MLS 114 LEC.pdf

MLS 114 LECTURE PRELIM INTRODUCTION TO PATHOLOGY "SCIENTIFIC STUDY OF THE MOLECULAR, CELLULAR, TISSUE, OR ORGAN SYST...

MLS 114 LECTURE PRELIM INTRODUCTION TO PATHOLOGY "SCIENTIFIC STUDY OF THE MOLECULAR, CELLULAR, TISSUE, OR ORGAN SYSTEM MEET THE FATHERS RESPONSE TO INJURIOUS AGENTS." FATHER OF PATHOLOGY: RUDOLF PATHOLOGY ANSWERS THE QUESTIONS: VIRCHOW WHAT IS THE DISEASE? FATHER OF HISTOLOGY: MARIE FRANÇOIS WHAT CAUSED THE DISEASE? XAVIER BICHAT HOW DID THE DISEASE DEVELOP? FATHER OF MICROSCOPY: ANTON VAN WILL THE DISEASE AFFECT THE PATIENT’S LEEUWENHOEK DAILY LIFE? FATHER OF MICROBIOLOGY: LOUIS PASTEUR PATHOPHYSIOLOGY FATHER OF CLINICOPATHOLOGIC relates the EFFECTS OF DISEASE TO THE CORRELATION: GIOVANNI B. MORGAGNI DISRUPTION OF NORMAL PHYSIOLOGICAL FUNCTIONS, e.g. the FATHER OF CELLULAR PATHOLOGY pathophysiology of essential hypertension Rudolf Virchow (1821-1905). German involves a raised peripheral vascular resistance pathologist who proposed cellular theory of and possibly an expansion of intravascular fluid disease and initiated biopsy pathology for volume. diagnosis of diseases. Pathophysiology, thus, includes STUDY OF DISORDERED FUNCTION (i.e. physiological FATHER OF BLOOD TRANSFUSION changes) and BREAKDOWN OF Karl Landsteiner (1863-1943). An Austrian HOMEOSTASIS IN DISEASES (i.e. pathologist who first discovered the existence biochemical changes). of major human blood groups in 1900 and was recipient of Nobel prize in 1930. HEALTH AND DISEASE FATHER OF EXFOLIATIVE CYTOLOGY Health George N Papanicolaou (1883- 1962). An complete physical, mental and social well American pathologist, who deve- loped Pap test being, not merely an absence of disease. for diagnosis of cancer of uterine cervix. Disease INTRODUCTION TO PATHOLOGY is expression of discomfort due to structural or Pathology consists of the abnormalities in functional abnormality. normal anatomy (including histology) and normal physiology owing to disease. Illness is the reaction of individual to disease in the The word PATHOLOGY is derived from two Greek form of symptoms. words- ‘Pathos’ meaning suffering and A DISEASE CAN FALL IN ONE OF THE FOLLOWING ‘logos’ means study. CATEGORIES: o Pathology is a study of the structural, DEVELOPMENTAL biochemical and functional changes in INFLAMMATORY cells, tissues and organs that underlie NEOPLASTIC disease. DEGENERATIVE STUDY OF DISEASE OR SUFFERING WHAT SHOULD WE KNOW ABOUT A DISEASE DESCRIBES THE EFFECTS, PROGRESS Definition AND CONSEQUENCE OF THE DISEASE Epidemiology - where & when? ATTEMPTS TO DETERMINE THE CAUSE Etiology - what is the cause? (ETIOLOGY) AND UNDERLYING Pathogenesis - evolution of disease MECHANISMS (PATHOGENESIS) Morphology - structural changes SINCE THE DISEASE EFFECT THE Functional consequences STRUCTURAL AND FUNCTIONAL Management COMPONENTS OF CELL, TISSUE OR Prognosis ORGAN OF THE BODY, IT IS THE Prevention 1 MLS 114 LECTURE PRELIM TERMINOLOGY IN PATHOLOGY 4. MICROBIOLOGY 1. Patient - is a person affected by the disease. deals with the study of microorganisms. 2. Lesion - is characteristic changes in tissue and 5. CHEMICAL PATHOLOGY cells. analysis of biochemical constituents of blood, 3. Morphology - is examination of diseased urine, semen, csf etc. tissue. (gross or microscopic) 6. IMMUNOLOGY 4. Etiology - is the cause of the disease. detection of abnormalities in the immune 5. Pathogenesis - is the mechanism by which the system of the body. disease is produced. 7. EXPERIMENTAL PATHOLOGY 6. Symptoms - subjective noticed by patient and study of disease in experimental animal. either reported or elicited on questioning 8. GEOGRAPHIC PATHOLOGY 7. Signs - objective and noticed by the clinician on study of diseases in populations in different examination, although occasionally may be parts of world. noticed by the patient 9. MEDICAL GENETICS 8. Pathognomonic - many disease have such It deals with the relationship between heredity consistent presentation to be almost diagnostic, and disease. e.g., a spiking fever, stiff neck and photophobia 10. MOLECULAR PATHOLOGY in meningitis; such definitive features are called detection and diagnosis of abnormalities at the _____________. level of dna 9. Syndrome - a well defined group of clinical features that commonly occur together, e.g., HISTOPATHOLOGY proteinuria, hypoproteinemia and edema concerned with the investigation and diagnosis together ‘nephrotic __________.’ of disease from examination of tissues 10. Prognosis - the probably outcome of a disease in a living individual (cure, morbidity or CYTOPATHOLOGY mortality). concerned with the investigation and diagnosis 11. Acute Illness - starts suddenly and resolves of disease from the examination of isolated either of its own accord or following treatment 12. Chronic Disease - starts insidiously and PATHOLOGY continues for a long time, possibly lifelong It involves the investigation of the causes of 13. Progressive Disease - if a chronic disease disease and the associated changes at the tend to deteriorate steadily levels of cells, tissues, and organs, which in turn o causes → changes → symptoms SUBDIVISION OF PATHOLOGY The range of the structural changes is from General Pathology - deals with general those affecting sub-cellular organelles principle of disease (molecular pathology) up to alterations seen by o e.g inflammation ,cancer, aging. the naked eye (gross pathology). Systemic Pathology - study of disease pertaining to the specific organs and body TWO IMPORTANT ASPECTS OF PATHOLOGY; systems. Etiology Pathogenesis SYSTEMIC PATHOLOGY ETIOLOGY 1. HISTOPATHOLOGY It means the origin of a disease, including the gross or macroscopic examination underlying causes and modifying factors. microscopic examination Most common diseases are caused by a IT IS FURTHER DIVIDED INTO combination of inherited genetic susceptibility surgical pathology and various environmental triggers. forensic pathology i.e. autopsy genetic → Disease ← environmental 2. CYTOPATHOLOGY exfoliative cytology PATHOGENESIS fnac Refers to the steps in the development of 3. HAEMATOLOGY disease. deals with the disease of blood and blood related components. 