Pathophysiology Lecture 1 PDF

Pathophysiology Pathophysiology, cell injury, adaptation, and cell death Presented by: Dr. Doaa Al-Saadi Lecture 1 2024 / 09 /18-19 Pathophysiology It is the science that study the functi...

Pathophysiology Pathophysiology, cell injury, adaptation, and cell death Presented by: Dr. Doaa Al-Saadi Lecture 1 2024 / 09 /18-19 Pathophysiology It is the science that study the functional or physiologic changes in the body which results from disease developments. It involves the study of the four aspects of disease: Etiology (cause of the diseases) Pathogenesis Morphologic changes Functional derangements and clinical significance Etiology The etiology of diseases can be: Genetic Acquired (infectious, nutritional, chemical ,physical, etc). Idiopathic is a term used when the cause of the disease is unknown Multifactorial disease is a term used when the diseases caused by genetic and acquired factors. Iatrogenic is a term used when the disease is caused by medical treatment; it usually results from a mistake made in diagnosis or treatment and can also be the fault of any member of the healthcare team.  Pathogenesis It is the mechanism in which which the causative agent produce the pathological and clinical responses The pathogenetic mechanisms take place in the incubation period. The morphologic changes refer to the structural alterations in cells or tissues that occur following the pathogenetic mechanisms The morphologic changes are: Gross morphologic changes (macroscopic changes): can be seen with the naked eye Microscopic changes: can only be seen under microscope Functional derangements and clinical significance It is represented by the signs and symptoms Symptoms are feelings or sensations a person has, whereas signs are observable characteristics others can see. The doctor uses symptoms, signs, and testing to make a diagnosis. For example, pain and nausea are symptoms while cough and swelling are signs Cell injury Cells can maintain their intracellular environment within a very narrow range of physiologic parameters (normal homeostasis). As cells encounter physiologic stresses or pathologic stimuli, they can undergo adaptation to achieve a new steady state and preserve viability and function. If physiologic stresses or pathologic stimuli exceeded the adaptation capacity of the cell, cell injury will develop, which is either reversible cell injury or irreversible ( death) Causes of cell injury The causes can be classified into five group: 1. Injury from physical agents 2. Radiation injury 3. Chemical injury 4. Injury from biologic agents 5. Injury from nutritional imbalances Mechanisms of Cell Injury There are at least three major mechanisms whereby most injurious agents exert their effects: Free radical formation Hypoxia and ATP depletion Disruption of intracellular calcium homeostasis  Free radical formation Highly reactive chemical species (also called reactive oxygen species). The radical is highly unstable and can enter reactions with cellular constituents, particularly key molecules in cell membranes and nucleic acids. Free radical formation is a by-product of many normal cellular reactions in the body, including energy generation, breakdown of lipids and proteins, and inflammatory processes Uncontrolled free radical production causes damage to cell membranes, cross-linking of cell proteins, inactivation of enzyme systems, or damage to the nucleic acids that make up DNA.  Hypoxia and ATP depletion Hypoxia (lack of sufficient oxygen) is the single most common mechanism of cellular injury. Hypoxia can result from ischemia (reduced blood supply), a reduced amount of oxygen in the air, loss of hemoglobin or hemoglobin function, decreased production of red blood cells, and as consequences of respiratory and cardiovascular system diseases Hypoxia can induce inflammation, and inflamed lesions can become hypoxic Hypoxia literally causes a power failure in the cell. As oxygen tension in the cell falls, oxidative metabolism ceases, and the cell reverts to anaerobic metabolism, using its limited glycogen stores to maintain vital cell functions. Cellular pH falls as lactic acid accumulates in the cell. This reduction in pH can have profound effects on intracellular structures. It will eventually lead to ATP depletion  Disruption of intracellular calcium homeostasis Calcium functions as a messenger for the release of many intracellular enzymes. Normally, intracellular calcium levels are kept extremely low compared with extracellular level Ischemia and certain toxins lead to an increase in cytosolic calcium because of increased influx across the cell membrane and the release of calcium stored in the mitochondria and endoplasmic reticulum. The increased calcium level activates several enzymes with potentially damaging effects. The enzymes include the phospholipases responsible for damaging the cell membrane, proteases that damage the cytoskeleton and membrane proteins, ATPases that break down ATP and hasten its depletion, and endonucleases that fragment chromatin  Cellular Adaptation Cells adapt to their environment to escape and protect themselves from injury. An adapted cell is neither normal nor injured—its condition lies between these two states. Cellular Adaptation is reversible change in cell size, number, phenotype, or functions of cells.  