Cell Adaptation, Injury, and Death PDF

CELL ADAPTATION, INJURY AND DEATH HELEN OWUSU-ASANTE (MRS) BEFORE WE BEGIN……….. As a pre-requisite for this course, you are expected to: revise cell structure and function of cell components Revise cell division ( cell cycle) Revise basic anatomy in general  BEFORE...

CELL ADAPTATION, INJURY AND DEATH HELEN OWUSU-ASANTE (MRS) BEFORE WE BEGIN……….. As a pre-requisite for this course, you are expected to: revise cell structure and function of cell components Revise cell division ( cell cycle) Revise basic anatomy in general  BEFORE WE START……………… Pathology is the study of disease. It describes the effects, progress and consequences of the disease and attempts to determine the cause (aetiology) and underlying mechanisms (pathogenesis). Histotechnology is a science centering on the microscopic detection of tissue abnormalities for disease diagnosis and the treatment INTRODUCTION The human body employs several mechanisms in the maintenance of cells, tissues, organs, and organ systems in a balanced, steady state of equilibrium known as homeostasis As cells encounter physiologic stresses or pathologic stimuli, they can undergo adaptation, achieving a new steady state and preserving viability and function.  However, such deviations are temporary and cannot be maintained indefinitely without injury. If demand exceeds adaptive capacity, an injurious imbalance may occur. For example, if blood sugar rises, the pancreas secretes insulin into blood to reduce it by enabling cells to use more. However, if the patient is diabetic, demand for insulin may exceed the ability of the pancreas to respond, and diabetic acidosis or coma may occur.  The main adaptive responses are hypertrophy, hyperplasia, atrophy, and metaplasia. If the adaptive capability is exceeded or if the external stress is inherently harmful, cell injury develops Within certain limits injury is reversible, and cells return to a stable baseline. However, severe or persistent stress results in irreversible injury and death of the affected cells.  Cells age and die like every other living thing. It is a normal, physiologic process distinct from disease. Natural, physiologic, planned cell death is apoptosis—a programmed commitment to die. Cell death caused by disease is necrosis. Cell death, caused by either apoptosis or necrosis, releases cell substances into blood, where their concentration can be measured by laboratory tests. CELL ADAPTATION Adaptations are reversible changes in the number, size, phenotype, metabolic activity, or functions of cells in response to changes in their environment. There are 2 types: Physiologic adaptations usually represent responses of cells to normal stimulation by hormones or endogenous chemical mediators (e.g., the hormone-induced enlargement of the breast and uterus during pregnancy).  Pathologic adaptations are responses to stress that allow cells to modulate their structure and function and thus escape injury. Such adaptations can take several distinct forms.  HYPERTROPHY: increased cell and organ size, often in response to increased workload; induced by mechanical stress and by growth factors; occurs in tissues incapable of cell division Causes can be physiologic or pathologic Hormonal stimulation: For example, following delivery, women’s breasts enlarge and become temporarily hyperfunctional in order to produce milk, a change induced by secretion of prolactin (a hormone) from the pituitary. enlargement of skeletal muscle with exercise.  - Increased functional demand. Increased functional demand stresses cells and causes them to enlarge and increase their activity. For example, a heart under the constant strain of high blood pressure increases in size because the individual cardiac muscle cells increase in size  HYPERPLASIA: increased cell numbers in response to hormones and other growth factors. Occurs only if cells are capable of dividing (cardiac myocytes and neurons in the brain do not undergo hyperplasia) Causes can be physiologic or pathologic : ❖Hormonal stimulation. For example, the increase of estrogen in female puberty causes an increase in the number of endometrial cells. ❖ Increased functional demand. For example, low atmospheric oxygen stimulates bone marrow production of RBC to carry oxygen. It is for this reason that people living at high altitude have increased numbers of circulating red blood cells (RBC). ❖Chronic stress or injury. For example, the stress of exceptionally high blood pressure on small arteries in the kidney causes cells in the arterial wall to divide and accumulate in layers Illustration of the difference between hypertrophy (increase in size of cells) and hyperplasia (increase in number of cells) Image by Lecturio.  ATROPHY: decreased size and function of a cell. It is an adaptive response to decreased demand or to increased stress; the cell shuts down its metabolic processes to conserve energy Causes include: Reduced functional demand. For example, muscle atrophy occurs in a limb encased in a cast.  Inadequate blood supply (ischemia). For example, atherosclerosis of the renal artery can impair blood flow enough to cause atrophy of a kidney. Absent or reduced neural or hormonal support. For example, to remain healthy, skeletal muscle cells must be continually stimulated by intact nerves; interruption of nerve supply leads to muscle atrophy. Chronic inflammation associated with chronic injury. For example, chronic inflammation of the stomach lining is associated with a condition known as chronic atrophic gastritis  METAPLASIA: Reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type. Usually occurs in response to stress or chronic irritation. Normally epithelial stem cells mature into the usual cell type, but when injured or stressed they mature into a different type of cell more suitable to existing conditions. Metaplastic epithelium usually reverts to normal when the injury stops.  