2 MLS 114 LECTURE PRELIM It describes how etiologic factors trigger cellular IMMUNOHISTOCHEMISTRY (IHC) AND and molecular changes that give rise to the IMMUNOFLUORESCENCE (IF): specific functional and structural abnormalities These techniques employ antibodies (with that characterize the disease antigen specificity) to visualize substances (for e.g. cellular proteins orsurface receptors) in tissue sections or cytological cell preparations. PATHOGENESIS OF ATHEROSCLEROSIS ELECTRON MICROSCOPY (EM): This has extended the range of pathology to the study of disorders at an organelle (subcellular) level and the demonstration of viruses in tissue samples from some diseases. The most common diagnostic use of electron microscopy Whereas etiology refers to why a disease arises, is the interpretation of renal biopsies i.e. helps pathogenesis describes how a disease develops. Thus, establish the diagnosis of various glomerular pathology provides the scientific foundation for the diseases. practice of medicine. BIOCHEMICAL TECHNIQUES AIM AND USES OF PATHOLOGICAL EXAMINATION By determining the changes in the chemical DIAGNOSIS OF DISEASES state of body help in the diagnosis and DETERMINING THE TREATMENT, understanding the various disease for example, raised levels of cardiac enzymes in the blood PROGNOSIS, AND GRADING. indicate damage to cardiac myocytes and thus MEDICO-LEGAL CONDITIONS, TO very helpful in establishing the diagnosis of DETERMINE THE CAUSE OF DEATH myocardial infarction (MI). RESEARCHES AND MEDICAL DISCOVERY HEMATOLOGICAL TECHNIQUES TECHNIQUES INCLUDED IN THE FIELD OF using complete blood picture, coagulation PATHOLOGY study, bone marrow, aspiration and flow cytometry. MACROSCOPIC PATHOLOGY (GROSS PATHOLOGY): CELL CULTURES this refers to the changes affecting various widely used in research and diagnosis to organs and tissues in diseases as evident to the prepare chromosome spreads for cytogenetic naked eye. analysis. MICROSCOPIC EXAMINATION determining the structural changes in tissue or organ under the microscope. HISTOCHEMISTRY the use of special stains that aid in demonstrating certain substances like Perl's stain for the detection of iron. 3 MLS 114 LECTURE PRELIM MEDICAL MICROBIOLOGY the study of diseases caused by organisms such as bacteria, fungi, viruses and parasites by using direct microscopical examination and culture/sensitivity. MOLECULAR PATHOLOGY concerned with the study of abnormal chromosomes and genes and their relevance to disease processes using in situ hybridization technique (ISH), polymerase chain reaction (PCR) and DNA microarrays. 4 MLS 114 LECTURE PRELIM CELL INJURY, CELL DEATH & ADAPTATIONS b. Extremes of temperature (burns and deep cold) An Overview c. Radiation and Electric shock Overview of Cellular Response to Stress and 3. Chemical Agents and Drugs Noxious Stimuli a. Poisons such as Arsenic and Cyanide Causes of Cell Injury b. Glucose or salts in hypertonic concentrations Overview of Cell Injury and Cell Death c. Environmental or Air Pollutants Necrosis d. Alcohol and Narcotic Drugs Apoptosis e. Insecticides and herbicides Cellular Adaptations 4. Infectious Agents: Like Viruses, Bacteria, Fungi, Intracellular Accumulations Parasites 5. Immunologic Reactions: Immune system serves Pathologic Calcification as defense against biologic agents; Immune reactions may in fact, cause cell injury , for example: OVERVIEW OF CELLULAR RESPONSES TO a. Autoimmune Diseases STRESS AND NOXIOUS STIMULI b. Anaphylactic Reactions 6. Genetic Derangements: Genetic defects may ́Adaptations are reversible functional and result in pathologic changes as conspicuous and structural responses to changes in physiologic obvious as the congenital malformations associated states (e.g., pregnancy) and some pathologic with down syndrome or a subtle as the single amino stimuli, during which new but altered steady acid substitution in haemoglobin S of Sickle Cell states are achieved, allowing the cell to survive Anaemia and continue to function. 7. Nutritional Imbalances a. Protein Calorie Deficiencies b. Vitamin Deficiency c. Lipids excess predispose to Atherosclerosis 8. Aging Cellular senescence leads to alterations in replication and repair abilities of individual cells and tissues. All of these changes result in a diminished ability to respond to damage and, eventually , the death of cells and of the organism OVERVIEW OF CELL INJURY & CELL DEATH Point of No Return Two phenomena consistently characterize irreversibility: 1. The inability to reverse mitochondrial dysfunction (lack of oxidative phosphorylation and ATP CAUSES OF CELL INJURY generation) even after resolution of original injury Oxygen Deprivation 2. Profound disturbances in membrane function Physical Agents Chemical Agents and Drugs Reversible Cell Injury: Morphologic Changes Infectious Agents The two main morphologic correlates of reversible cell Immunologic Reactions injury are: Genetic Abnormalities 1. Cellular Swelling: It is the result of failure of energy Nutritional Imbalances dependent ion pumps in the plasma membrane, leading to an inability to maintain ionic and fluid 1. Oxygen Deprivation (Hypoxia) homeostasis. a. Ischemia: Loss of blood supply to a tissue 2. Fatty Change: It occurs in hypoxic injury and b. Anaemia: Decreased haemoglobin, which in various forms of toxic or metabolic injury. It is turns leads to decreased oxygenation manifested by the appearance of small or large 2. Physical Agents lipid vacuoles in the cytoplasm. It occurs mainly in a. Mechanical trauma. cells involved in and dependent on fat 5 MLS 114 LECTURE PRELIM metabolism, such as hepatocytes and myocardial cells Necrotic (irreversible) 1. Cellular Swelling cell injury of epithelial It is the first manifestation of almost all forms of cells with loss of nuclei injury to cells. It is difficult to appreciate with and fragmentation of light microscope; it may be more apparent at cells and leakage of the level of whole organ. contents Gross Examination: When it effects many cells in an organ, it causes some pallor, increased turgor, and increase in weight of the organ. Microscopic Examination: May reveal small, clear vacuoles, within the cytoplasm ; these A normal cell and changes in reversible and represent distended and pinchedoff segments irreversible cell injury (Necrosis) of the endoplasmic reticulum. This pattern of non- lethal injury is sometimes called hydropic change or vacuolar degeneration. 2. Fatty Change It is manifested by the appearance of lipid vacuoles in the cytoplasm. Injured cells may also show increased eosinophilic staining. This eosinophilic staining becomes more pronounced with progression to necrosis Ultra structural changes of Reversible Cell Injury 1. Blebbing of plasma membrane 2. Blunting or distortion of microvilli 3. Loosening of intercellular attachments 4. Swelling and appearance of phospholipid – rich amorphous densities in mitochondria 5. Dilation of endoplasmic reticulum CELL DEATH 6. Detachment of ribosomes There are two principal types of cell death, necrosis and 7. Nuclear alterations with clumping of chromatin apoptosis, which differ in their mechanisms, morphology, and roles in physiology and disease. Morphologic changes in reversible and irreversible 1. Necrosis cell injury (necrosis) 2. Apoptosis NECROSIS Normal kidney tubules with “Sum of the morphologic changes that follow cell death viable epithelial cells in a living tissue or organism’’. Two mechanisms are involved in necrosis: 1) Enzymatic digestion of cells by catalytic enzymes a) Autolysis: Catalytic enzymes derived from the lysosomes of dead cells. b) Heterolysis: Catalytic enzyme derived from lysosomes of immigrant leukocytes. Early (reversible) ischemic 2) Denaturation of Proteins injury showing surface blebs, Increased Morphologic