Atrophy Atrophy is a decrease or shrinkage in cellular size. It is most common in skeletal muscle, the heart, secondary sex organs, and the brain The mechanisms of atrophy include decrease in protein synthesis or increase in protein degradation, or both. Atrophy can be classified as: Physiologic: with aging, brain cells become atrophic and endocrine-dependent organs, such as the gonads, shrink as hormonal stimulation decreases. Pathologic: it can be grouped based on cause into five categories: (1) disuse, (2) denervation, (3) loss of endocrine stimulation, (4) inadequate nutrition, and (5) ischemia  Pathologic atrophy Disuse atrophy: muscles of extremities that have been encased in plaster casts. Denervation atrophy: occurs in the muscles of paralyzed limbs. Lack of endocrine stimulation: In women, the loss of estrogen stimulation during menopause results in atrophic changes in the reproductive organs. Inadequate nutrition and ischemia: cells decrease their size and energy requirements as a means of survival.  Hypertrophy Hypertrophy is an increase in the size of cells by increasing the amount of structural proteins and organelles. The cells of the heart and kidneys are particularly responsive to enlargement. Hypertrophy caused by increased demand or workload, and controlled by hormones, and growth factors. Hypertrophy can be: Physiologic: avid weightlifter who develop a rippled physique. Pregnancy is an example of physiologic hypertrophy and hormone-induced uterine enlargement. Pathologic: may be adaptive or compensatory.  Pathologic hypertrophy Adaptive hypertrophy: myocardial hypertrophy that results from valvular heart disease or hypertension. Compensatory hypertrophy: if one kidney is removed, the remaining kidney enlarges to compensate for the loss. Prolonged cardiac hypertrophy progresses to contractile dysfunction, decompensation, and finally heart failure. If not treated, it will result in death.  Hyperplasia Hyperplasia is an increase in the number of cells in an organ or tissue resulting from an increased rate of cellular division. The main mechanism for hyperplasia is the production of growth factors. Another mechanism is increased output of new cells from tissue stem cells. For example, if liver cells are compromised, new cells can regenerate from intrahepatic stem cells. Hyperplasia and hypertrophy can occur together It occurs in tissues with cells that are capable of mitotic division, such as the epidermis, intestinal epithelium, and glandular tissue  Hyperplasia Hyperplasia can be: Physiologic: which divided into ✓Compensatory hyperplasia: removal of part of the liver leads to hyperplasia of the remaining liver cells (hepatocytes) to compensate for the loss. ✓Hormonal hyperplasia: After ovulation, estrogen stimulates the endometrium to grow and thicken for reception of the fertilized ovum. If pregnancy occurs, hormonal hyperplasia, as well as hypertrophy, enables the uterus to enlarge Pathologic: hyperplasia of the endometrium, which causes excessive menstrual bleeding, is due to an imbalance between estrogen and progesterone levels with relative increases of estrogen, Benign prostatic hyperplasia, which is a common disorder of men older than 50 years, is related to the synergistic action of estrogen and androgens, Skin warts are an example of hyperplasia caused by growth factors produced by the human papillomaviruses  Dysplasia Dysplasia refers to abnormal changes in the size, shape, and organization of mature cells. Dysplasia is not considered a true adaptive process but is related to hyperplasia and is often called atypical hyperplasia. Dysplasia is strongly implicated as a precursor of cancer. However, it may or may not progress to cancer. Dysplasia that do not involve the entire thickness of epithelium may be completely reversible. When dysplastic changes penetrate the basement membrane it is considered a preinvasive neoplasm and is known as carcinoma in situ.  Metaplasia Metaplasia is the reversible replacement of one mature cell type (epithelial or mesenchymal) by another, less differentiated, cell type. Beneficial metaplasia: replacement of squamous epithelium of the esophagus by glandular epithelium, which tolerate the acidic environment, in cases of gastroesophageal reflux damages Non-Beneficial metaplasia. Replacement of normal ciliated columnar epithelial cells of the trachea and bronchi by stratified squamous epithelial cells in the long- term cigarette smoker. The newly formed squamous epithelial cells have better survival chances, but they do not secrete mucus or have ciliary clear the particulate matter, causing loss of a vital protective mechanism. Reversible Cell Injury and Cell Death  Reversible Cell Injury Reversible cell injury, although impairing cell function, does not result in cell death. Two patterns of reversible cell injury can be observed under the microscope: cellular swelling and fatty change. Cellular swelling occurs with impairment of the energy-dependent Na+/K+ ATPase membrane pump, usually as the result of hypoxic cell injury. Fatty changes are linked to intracellular accumulation of fat. When fatty changes occur, small vacuoles of fat disperse throughout the cytoplasm  Apoptosis Apoptosis (cell suicide or programmed cell death) is a form of cell death that leads to the elimination of cells without releasing harmful substances Apoptotic cell death eliminates cells that are worn out, have been produced in excess, have developed improperly, or have genetic damage. Cells appear to initiate their own death through the activation of endogenous enzymes. This results in cell shrinkage brought about by disruption of the cytoskeleton, condensation of the cytoplasmic organelles, disruption and clumping of nuclear DNA, and a distinctive wrinkling of the cell membrane. As the cell shrinks, the nucleus breaks into spheres, and the cell eventually divides into membrane covered fragments. During the process, membrane changes occur, signaling surrounding phagocytic cells to engulf the cell fragments and complete the degradation process (no inflammation)  Apoptosis Apoptosis can be physiological