DYSPLASIA a premalignant change of cells. Dysplasia typically occurs in previously normal epithelium, which features an orderly arrangement of cells of uniform size, shape, and appearance. In dysplastic epithelium this bland appearance is replaced by a disorderly overgrowth of cells with enlarged, dark, irregular nuclei. Dysplasia is a milepost on the way to malignancy; however, it is reversible and not yet malignant.  CELL INJURY Cells encounter many stresses as a result of changes in their internal and external environments. Patterns of response to such stresses is the cellular basis of disease If an injury exceeds the adaptive capacity of the cell, the cell dies. In general, mammalian cells adapt to injury by conserving resources: decreasing or ceasing differentiated functions and focusing exclusively on its own survival  Cell injury results when cells are stressed so severely that they are no longer able to adapt or when cells are exposed to inherently damaging agents or suffer from intrinsic abnormalities. It is when environmental changes exceed the cell’s capacity to maintain normal homeostasis that we recognize acute cell injury.  If the stress is removed in time or if the cell can withstand the assault, cell injury is reversible, and complete structural and functional integrity is restored On the other hand, if the stress is severe, irreversible injury leads to death of the cell. The precise moment at which reversible injury gives way to irreversible injury, the “point of no return,” cannot be identified at present.  Cellular injury may or may not result in the death of the cell. Four cellular systems are especially vulnerable to cellular injury, and include: 1. DNA 2. Cell membranes 3. Protein generation 4. Adenosine triphosphate (ATP) production Causes of Cell Injury Hypoxia and ischemia i.e. oxygen deficiency and blood flow deficiency respectively. “Chemical” agents eg. drugs and alcohol “Physical” agents eg. trauma and heat Infections eg. bacterial and viral  Immunological reactions i.e. anaphylaxis and loss of immune tolerance that results in autoimmune disease Genetic defects eg. hemoglobin S in SS disease, inborn errors of metabolism Nutritional defects: including vitamin deficiencies, obesity leading to type II DM, fat leading to atherosclerosis. Aging: including degeneration as a result of repeated trauma, and intrinsic cellular senescence. General Principles of Cell injury Cell response to injury is not an all-or-nothing phenomenon: The stronger and the longer the stimulus, the larger the damage Response to a given stimulus depends on the type, status, and genetic make-up of the injured cell: Contrast ischemia in skeletal muscle (tolerates 2 hours) versus cardiac muscle (tolerate 20 minutes).  Cells are complex interconnected systems, and single local injuries can result in multiple secondary and tertiary effects: Cyanide indirectly affects osmotic regulation by loss of function of Na/K-ATPase Cell function is lost far before biochemical and subsequently morphological manifestations of injury become detectable BIOCHEMICAL MECHANISMS OF CELL INJURY Loss of energy (ATP depletion, O2 depletion) Mitochondrial damage Loss of calcium homeostasis Defects in plasma membrane permeability Generation of reactive oxygen species (O2 , H2O2, OH ) and other free radicals MORPHOLOGIC CHANGES IN CELL INJURY Reversible cell injury: cell swelling, fatty change, plasma membrane blebbing and loss of microvilli, mitochondrial swelling, dilation of the ER, eosinophilia (due to decreased cytoplasmic RNA) CELL DEATH The inability to reverse mitochondrial dysfunction (lack of oxidative phosphorylation and ATP generation) even after resolution of the original injury, and profound disturbances in membrane function lead to cell death. Note that cells may rapidly become nonfunctional after the onset of injury, although they are still viable, with potentially reversible damage; a longer duration of injury may eventually lead to irreversible injury and cell death. Note also that cell death typically precedes ultrastructural, light microscopic, and grossly visible morphologic changes.  There are two types of cell death— necrosis and apoptosis—which differ in their morphology, mechanisms, and roles in disease and physiology When damage to membranes is severe, enzymes leak out of lysosomes, enter the cytoplasm, and digest the cell, resulting in necrosis. Cellular contents also leak out through the damaged plasma membrane and elicit a host reaction (inflammation).  Necrosis is the major pathway of cell death in many commonly encountered injuries, such as those resulting from ischemia, exposure to toxins, various infections, and trauma. When a cell is deprived of growth factors or the cell’s DNA or proteins are damaged beyond repair, the cell kills itself by another type of death, called apoptosis, which is characterized by nuclear dissolution without complete loss of membrane integrity. Whereas necrosis is always a pathologic process, apoptosis serves many normal functions and is not necessarily associated with pathologic cell injury. MORPHOLOGIC CHANGES IN CELL DEATH Necrosis: Apoptosis: increased eosinophilia; nuclear chromatin nuclear shrinkage, condensation; fragmentation, and dissolution; formation of apoptotic breakdown of plasma bodies (fragments of membrane and nuclei and cytoplasm) organellar membranes; myelin figures; leakage and enzymatic digestion of cellular contents