Changes in Necrosis eosinophilia of cytoplasm A. Changes in Cytoplasm ,and swelling of occasional Increased Eosinophilia: It is due to: cells. a. Loss of normal basophilia imparted by RNA in the cytoplasm b. Increased binding of Eosin to denatured intracytoplasmic proteins 6 MLS 114 LECTURE PRELIM Cell will assume a glassy homogenous early reaction to necrotic muscle. Compare with A and appearance. It is due to loss of glycogen with normal fibers in the lower part of figure particles Due to digestion of cytoplasmic organelles by COAGULATIVE NECROSIS – MYOCARDIAL enzymes, the cytoplasm will appear INFARCTION vacuolated and appear moth-eaten When there is Calcification of dead cell may occur marked cell injury, there is cell death. B. Changes in Nucleus This microscopic Pyknosis: Shrinkage of nucleus appearance of Karyolysis: Dissolution of nucleus myocardium is a Karyorrhexis: Fragmentation of nucleus mess because so many cells have TYPES OF NECROSIS died that the tissue is not recognizable. Many nuclei Several distinct types of necrosis are recognized: have become Pyknotic (shrunken and dark) and have 1. Coagulative Necrosis then undergone Karorrhexis (fragmentation) and 2. Liquefactive Necrosis Karyoloysis (dissolution). The cytoplasm and cell 3. Caseous Necrosis borders are not recognizable 4. Gangrenous Necrosis 5. Fibrinoid Necrosis II. LIQUEFACTIVE NECROSIS 6. Fat Necrosis Liquefactive Necrosis is characteristically seen in: a. Hypoxic death of cells within the central nervous I. COAGULATIVE NECROSIS system Coagulative Necrosis is the most common type b. Bacterial or occasionally fungal infections. of necrosis. Liquefaction completely digests the dead cells. The process of coagulative necrosis, with The end result is transformation of the tissue into preservation of the general tissue architecture a liquid viscous mass. If the process had been is characteristic of hypoxic death of cells (due initiated by acute inflammation, the material is to lack of blood supply) in all tissues except frequently creamy yellow because of the brain presence of dead white cells and is called pus. The pathogenesis of coagulative necrosis is A focus of liquefactive denaturation of proteins. necrosis in the kidney Myocardial Infarction is an important example caused by fungal of coagulative necrosis. It is also seen in seeding. The focus is infarcts of heart, kidney and spleen. filled with white cells and cellular debris, Part of kidney crating a renal abscess deprived of its that obliterates the normal architecture blood supply by an arterial LIQUEFACTIVE NECROSIS BRAIN embolus. This is an example of caogulative necrosis Cellular and nuclear detail has been Lost. The ghost outline of a glomerulus can be seen in the centre, with remnants of tubule elsewhere Grossly, the cerebral infarction at the upper left here demonstrates liquefactive necrosis. Eventually, the removal of dead tissue leaves behind a cavity. III. CASEOUS NECROSIS A distinctive form of coagulative necrosis. It is Fig. A: Normal Myocardium encountered most often in foci of Tuberculosis Fig B: Myocardium with coagulation necrosis (upper two Infection. The term caseous is derived from gross thirds of figure), showing strongly eosinophilic anucleate appearance of tissue (white and cheesy). myocardial fibers. Leukocytes in the interstetium are an 7 MLS 114 LECTURE PRELIM Microscopic Appearance: The necrotic focus associated severe toxaemia (spread of poisons appears as amorphous granular debris composed in the blood) of fragmented, coagulated cells and amorphous granular debris enclosed within a distinctive inflammatory border known a “Granulomatous Reaction” (ii) Secondary Secondary Gangrene: This is due to invasion of necrotic tissue usually by a mixed bacterial flora including putrefactive organisms and occurs in two forms: a. Wet gangrene: It occurs due to Arterial and venous occlusion. The tissues are moist at the start of the process either due to oedema or EXTENSIVE CASEOUS venous congestion. Examples are in NECROSIS LUNG IN strangulation of viscera and occlusion of leg TUBERCULOSIS arteries in obese diabetic patients Extensive caseous necrosis lung in Tuberculosis, with confluent cheesy granulomas in the upper portion. b. Dry Gangrene: It occurs due to Arterial IV. GANGRENOUS NECROSIS occlusion. Occurs especially in the toes and feet of elderly suffering from gradual arterial Gangrene is massive necrosis (Caused by occlusions; the putrefactive process is very acute ischemia or severe bacterial infection) slow and only small numbers of putrefactive followed by putrefaction organisms are present. Gangrene is a special type of necrosis, in which bacterial infection is superimposed on In Dry gangrene distal to coagulative necrosis and coagulative necrosis arterial occlusion, tissue is modified by the liquefactive action of the fluid formation will stop, but bacteria since veins are patent, the The bacteria proliferate in and digest the dead already present tissue fluid tissue often with the production of foul smelling will be drained into the gases. The tissue becomes green or black veins as normal because of the production of iron sulphide from degraded haemoglobin (PUTREFACTION) There are two main types of gangrene: (i) primary ; Primary (Gas Gangrene): It is due to infection of deep contaminated wounds in which there is considerable muscle damage, by bacteria of the CLOSTRIDIA group- anaerobic spore forming gram positive bacilli which produce saccharolytic and proteolytic enzymes resulting in digestion of muscle tissue with gas formation. The infection rapidly spreads and there is 8 MLS 114 LECTURE PRELIM DRY GANGRENE TOES VI. FIBRINOID NECROSIS This is Gangrene, or Fibrinoid Necrosis is a type of Connective necrosis of toes. The Tissue Necrosis It is seen particularly in toes were involved in a conditions where there is Deposition of frost bite injury. This is Antigen – Antibody Complexes. an example of ‘dry The important examples are Autoimmune gangrene’ in which Disorders like Systemic Lupus Erythematosus, there is mainly Rheumatic Fever and Polyartirtis Nodosa. In coagulative necrosis due to anoxic injury. these conditions the media and smooth muscle of blood vessels are especially involved. WET GANGRENE LEG Fibrinoid Necrosis is characterized by loss of normal structure and replacement by a This is Gangrene of the homogenous, bright pink-staining necrotic lower extremity. In this material that resembles fibrin microscopically. case the term ‘wet Note, however, that “fibrinoid” is not the same gangrene’ is more as occurs in inflammation and blood applicable because of coagulation. Areas of fibrinoid necrosis contains the liquefactive various amounts of Immunoglobulins, component from complement, albumin, break down products of superimposed infection in addition to the coagulative collagen and fibrin necrosis from loss of blood supply. This patient had Diabetes Mellitus. V: FAT NECROSIS Fat Necrosis may be