissue laceration & saprophytic bacteria then digest the dead tissue , there are two types : Dry gangrene Wet gangreneDry gangrene
Due to gradual cut of blood supply. The line of demarcation between dead and living tissue is clear. The lesion remains localized .Wet gangrene
The infected tissue are edematous due to large amount of subcutaneous fluid. The demarcation between dead and living is indistinct. May extend proximally beyond the site of infective. Wet gangrene is seen in the bowel due to mesenteric vascular occlusion and in diabetic limb.7- Gummatous necrosis Derived its name from gumma, which is a necrotic lesion seen in the tertiary syphilis It is modified type of coagulative necrosis
What’s the fate of necrotic tissue???Body treats necrotic tissue as a foreign materialsIt stimulates an inflammatory reaction that eventually removes the necrotic tissue & prepare the scene for the process of repairRepair process by Regeneration to the normal state.Organization by granulation tissue and fibrosis.
Apoptosis ( Programmed cell death) Death of single cell as a result of the activation of a genetically programmed (suicide) pathway through which the cell removed with minimal damage to the tissue containing them.
How the process of apoptosis is initiated? Different types of stimuli causing activation of caspases enzymes, which play the key role in the apoptosis, this activate cytoplasmic endonuclease, proteases & transglutaminase Endonuclease cleavage the DNA into fragments of double stranded DNA Protease degrade cytoskeleton & nuclear proteins Transglutaminase cause cross linking of cytoplasmic proteins causing shrinkage of the cells
Examples where apoptosis occurs include: a-Physiologic apoptosis 1-During embryogenesis; i.e. it is responsible for shaping various organs and structures . 2- Hormone- dependent involution. e.g. of endometrium during the menstrual cycle & lactating breast after weaning. 3-Proliferating cell populations: e.g. intestinal epithelium, skin & blood cells.
b-Pathological apoptosis; 1-Atrophy of the prostate after castration. 2-Virally infected cells attacked by cytotoxic T -lymphocytes, as in acute viral hepatitis (Councilman body) 3- Neoplasia. 4-Radiation 5-Cytotoxic drugs 6-Some mature B & T lymphocytes cannot distinguish self from non self antigens, if that remain, will lead to destroy healthy body cells (autoimmune). 7-Dermatosis (Civette bodies)
The cytoplasm is intensely esoniphilic (pinkish) and the nucleus condensed (pyknotic)
So, failure of cells to undergo apoptosis may result in undesirable effects that includes: 1-Anomalous development of various organs and tissues. 2-Progrssive acceleration of tumor growth. 3-Autoimmune diseases e.g. SLE. , rheumatoid arthritis.Differences between apoptosis & necrosis
ApoptosisNecrosis
Active process Occur in single cells Physiological & pathological No inflammatory reaction Step-ladder appearance on gel-electrophoresis for DNA material Programmed process Mechanism; Gene activation Caspases activation causing activation of activate cytoplasmic endonuclease, proteases & transglutaminase
Passive process Affects mass of cells Always pathological Stimulate inflammation Smudge pattern appearance of DNA material on gel-electrophoresis Random process Mechanism; ATP depletion Cell membrane injury
Differences between apoptosis & necrosis
ApoptosisNecrosis
Morphology: Cell shrinkage Nuclear condensation & fragmentation Formation of apoptotic bodies Apoptotic bodies engulf by macrophages
Morphology Cell swelling Nuclear changes (pyknosis, karyorrhexis & karyolysis) Eosinophilic cytoplasm Necrotic area infiltrate & cleaned by inflammatory cells
Cellular adaptations The adaptive responses include 1-Atrophy 2-Hypertrophy. 3-Hyperplasia. 4-Metaplasia.
1- Atrophy refer to the decrease in the size the organ as a result of decrease in size of cells with loss of cell substances. Cells exhibit autophagy with increase in number of autophagic vacuoles & lipofuscin pigment causes: Pathological & physiological 1-Decrease in the workload 2-Denervation: e.g. paralysis of limb due to nerve injury or poliomyelitis. 3-Under nutrition as in starvation 4-Loss of endocrine stimulation e.g. atrophy of the gonads in hypopituitarism. 5-Aging 6-Diminish blood supply
A. Normal brain of a young adult. B. Atrophy of the brain in an old male with atherosclerotic disease. Atrophy of the brain is due to aging and reduced blood supply. Note that loss of brain substance narrows the gyri and widens the sulci.
2- Hypertrophy Refer to increase in the size of organ as a consequence of the increase of cell size It can be physiological or pathological e.g., Uterus in pregnancy, skeletal m. in athletes, or manual workers, left ventricular hypertrophy (pathological). Hepatocytes hypertrophy in barbiturate drug therapy Compensatory mechanism after nephrectomy
Hypertrophic cardiomyopathy is an example of pathological hypertrophy due to increase demand, this ultimately results in increase in the size of the organ
3- Hyperplasia Is refer to the increase in the size of the organ as a result of increase in the number of cells Cells that undergo hyperplasia are those capable of cell division (labile cells) Hyperplasia is divided into: Physiological: which is either hormonal (proliferation of the breast glandular epithelium of female at puberty, or during pregnancy. or compensatory (e.g. after partial hepatectomy). Pathological: Extensive hormonal stimulation (e.g. endometrial hyperplasia). Or effect of growth factors as in healing of wounds forming keloid ( exaturated scar)
Endometrial hyperplasia is an example of hormone-induced hyperplasia due to hyperestrogenism.