process: Separation of the webbed fingers and toes of the developing embryo Control of immune cell numbers and destruction of autoreactive T cells in the thymus Hormone dependent involution of endometrial cells during the menstrual cycle Regression of breast tissue after weaning from breast-feeding Apoptosis can be pathological process: neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease. hepatitis B and C, the virus seems to sensitize the hepatocytes to apoptosis. Injured cells may induce apoptotic cell death through increased cytoplasmic calcium, which leads to activation of nuclear enzymes that break down DNA  Apoptosis It is initiated by two pathways: 1. Mitochondrial (intrinsic) pathway is triggered by Loss of survival signals, DNA damage beyond repair, accumulation of misfolded proteins (ER stress). E.g Aging, cystic fibrosis and Neurodegenerative Diseases. 2- Death receptor (extrinsic) pathway is responsible for elimination of self- reactive lymphocytes and damage by cytotoxic T lymphocytes. It is initiated by engagement of death receptors (members of the Tumor necrotizing factor (TNF) receptor family) by ligands on adjacent cells.  Necrosis Necrosis is death of group of cells within a living body Necrosis differs from apoptosis in that it involves unregulated enzymatic digestion of cell components, swelling, loss of cell membrane integrity with uncontrolled release of the products of cell death into the intracellular space, and initiation of the inflammatory response. Necrosis often interferes with cell replacement and tissue regeneration.  FEATURE NECROSIS APOPTOSIS Enlarged (swelling) Reduced (shrinkage) Cell size Fragmentation into nucleosome-size Nucleus Pyknosis → karyorrhexis → karyolysis fragments Intact; altered structure, especially orientation Plasma membrane Disrupted of lipids Cellular contents Enzymatic digestion; may leak out of cell Intact; may be released in apoptotic bodies Adjacent Frequent No inflammation Often physiologic, means of eliminating Physiologic or Invariably pathologic (culmination of unwanted cells; may be pathologic after some pathologic role irreversible cell injury) forms of cell injury, especially DNA damage  Types of necrosis 1. Coagulative necrosis: occurs primarily in the kidneys, heart, and adrenal glands Etiology: hypoxia caused by severe ischemia or by chemical injury, especially ingestion of mercuric chloride. Coagulation is caused by protein denaturation, which causes the protein albumin to change from a gelatinous, transparent state to a firm, opaque state, similar to that of a cooked egg white. Coagulative necrosis of myocardium of posterior wall of left ventricle of heart. A large anemic (white) infarct is readily apparent Types of necrosis 2. Liquefactive necrosis: Etiology: commonly results from ischemic injury to neurons and glial cells in the brain. As the brain cells are digested by their own hydrolases, the tissue becomes soft, liquefies, and is walled off from healthy tissue, forming cysts Liquefactive necrosis can also result from bacterial infection (staphylococci, streptococci, and Escherichia coli). In this case the hydrolases are released from the lysosomes of neutrophils (phagocytes attracted to the infected area to kill the bacteria). Liquefaction of bacterial cells and neighboring tissue cells by neutrophilic hydrolases results in the accumulation of pus Liquefactive necrosis of the brain. The area of infarction is softened as a result of liquefactive necrosis  Types of necrosis 3. Caseous necrosis: commonly results from tuberculous pulmonary infection, particularly Mycobacterium tuberculosis, is a combination of coagulative and liquefactive necrosis Tissues appear soft and granular and resemble clumped cheese, hence its name. Tuberculosis of the lung, with a large area of caseous necrosis containing yellow-white and cheesy debris  Types of necrosis 4. Fat necrosis: occurs in the breast, pancreas, and other abdominal structures, is cellular dissolution caused by powerful enzymes called lipases. Lipases break down triglycerides, releasing free fatty acids, which then combine with calcium, magnesium, and sodium ions, creating soaps (a process known as saponification). The necrotic tissue appears opaque and chalk white Fat necrosis of pancreas. Interlobular adipocytes are necrotic; these are surrounded by acute inflammatory cells  Types of necrosis 5. Gangrenous necrosis: results from severe hypoxic injury because of arteriosclerosis, or blockage of major arteries, especially in the lower leg. With hypoxia and subsequent bacterial invasion, the tissues can undergo necrosis It is classified as dry, wet, and gas gangrene Dry gangrene is usually the result of coagulative necrosis. The skin becomes very dry and shrinks, resulting in wrinkles, and its color changes to dark brown or black Wet gangrene develops when neutrophils invade the site, causing liquefactive necrosis. This usually occurs in internal organs and extremities, causing the site to become cold, swollen, and black. A foul odor is present caused by bacterial action that produce pus, and if systemic symptoms become severe, death can ensue. Dry gangrene can be converted to wet gangrene by bacterial involvement  Types of necrosis Gas gangrene, a special type of gangrene, is caused by infection of injured tissue by one of many species of Clostridium. These anaerobic bacteria produce hydrolytic enzymes and toxins that destroy connective tissue and cellular membranes and cause bubbles of gas to form in muscle cells. Gas gangrene can be fatal if enzymes lyse the membranes of red blood cells, destroying their oxygen-carrying capacity. Death is the result of shock. What type of necrosis are these? Thank you for listening