due to: a. Direct Trauma to adipose tissue and extracellular liberation of fat. The result may be a palpable mass, particularly at a superficial site such as the breast b. Enzymatic lysis of fat due to release of Lipases. In Acute Pancreatitis there is release of pancreatic lipase. As a result, fat cells have their stored fat split into fatty acids, which then combine Fibrinoid Necrosis in with calcium to precipitate out as white soaps. an artery in a patient with polyarteritis FAT NECROSIS PANCREAS nodosa. The wall of Cellular injury to the the artery shows a pancreatic acini leads to circumferential bright release of powerful pink area of necrosis enzymes which damage with protein deposition fat by the production of and inflammation ( dark nuclei of neutrophils) soaps (combination of calcium salts with fat; fat saponification)), and these appear grossly as the soft Chalky white areas seen in this cut surface Fat Necrosis in acute pancreatitis: The areas of chalky white deposits represents foci of fat necrosis with calcium soap formation (Saponification) at sites of lipid breakdown in the mesentery 9 MLS 114 LECTURE PRELIM together to fill the vacant space leaving virtually no evidence of the process. PATHOGENESIS OF APOPTOSIS Apoptosis results from the action of intracellular cysteine protease called CASPASES which are activated following cleavage and lead to endonuclease digestion of DNA and disintegration of the cell skeleton. There are two major pathways by which caspases are activated: a. Activation through Death Factor (Fas Ligand): The is by signaling through membrane proteins such as Fas or TNF receptor intracellular death APOPTOSIS domain. An example of this mechanism is shown “Programmed Cell Death” by activated cytotoxic T cells expressing Fas It is a form of cell death designed to eliminate ligand. unwanted host cells through activation of b. Release of Cytochrome – C from the coordinated, internally programmed series of Mitochondria: The second pathway is via the events effected by a dedicated set of gene release of Cytochrome – C from mitochondria. products. Cytochrome – C binds to Apaf – 1 which then Apoptosis occurs when a cell dies through activates caspases. DNA damage induced by activation of an internally controlled suicide irradiation or chemotherapy may act through this program. pathway. It is a subtly orchestrated disassembly of cellular components designed to eliminate unwanted cells, during embryogenesis and in various physiologic processes. Doomed cells are removed with minimum disruption to the surrounding tissue. It also occurs, however, under pathologic conditions, in which it is sometimes accompanied by necrosis Apoptosis refers to a mechanism of cell death affecting usually single cells or a group of cells scattered in a population of healthy cells. It differs from necrosis and represents most of the times a physiological or at times a pathological response Mechanisms of Apoptosis: the two pathways of by which defective cells and abnormal cells die apoptosis differ in their induction and regulation, and and are eliminated. both culminate in the activation of caspases. In the mitochondrial pathway, proteins of Bcl-2 family, which The process is rapid and (completed in few hours), and regulate mitochondrial permeability become is considered in 2 stages: imbalanced and leakage of various substances from mitochondria leads to caspase activation. In the death Stage 1 (Dying Process): receptor pathway , signals form plasma membrane a. Active metabolic changes in the cell cause receptors lead to assembly of adaptor protiens into a cytoplasmic and nuclear condensation and “death – inducing signaling complex” ,which activates nuclear membrane is intact. caspases and the end result is the same b. Cell disintegrates into multiple Apoptotic Bodies, each surrounded by a part of plasma APOPTOSIS SPECIFIC GENE membrane. Gene that stimulates Apoptosis o e.g., bax – gene Stage 2 (Elimination Process): Phagocytosis of Apoptotic Bodies by surrounding APOPTOSIS INHIBITING GENE cells, e.g., liver cells, tumour cells. This is followed Gene that blocks apoptosis by rapid digestion. The surrounding cells move o e.g., bcl - gene 10 MLS 114 LECTURE PRELIM PHYSIOLOGIC CONDIITONS HAVING EVIDENT The sequential ultra APOPTOSIS structural changes 1. The programmed destruction of cells during seen in coagulation embryogenesis. necrosis (left) & 2. Hormone dependent involution in the adults, such Apoptosis (right). In as endometrial breakdown during menstrual cycle apoptosis, the initial and regression of lactating breast after weaning changes consist of 3. Cell depletion in proliferating cell population, such nuclear chromatin as intestinal crypt epithelia, in order to maintain a condensation and constant number fragmentation, followed 4. Elimination of cells that have served their useful by cytoplasmic budding purpose, such as neutrophils in an acute and phagocytosis of the extruded apoptotic bodies. inflammatory response and lymphocytes at the end Signs of coagulation necrosis include chromatin of an immune situations clumping, organellar swelling, and eventual membrane 5. Elimination of potentially harmful self-reactive damage. lymphocytes either before or after they have completed their maturation, in order to prevent Apoptosis of a liver cell reactions against the body’s owns tissues in viral hepatitis. The cell 6. Cell death induced by cytotoxic T lymphocytes, a is reduced in size and defense mechanism against viruses and tumours contains brightly that serves to kill virus-infected and neoplastic cells. eosinophilic cytoplasm 7. DNA damage: Radiation, cytotoxic anticancer and a condensed drugs, extremes of temperatures and even hypoxia nucleus can damage DNA, either directly or through production of free radicals. 8. Accumulation of misfolded proteins :Importantly folded proteins may arise because of mutations in DYSREGULATED APOPTOSIS (“too little or too the genes encoding these proteins or because of much’) extrinsic factors ,such as damage caused by free Disorders associated with reduced apoptosis: radicals. Excessive accumulation of these proteins An inappropriately low rate of apoptosis may in the ER leads to a condition called Endoplasmic prolong survival of abnormal cells. These Reticulum Stress (ER Stress), which culminates in accumulated cells then give rise to: a apoptotic death of cells a. Cancers, especially those carcinomas with 9. Cell injury in certain infections, particularly viral p53 mutations infections, in which loss of infected cells is largely b. Autoimmune disorders, which could arise, if due to apoptotic death may be induced by the virus autoreacitve lymphocytes are not removed ( as in adenovirus and HIV infections) after immune response. 