Endometrial hyperplasia-there is hyperplasia of the both glandular & stromal elements.
4- Metaplasia; this refer to replacement of one mature cell type by an other mature cell type, which could be either epithelial or mesenchymal It is an adaptive reversible process It may represents an adaptation of cells more sensitive to stress by other that are more resistant to the adverse environment. E.g. Squamous metaplasia of the laryngeal and bronchial respiratory epithelium due to smoking. Columnar metaplasia of esophageal sq. epithelium. as a result of prolonged reflux esophagitis. Squamous metaplasia of urothelium of the bladder due to bilharzias or stone.Metaplasia of normal columnar (left) to squamous epithelium (right) in a bronchus
Barrett esophagus (Columnar metaplasia ): Metaplastic transformation (arrow) of the normal esophageal stratified squamous epithelium (Lt) to mature columnar epitheliumCalcification This refer to abnormal deposition of calcium salt. There are two forms of calcification; 1- Dystrophic calcification: refer to deposition of calcium in non viable or dying tissues in the presence of normal serum level of calcium with normal calcium metabolism. E.g., Areas of necrosis (caseous, coagulative or fat necrosis) Wall of artery in atherosclerosis Disease of valve Dead parasites & their ova
Pathogenesis
dystrophic calcificationDystrophic calcification of a vessel at the base of gastric ulcer
Dystrophic calcification of dead parasite in the lung
2-Metastatic calcification: refer to deposition of calcium in viable tissue in the presence of high serum calcium level. Causes of hypercalcaemia Hyperparathyrodism Vitamin D intoxication Sarcodosis Metastatic cancer to the bone Some other non metastatic cancer Organ affected are: kidneys, stomach, lungs & arteriesmetastatic calcification
Hyaline change A descriptive term referring to any alteration within the cells or in the extracellular spaces or structures that gives a homogenous, glassy-pink appearance in routine histologic sections stained with H & E Example of intracellular hyaline Hyaline droplets in PCT of kidney in proteinuria Russell bodies in plasma cells Alcoholic hyaline in hepatocytes Viral inclusion Example of extracellular hyaline Hyaline arteriolosclerosis , Amyloid , Scar.Fatty changes( Steatosis) Is abnormal accumulation of fat of triglyceride type within parenchymal cells rather than adipocytes. It is an example of reversible cell injury, seen often in the liver in which fat centrally metabolized & to less extend in heart & kidney
Causes of fatty change Toxins including alcohol Starvation & protein malnutrition Diabetes mellitus Oxygen lack (anemia & ischemia) Drugs & chemicals e.g., CCL4 Obesity Complicated pregnancy Reye syndrome
Morphology of Fatty liver Gross features : In the liver mild fatty changes shows no changes, but with further accumulation the organ enlarges & become increasingly yellow, soft & greasy to touch. Microscopically : In the early stages there are small fat vacuoles around the nucleus (microvesicular steatosis). With progression the vacuoles fuse together creating large clear space that displaces the nucleus to the periphery (macrovesicular steatosis).
Colored substances (pigments) A-Exogenous e.g. Carbon (coal dust), accumulation of carbon pigment in the lung give it black color called (anthracosis). Tattooing, the pigment inoculated is taken by dermal macrophages.
Carbon particles- Lung & LN
B-Endogenous pigments: 1-Lipofuscin (lipochrom pigment), is a yellow brown, intracytoplasmic pigment, which is seen in the cells undergoing slow atrophy. It represents residue of oxidized lipid derived from digested membrane of organelles 1-Particularly prominent in the cells of the liver & heart of the elderly (brown atrophy of the heart). It is called wear & tear pigment 2-Patein with sever malnutrition and cancer cachexia.
Lipofuscin pigment-liver wear & tear pigments
2-Melanin: this is an endogenous non-hemoglobin-derived brown black pigment. The skin pigment is produced by the oxidation of tyrosine through the help of tyrosinase enzyme within the melanocytes.Lesions associated with melanocytes areMoles (nevi) …….benign lesionMelanoma………..Malignant3-Bilirubin: It is a normal major pigment of bile , which is derived from the heme portion of hemoglobin. The conversion to bile occur in the liver. Jaundice: result from excess of bilirubin pigment
4-Hemosidrin: Is a hemoglobin-derived, golden-yellow to brown granules. Excess iron in the body causes hemosiderin to accumulate within the cell. Excess deposition is termed as hemosiderosis which is either localized or systemic.Special stain for iron is Prussian blue or Perl’s stain Localized hemosiderosis: result from local hemorrhage e.g. bruise, cerebral hemorrhage.