Chapter 2: Cell Injury, Cell Death, and Adaptations Flashcards
1
Q
Pyknosis, karyorrhexis, karyolysis are features of what process?
A
Necrosis (not apoptosis)
2
Q
2 main features of reversible cell injury?
A
- Early alterations in reversible injury include generalized swelling of the cell and its organelles, blebbing of the plasma membrane, detachment of ribosomes from the endoplasmic reticulum (ER), and clumping of nuclear chromatin. Swelling of cells results from influx of water. This is usually caused by failure of the adenosine triphosphate (ATP)-dependent Na+-K+ plasma membrane pump due to depletion of ATP resulting from oxygen deficiency, which interferes with mitochondrial oxidative phosphorylation, or mitochondrial damage by radiation or toxins.
- Fatty change occurs in organs that are actively involved in lipid metabolism (e.g., liver). It results when toxic injury disrupts metabolic pathways and leads to rapid accumulation of triglyceride-filled lipid vacuoles.
3
Q
EM features of reversible cell injury?
A
- Plasma membrane alterations, such as blebbing, blunting, and loss of microvilli
- Mitochondrial changes, including swelling and the appearance of small amorphous densities
- Accumulation of “myelin figures” in the cytosol composed of phospholipids derived from damaged cellular membranes
- Dilation of the ER, with detachment of polysomes
- Nuclear alterations, with disaggregation of granular and fibrillar elements
4
Q
What two phenomena consistently characterize irreversibility?
A
- The inability to reverse mitochondrial dysfunction (lack of oxidative phosphorylation and ATP generation) even after resolution of the original injury)
- Profound disturbances in membrane function
5
Q
List different patterns of tissue necrosis and typical etiology/pathogenesis?
A
- Coagulative: ischemia caused by obstruction in a vessel may lead to coagulative necrosis of the supplied tissue in all organs except the brain
- Liquefactive: seen in focal bacterial or, occasionally, fungal infections, because microbes stimulate the accumulation of leukocytes and the liberation of enzymes from these cells
- Gangrenous: when a limb, generally the lower leg, looses its blood supply and undergoes necrosis (typically coagulative necrosis) involving multiple tissue planes +/- superimposed bacterial infection (wet gangrene)
- Caseous: most often in foci of tuberculous infection
- Fat: from release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity
- Fibrinoid: from deposition of immune complexes with vascular damage
6
Q
Physiologic causes of apoptosis?
A
- The removal of supernumerary cells (in excess of the required number) during development. Cell death is critical for involution of primordial structures and remodeling of maturing tissues. Apoptosis is a generic term for this pattern of cell death, regardless of the context, while programmed cell death refers only to apoptosis during development.
- Involution of hormone-dependent tissues on hormone withdrawal, such as endometrial cell breakdown during the menstrual cycle, ovarian follicular atresia in menopause, and regression of the lactating breast after weaning.
- Cell turnover in proliferating cell populations, such as immature lymphocytes in the bone marrow and thymus, B lymphocytes in germinal centers that fail to express useful antigen receptors (Chapter 6), and epithelial cells in intestinal crypts, to maintain a constant cell number (homeostasis).
- Elimination of potentially harmful self-reactive lymphocytes to prevent immune reactions against one’s own tissues (Chapter 6).
- Death of host cells that have served their useful purpose, such as neutrophils in an acute inflammatory response, and lymphocytes at the end of an immune response.
7
Q
Pathologic causes of apoptosis?
A
- DNA damage. Radiation and cytotoxic anticancer drugs can damage DNA, either directly or via production of free radicals. If repair mechanisms cannot correct the damage, the cell triggers intrinsic mechanisms that induce apoptosis. In these situations, apoptosis has a protective effect by preventing the survival of cells with DNA mutations that can lead to malignant transformation.
- Accumulation of misfolded proteins. Cell death triggered by improperly folded intracellular proteins and the subsequent endoplasmic reticulum (ER) stress response.
- Apoptosis can be induced during certain infections, particularly viral infections, as a result of the virus itself (as in adenovirus and HIV infections) or the host immune response (as in viral hepatitis). An important host response to viruses consists of cytotoxic T lymphocytes (CTLs) specific for viral proteins, which induce apoptosis of infected cells in an attempt to eliminate reservoirs of infection. During this process, there can be significant tissue damage. The same CTL-mediated mechanism is responsible for killing of tumor cells, cellular rejection of transplants, and tissue damage in graft-versus-host disease.
- Apoptosis may also contribute to pathologic atrophy in parenchymal organs after duct obstruction, such as occurs in the pancreas, parotid gland, and kidney.
8
Q
Morphologic features of apoptosis?
A
- Cell shrinkage
- Chromatin condensation
- Formation of cytoplasmic blebs and apoptotic bodies
- Phagocytosis of apoptotic cells or cell bodies, usually by macrophages
9
Q
2 pathways of apoptosis (initiation phase) with respective trigger(s) and mediator(s)?
A
- The Mitochondrial (Intrinsic) Pathway of Apoptosis: most physiologic and pathologic situations; pro-apoptotic proteins (BAX, BAK), anti-apoptotic proteins (BCL2), regulated apoptosis initiators (BAD…), cytochrome c and other death-inducing proteins (from mitochondria)… CASPASE
- The Extrinsic (Death Receptor–Initiated) Pathway of Apoptosis: elimination of potentially harmful self-reactive lymphocytes, and certain infections, particularly viral infections; plasma membrane death receptors (type 1 TNF receptor (TNFR1) and a related protein called Fas), respective ligands and adaptor proteins… CASPASE
10
Q
Main mediators of the execution phase of apoptosis?
A
- Initiator caspases
- Executioner caspases
- DNase
11
Q
3 disease states in which dysregulation of autophagy occurs?
A
- Cancer
- IBD
- Neurodegenerative diseases
12
Q
List the 4 principal free radicals involved in cell injury.
A
- Superoxide anion
- Hydrogen peroxide
- Hydroxyl radical
- Peroxynitrite
13
Q
List ways in which free radicals are generated.
A
- As a part of normal respiration
- Absorption of radiant energy (ionizing radiation)
- Inflammation
- Enzymatic metabolism of exogenous chemicals or drugs
- Transition metals (iron and copper)
- Nitric oxide (an important chemical mediator generated by endothelial cells, macrophages, neurons, and other cell types)
14
Q
Mechanisms to remove free radicals?
A
- Antioxidants (lipid-soluble vitamins E and A as well as ascorbic acid and glutathione in the cytosol)
- Binding of transition metals to storage and transport proteins (e.g., transferrin, ferritin, lactoferrin, and ceruloplasmin)
- Catalase, present in peroxisomes, decomposes H2O2
- Superoxidase dismutases (SODs) are found in many cell types and convert superoxide anion to H2O2
- Glutathione peroxidase also protects against injury by catalyzing free radical breakdown
15
Q
Three reactions particularly relevant to cell injury (ROS)?
A
- Lipid peroxidation in membranes
- Oxidative modification of proteins
- Lesions in DNA
18
Q
Mechanism of cell injury in ischemia?
A