10. Pathologic atrophy in parenchymal organs after Disorders associated with increased apoptosis. duct obstruction, such as occurs in the pancreas, These disorders are characterized by a marked loss parotid gland and kidney of normal or protective cells and include: a. Neurodegenerative diseases MORPHOLOGIC CHANGES IN APOPTOSIS b. Virus – induced lymphocyte depletion Cell Shrinkage: Cell is smaller in size; Cytoplasm c. Aplastic Anaemia is dense; organelles are tightly packed. Chromatin Condensation: Chromatin aggregates peripherally, under the nuclear membrane; nucleus may break in fragments Formation of cytoplasmic blebs and apoptotic bodies. Phagocytosis of apoptotic bodies by adjacent healthy cells ON HISTOLOGIC SECTIONS: Apoptosis involves single cell or small clusters of cells. The apoptotic cell appears as a round or oval mass of intensely eosinophilic cytoplasm with dense nuclear chromatin 11 MLS 114 LECTURE PRELIM CELLULAR ADAPTATIONS Cardiac Hypertrophy Different Cellular adaptive responses are: Cardiac Hypertrophy (i) Hyperplasia involving left ventricle. (ii) Hypertrophy The number of (iii) Atrophy myocardial fibres (iv) Metaplasia does not increase, but their size can HYPERTROPHY increase in response Hypertrophy constitutes an increase in the size of to an increased work load leading to the marked cells and with such change an increase in the size thickening of the left ventricle in this patient with of organ. Thus, there are no new cells, just large Systemic Hypertension cells. Moreover, these cells are not enlarged by simple cellular edema but by the increased Benign Prostatic Hyperplasia and Hypertrophy synthesis of more structural proteins and The normal adult male organelles. prostate is about 3 to 4 Hypertrophy can be Physiologic or Pathologic cm in diameter. The and is caused by increased functional demand or number of Prostatic due to specific hormonal stimulation. glands, as well as Pure hypertrophy without accompanying stroma, has increased hyperplasia occurs in muscle , and the stimulus is in this enlarged almost a mechanical one prostate seen in cross section. The pattern of increase in this case is uniform, but nodular a) Cardiac Muscle Hypertrophy: Any demand for increased work load on cardiac muscle, i.e., in Physiologic Hypertrophy of the Uterus during hypertension, valvular lesions or congenital heart Pregnancy diseases, leads to hypertrophy of the fibers of the chamber affected. b) Smooth Muscle Hypertrophy: Any obstruction to the A: Gross appearance of a normal uterus (right) and a outflow of the contents of a hollow viscus results in gravid uterus (left) that was removed for postpartum hypertrophy of its muscle coat. The following are bleeding examples of smooth muscle hypertrophy: B: Small spindle – shaped uterine smooth muscle cells Bladder: Seen in Prostatic enlargement and from a normal uterus Urethral stricture C: Large , plump hypertrophied smooth muscle cells Oesophagus: Seen in carcinoma from a gravid uterus Stomach: Seen in pyloric stenosis due to ulcer or carcinoma Hypertrophy And Hyperplasia – Compared Intestine: Stricture following Tuberculous Both are cellular responses to an increased demand for enteritis work. The cells either enlarge or divide depending upon Colon: Seen in carcinoma and diverticular their growth potentialities. The stimulus for this is usually disease mechanical in hypertrophy, and chemical or hormonal in hyperplasia. When the stimulus is withdrawn, the c) Skeletal Muscle Hypertrophy: The bulging muscle of condition regresses and the tissue reverts to normal. the athlete provide a simple illustration of hypertrophy However, secondary structural alterations in the general due to a mechanical stimulus architecture due to an accompanying degeneration may render a complete return to normal impossible. Hypertrophy – stimulus in mechanical Hyperplasia – stimulus in chemical and hormonal 12 MLS 114 LECTURE PRELIM Endometrial Hyperplasia is a common cause of abnormal menstrual bleeding. It is important to note that the hyperplasic process remains controlled. If Estrogenic stimulation abates, the hyperplasia disappears. This differentiates the process from cancer, in which cells continue to grow despite the absence of hormonal stimulus. Nevertheless, pathologic hyperplasia constitutes a HYPERPLASIA fertile soil in which cancerous proliferation may Hyperplasia constitutes an increase in the number eventually arise. Thus patients with hyperplasia of the of cells in an organ or tissue, that also leads to an endometrium are at increased risk of developing increase in size of an organ and tissue endometrial cancer Hypertrophy and Hyperplasia are closely related and often develop concurrently in tissues, so that b) Compensatory hyperplasia of bone marrow: both may contribute to an overall increase in organ Following haemorrhage size. c) Reactive hyperplasia of lymphoid tissue in It is important to note that those hyperplasia due to response to antigenic stimulation. a specific stimulus persist only for so long as that d) Thyroid Hyperplasia (Graves’ Disease): Result stimulus is applied. When it is removed, the tissue from the action of auto antibodies which act on tends to revert to its normal size. In this respect follicular cells of thyroid and then lead to hyperplasia differs from neoplasia, for neoplastic hyperplasia of follicular cells, which in turn leads to tissue continues to grow even when the stimulus is increased release of T3 and T4 withdrawn. e) Hyperplasia of the Prostate Gland: It is common in older age and is due to hyperplasia of both Hyperplasia can be Physiologic or Pathologic: glandular and the stromal element PHYSIOLOGIC HYPERPLASIA a) Hormonal Hyperplasia: Exemplified by the proliferation of glandular epithelium of the female breast at puberty and during pregnancy b) Compensatory Hyperplasia: Occurs when a portion of tissue is removed or diseased. For example, when a portion of liver is removed, hyperplasia by mitotic activity in the remaining cells begins as early as 12 hours later, eventually restoring the liver to its normal weight – at which time cell proliferation ceases. The stimuli for hyperplasia in this setting are polypeptide growth factors. After restoration of the liver mass, cell proliferation is “turned Off” by growth inhibitors PATHOLOGIC HYPEPRLASIA Pathologic Hyperplasia and Hypertrophy occur in the absence of an appropriate stimulus of increased functional demand a) Endometrial Hyperplasia: After a normal menstrual period there is a burst of essentially physiologic hyperplasia. This proliferation is normally tightly regulated between stimulation by pituitary hormones and ovarian Estrogen, and inhibition by Progesterone. However, if the balance between estrogen and progesterone is disturbed (e.g., if there is absolute or relative increases in estrogen), Pathologic Hyperplasia results. 13 MLS 114 LECTURE PRELIM ATROPHY (v) Loss of Endocrine Stimulation: Many Atrophy is the decrease in size of cell or of an organ endocrine glands, the breast, and the by loss of cell substance reproductive organs are dependent on endocrine stimulation for normal function. Atrophy represents a reduction in the structural Loss of estrogen stimulation after the components of the cell. menopause results in physiologic atrophy In the changing circumstances the cells adopt of the endometrium, vaginal epithelium and themselves to survive with lesser amounts of breast. cellular substance, hence a new equilibrium is (vi) Aging (Senile Atrophy): The aging process is associated with cell loss. achieved. Morphologically, it is seen in tissues Although atrophic cells may have diminished containing permanent cells, particularly in function, they are not dead. the brain and heart. If the blood supply is inadequate even to maintain (vii) Pressure: Tissue compression for any the life of shrunken cells then atrophy may progress length of time can cause atrophy. An to the point at which cells are injured and die. The enlarging benign tumour can cause atrophy in the surrounding compressed tissues. atrophic tissue is then replaced by fatty in growth. Atrophy in this setting is probably the result of ischemic changes caused by a blockade (I) PHYSIOLOGIC ATROPHY: of blood supply produced by the expanding Physiologic Atrophy occurs at times from very mass early embryonic life, as part of the process of morphogenesis. The process of atrophy Atrophy Brain contributes to the physiological involution of Cerebral atrophy in a different organs patient with Some examples of Physiologic Atrophy are: Alzheimer disease. o Physiologic involution of Thymus. The gyri are o post menopausal atrophy of Uterus narrowed and the o and Endometrium intervening sulci widened particularly o Senile atrophy of cerebrum pronounced towards o Bone marrow atrophy in old age the frontal lobe. (II) PATHOLOGIC ATROPHY Pathologic atrophy depends on the basic cause and can be local or generalized. The common causes of atrophy are: (i) Decreased workload (Atrophy of Disuse): a. Skeletal muscle atrophy , when a broken limb is immobilized in a plaster cast. b. Skeletal muscle atrophy when a patient is restricted to complete bed rest. (ii) Loss of innervation (Denervation Atrophy): Damage to the nerves leads to the rapid atrophy of the muscle fibers supplied by A. Physiologic atrophy of the brain in an 82 years old those nerves, for example in poliomyelitis man and in paraplegics. B. Normal brain of a 36 years old male (iii) Diminished Blood Supply (Ischemia): In late METAPLASIA adult life, the brain undergoes progressive Metaplasia is a reversible change in which one adult atrophy , presumably as atherosclerosis cell type (epithelial or mesenchymal) is replaced by narrows its blood supply. another cell type. (iv) Inadequate Nutrition: Metaplasia often represents an adaptive response a. Profound protein – calorie malnutrition of a tissue to some stress, and is presumed to be (marasmus) is associated with marked due to the activation and/or repression in tissue muscle wasting. stem cells of group of genes involved in tissue b. In starvation. differentiation. The transdifferentiated cells replace the original cells. c. Cachexia: An extreme form of systemic atrophy, usually seen in cancer Metaplasia is of two types patients 1. Epithelial Metaplasia Columnar to Squamous 14 MLS 114 LECTURE PRELIM Squamous to Columnar do not contain these elements. For example, 2. Connective Tissue Metaplasia bone formation in muscle, designated Myositis Ossificans , occasionally occur after bone Schematic Diagram of Columnar to Squamous fracture. Metaplasia This type of metaplasia is less clearly seen as an adaptive response. Hyperplasia Versus Metaplasia Metaplasia of Respiratory Epithelium Metaplasia of laryngeal respiratory epithelium has occurred here in a smoker. The chronic irritation has led to an exchange of one type of epithelium (the normal respiratory epithelium at the right ) for another ( more resilient squamous epithelium at the DYSPLASIA left). Metaplasia is not a normal physiologic process Dysplasia is a premalignant condition and may be a first step toward neoplasia characterized by the loss of the uniformity of the individual cells as well as a loss in their (ii) Columnar Metaplasia: architectural orientation. Metaplasia from squamous to columnar type may also occur: Dysplasia can be caused by longstanding irritation a. Barrett Esophagitis: In this condition the of a tissue, with chronic inflammation, or by squamous esophageal epithelium is exposure to carcinogenic substances. replaced by intestinal-like columnar cells. Dysplasia may occur in tissues which has The resulting cancers that may arise are coincident metaplasia, e.g. dysplasia developing glandular (adeno) carcinomas. b. Cervical Erosion: Squamous epithelium of in metaplastic squamous epithelium from the cervix is replaced by columnar epithelium. bronchus of smokers Dysplasia may also develop without co-existing metaplasia, for example in squamous epithelium Metaplastic transformation of the uterine cervix, glandular epithelium of the of esophageal stratified stomach or the liver squamous epithelium to Dysplasia may be present for many years before mature columnar a malignant neoplasm develops, and this epithelium (so-called observation can be used to screen populations at Barrett metaplasia) high risk of developing tumours Dysplatic cells exhibit following characteristic Metaplasia of the findings: normal esophageal Cellular Pleomorphism: Cells show variations in squamous mucosa has size & shape occurred, with the Hyperchromatic Nuclei: Deeply stained nuclei, appearance of gastric which are abnormally large for the size of cell. type columnar Increased Mitotic Activity: Mitotic figures are epithelium more abundant than usual, although almost invariably they conform to normal patterns. In CONNECTIVE TISSUE METAPLASIA dysplasia the mitoses are not confined to the Connective tissue metaplasia is the formation basal layers and may appear at all levels and of cartilage, bone or adipose tissue even in surface cells. (mesenchymal tissues) in tissues that normally 15 MLS 114 LECTURE PRELIM Architectural Anarchy : There is considerable INTRACELLULAR ACCUMULATIONS architectural anarchy. For example, the usual One of the manifestations of metabolic derangements progressive maturation of tall cells in the basal in cells is the intracellular accumulation of abnormal layer to flattened squamous on the surface may amounts of various substances be lost and replaced by a disordered The stockpiled substance fall into three categories: scrambling of dark basal- appearing cells. This (I) A normal cellular consistent accumulates in excess is also labeled as ‘loss of epithelial polarity’ a. Fatty change liver Carcinoma in situ: When dysplastic changes b. Haemosidrosis are marked and involve the entire thickeness of c. Bilirubin accumulation the epithelium, but the basement membrane is (II) A normal or abnormal substance, accumulates intact the lesion is considered as preinvasive because of the genetic or acquired defects to neoplasm and is referred as carcinoma in situ. metabolize it: Glycogen Storage diseases (III) An abnormal exogenous substance accumulates because body can not metabolize it (PIGMENTATION) a. Accumulation of carbon particles in lungs b. Tattooing (IV) Specialized Accumulations a. Calcification b. Amyloidosis (i) A normal endogenous substance is produced at a normal or increased rate, but the rate of metabolism is inadequate to remove it Example: Fatty Change of Liver DYSPLASIA CERVIX The normal cervical squamous epithelial at left transform to dysplastic change at right. There is also underlying chronic FATTY CHANGE OF LIVER inflammation because abnormal epithelial surfaces do The term Steatosis and Fatty Change describe not provide the same protective barrier as normal abnormal accumulation of triglycerides within epithelial surfaces do parenchymal cells. Fatty change is often seen in the liver because PAP SMEAR CERVIX it is the major organ involved in the fat metabolism, but it also occurs in heart, muscle, PAP SMEAR: and kidney Cytologic features of The causes of fatty change include: normal squamous o Toxins. epithelial cells can be o Protein malnutrition. seen at the center o Diabetes mellitus. top bottom, with o Obesity. orange to pale blue o Anorexia plate- like squamous o Alcohol abuse ( In industrialized world it is cells that have small pyknotic nuclei. The dysplastic the most common cause) cells in the center extending to upper right are smaller with darker, more irregular nuclei 16 MLS 114 LECTURE PRELIM Fatty Change Liver Proteins accumulation Protein appears as eosinophilic droplets in the cytoplasms In certain disorders excessive accumulation of protein takes place: Reabsorption droplets in proximal renal tubules: Seen in renal diseases associated with protein loss in the urine (Proteinuria) Intracellular accumulation of a variety of materials can Excessive synthesis of proteins: occurs in occur in response to cellular injury. Here is fatty plasma cell dyscrasisias like Multple Myeloma metamorphosis (Fatty change) of the liver in which where there is excessive immunoglobulin deranged lipoprotein transport from injury (most often synthesis Alcoholism) leads to accumulation of lipid in the cytoplasm of hepatocytes. Multiple myeloma-Plasma Cells With Inclusions Cholesterol and Cholesterol Esters accumulation Most cells use cholesterol for cell membrane synthesis, without intracellular accumulation of cholesterol esters. In several pathologic conditions intracellular accumulation of cholesterol can be manifested Atherosclerosis: In atherosclerotic plaques smooth muscle cells and macrophages are Glycogen accumulation filled with fat vacuoles most of which are made Excessive intracellular accumulation of glycogen are of cholesterol and cholesterol esters ( Foam seen in patients with an abnormality in either glucose or Cells) glycogen metabolism. Xanthomas: In hereditary and acquired Diabetes mellitus: It is the prime example of a hyperlipedimic states clusters of foam cells are disorder of glucose metabolism found in the sub epithelial connective tissue of Glycogen storage diseases: A group of genetic the skin and tendons producing tumourous disorders. In these enzymatic defects in masses known as Xanthomas glycogen synthesis or breakdown leads to Inflammation and Repair: Foamy excessive accumulation of glycogen in cells macrophages are frequently found at sites of cell injury and inflammation, owing to Calcification phagocytosis of cholesterol from membranes of Calcification is the abnormal deposition of Calcium injured cells salts, at sites other than osteoid and enamel along Cholesterolosis: This refers to focal with smaller amounts of iron, magnesium and other accumulation of cholesterol –laden mineral salts macrophages in the lamina propria of gall bladder Calcification is of two types: 1. Dystrophic Calcification: Deposition in dead or dying tissue 2. Metastatic Calcification: Deposition in living tissue 17 MLS 114 LECTURE PRELIM Dystrophic calcification: Examples bone resorption seen in 1. In areas of necrosis. The necrosed tissue can get Hyperparathyroidism due to parathyroid converted in a calcified mass tumours 2. The atheromas of advanced atherosclerosis. Ectopic secretion of Parathyroid hormone by 3. Aging or damaged heart valves malignant tumours 4. Aged pineal gland. 2. Destruction of bone tissue seen with 5. Dead parasites primary tumours of bone marrow like: 6. Dead retained fetus. o Multiple Myeloma 7. Dystrophic Calcification can be seen in o Leukaemias carcinomas. For example “Psammoma bodies” Diffuse skeletal metastasis (e.g., breast cancer) seen in capillary carcinoma of thyroid. Accelerated bone turn over like in Paget disease or in immobilization. 3. Renal Failure, which causes retention of Phosphate, Aortic valve in a heart leading to secondary hyperparathyroidism. with calcific aortic 4. Vitamin – D related disorders including Vitamin- D stenosis. The semilunar intoxication and Sarcoidosis. cusps are thickened and fibrotic. Behind Calcification: Morphology each cusp are seen Regardless of the site, calcium salts are seen on irregular masses of gross examination as fine white granules or pilled- up dystrophic calcification clumps. Often felt as gritty deposits Dystrophic Calcification Dystrophic calcification is common in areas of This is dystrophic caseous necrosis. calcification in the wall On histologic examination calcification appears as of the stomach. At the intracellular and/or extracellular basophilic far left is an artery with deposits. Calcification in its wall. Overtime, heterotrophic bone may be formed in There are also irregular the focus of calcification bluish – purple Metastatic calcification can occur widely deposits of calcium in the sub mucosa. Calcium is more throughout the body but principally affects the likely to be deposited in the tissues that are damaged. interstitial tissues of the vasculature, kidneys, lungs and gastric mucosa. Psamomma Bodies – Dystrophic Calcification Seen Calcium deposits, in metastatic calcification, in Malignant Tumours morphologically resemble those as in dystrophic calcification. Metastatic Calcification Metastatic calcification in the lung of a patient with a very high serum Calcium level (Hyperplasia) Metastatic calcification, lung Metastatic Calcification: Examples There are four principal causes in groups of patients with Hypercalcemia who can have Metastatic Calcification: 1. Increased secretion of Parathyroid Hormone with subsequent 18 MLS 114 LECTURE PRELIM PIGMENTS Lipofuscin Accumulation Pigments are colored substances which The yellow brown accumulate in cells. granular pigment seen Based on the source pigments can be of two types in the hepatocytes 1. Exogenous pigments here is Lipochrome 2. Endogenous pigments (Lipofuscin) which accumulates over time (I) Endogenous Pigments in cells (particularly 1. Lipofuscin liver and heart) as a 2. Melanin result of “wear and tear” with aging. It is of no major 3. Bilirubin consequence , but illustrates the end result of the 4. Haemosidrin process of autophagocytosis in which intracellular debris is sequestered and turned into these residual (II) Exogenous Pigments bodies of lipochrome within the cell cytoplasm 1. Anthracosis 2. Pneumoconiosis Jaundice 3. Tattoing The Sclera of the eye is (I) ENDOGENOUS PIGMENTS yellow because the These are the pigments which are synthesized inside patient has jaundice, or the body Icterus. The normally a. Lipofuscin or Wear and tear pigment: It is white sclera of the eyes composed of polymers of lipid and is a good place on phospholipids complexed with proteins, physical examination to look for jaundice. suggesting that it is derived through lipid peroxidation of polyunsaturated lipids of sub cellular membranes. It is the tell tale sign of free Bilirubin: Yellow – radical injury. Microscopic appearance: Yellow green globular brown intracytoplasmic granules. material seen in b. Melanin: Brown black pigment derived from small bile ductules melanocytes of skin. Examples of melanin in liver accumulation; Suntan Melasma In pregnancy Haemosidrin granules in liver cells c. Haemosidrin: Golden yellow to brown granular pigment. It is the form in which iron is accumulated in cells. The main storage form of iron is ferritin. But when there is local or systemic excess of iron, ferritin aggregates in the form of haemosidrin. Haemosidrosis ( increased sysmteimic A: H& E showing golden brown , finely granular pigment accumulation of iron) is seen in: B: Prussian Blue , specific for iron i. Increased absorption of dietary iron. ii. Impaired use of iron. Suntan iii. Haemolytic anaemias , for example beta thalassaemia major iv. Repeated blood transfusions. d. Bilirubin: Jaundice is the common clinical disorder caused by excesses of Bilirubin within cells and tissues. 19 MLS 114 LECTURE PRELIM Melasma Tattooing Endogenous substances accumulating in tissues (II) EXOGENOUS PIGMENTS as a result of deranged metabolism These are the pigments which come from outside the body. a. Anthracosis (Carbon or coal dust accumulation): It is the main pollutant of the urban life. When inhaled, it is picked up by macrophages within the alveoli and is then transported through lymphatic channels to regional lymph nodes. Accumulation of this pigment blackens the tissues of lung ( Anthracosis). b. Coal worker’s pneumoconiosis: In coal miners and those living in heavily polluted environments , the aggregates of carbon dust may induce a fibroblastic reaction or even emphysema and thus cause a serious lung disease known as coal worker’s pneumoconiosis. c. Tattooing: A form of localized exogenous pigmentation. The pigments inoculated are ingested by dermal macrophages, where they reside permanently. Anthracosis pigment in macrophages in hilar lymph node: Anthracosis is accumulation of carbon pigment from breathings bad sir. Smokers have the most pronounced Anthracosis. Exogenous pigment Anthracosis of lung 20 MLS 114 LECTURE PRELIM INFLAMMATION 4.Extracellular matrix and stromal cells Inflammation is a response of vascularized tissues that Mast cells, fibroblasts, macrophages & delivers leukocytes and molecules of host defense from lymphocytes. the circulation to the sites of infection and cell damage Structural fibrous proteins, adhesive in order to eliminate the offending agents. glycoproteins, proteoglycans, basement membrane. EFFECTS OF INFLAMMATION Elimination of the cause of cell injury. COMPONENTS OF INFLAMMATION Elimination of the necrotic cells. Paves the way for repair. May lead to harmful results. INFLAMMATION Nomenclature itis (- after name of tissue) e.g. Appendix Appendicitis Dermis Dermatitis Gallbladder Cholecystitis Duodenum Duodenitis Meninges Meningitis, etc. INFLAMMATORY REACTION ACUTE VS CHRONIC INFLAMMATION The typical inflammatory reaction develops through a series of sequential steps 1. Recognition of the noxious agent that is the initiating stimulus for inflammation. 2. Recruitment of leukocytes and plasma proteins into the tissues. 3. Removal of the stimulus for inflammation is accomplished mainly by phagocytic cells 4. Regulation of the response. 5. Repair consists of a series of events that heal damaged tissue. Acute inflammation has three major components: 1. dilation of small vessels leading to an increase in CAUSES OF INFLAMMATION blood flow Microbial infections: bacteria, viruses, fungi, parasites. 2. increased permeability of the microvasculature Immunologic: hypersensitivity (contact with enabling plasma proteins and leukocytes to leave some substances), autoimmune reactions. the circulation Physical agents: trauma, heat, cold, ionizing 3. emigration of leukocytes from the microcirculation, radiation, etc. their accumulation in the focus of injury, and their Chemical agents: acids, alkali, bacterial toxins, activation to eliminate the offending agent metals, etc. LOCAL MANIFESTATIONS OF ACUTE Foreign materials: sutures, dirt, etc. INFLAMMATION Tissue necrosis: ischemic necrosis. CELLS IN INFLAMMATION 1. White blood cells and platelets Neutrophils, monocytes, lymphocytes, eosinophils, basophils. 2. Plasma proteins Coagulation / fibrinolytic system, kinin system, complement system. 3. Endothelial cells and smooth muscles of vessels. 21 MLS 114 LECTURE PRELIM ACUTE INFLAMMATION (PNEUMONIA) Pain. (dolor) Loss of function. (functio laesa) THE FIVE CLASSIC SIGNS OF ACUTE INFLAMMATION VASCULAR CHANGES Arteriolar dilatation follows transient vasoconstriction. HOW DOES INFLAMMATION LEAD TO LEAKINESS Increased vascular permeability and stasis: OF ENDOTHELIAL CELLS? Arteriolar vasodilatation → ↑hydrostatic pressure → transudate. Late phase: leaky vessels → loss of proteins → exudate. Margination of leukocytes. FLUID MOVEMENT IN MICROCIRCULATION IN NORMAL TISSUE FLUID MOVEMENT IN MICROCIRCULATION IN INFLAMED TISSUE THE FIVE CLASSIC SIGNS OF ACUTE INFLAMMATION Heat. (calor) Redness. (rubor) Swelling. (tumor) 22 MLS 114 LECTURE PRELIM EDEMA IN INFLAMMATION NEUTROPHIL MARGINATION TRANSUDATE EXUDATE Mechanism: hydrostatic Mechanism: alteration in pressure imbalance normal permeability of across vascular small blood vessels in endothelium. area of injury. Fluid of low protein Fluid of high protein content (ultrafiltrate of content (>.3g/dl) & blood plasma). increased cellular debris. Specific gravity 1.020. CELLULAR EVENTS 1. Margination, rolling and adhesion. 2. Transmigration between endothelial cells. 3. Migration in the interstitium toward the site of ENDOTHELIAL AND LEUKOCYTE ADHESION stimulus. MOLECULE INTERACTIONS 4. Phagocytosis and degranulation. ENDOTHELIUM WBC FUNCTION P & E-selectins Sialyl-Lewis X Rolling 5. Release of leukocyte products. GlyCAM-1, L-selectin Rolling CD34 VCAM-1 VLA-4 Adhesion LEUKOCYTE RECRUITMENT TO SITES OF ICAM-1 CD11/CD18 Adhesion, INFLAMMATION (LFA1, MAC1) The changes in blood flow and vascular CD31 (PECAM- Transmigration permeability are quickly followed by an influx of 1) CD31 leukocytes into the tissue.