A&P Lecture 1. The Cell, Cell Adaptation, Injury, and Death PDF

The Cell, Cell Adaptation, Injury, and Death Baha ADAM, MD, MSc, Ph.D., DABCC Professor, Basic Pharmaceutical Science Physician Assistant Program College of Pharmacy, Xavier University of Louisiana  The outline of this chapter: The stru...

The Cell, Cell Adaptation, Injury, and Death Baha ADAM, MD, MSc, Ph.D., DABCC Professor, Basic Pharmaceutical Science Physician Assistant Program College of Pharmacy, Xavier University of Louisiana  The outline of this chapter: The structure and function of the normal cell Cell adaptation Cell injury (1) ischemic and hypoxic injury, (2) ischemia-reperfusion injury, (3) oxidative stress or accumulation of oxygen- derived free radicals-induced injury, and (4) chemical injury. Cellular death Necrosis Apoptosis Autophagy  Cellular Functions Movement: The cells can generate forces that produce motion. Conductivity: Conduction as a response to a stimulus is manifested by a wave of excitation. Metabolic absorption: All cells can take in and use nutrients and other substances from their surroundings. Secretion: Certain cells can secrete mucus, saliva, CSF, synovial and serous fluid etc.  Cellular Functions Excretion: All cells can rid themselves of waste products resulting from the metabolic breakdown of nutrients. Respiration: Cells absorb oxygen, which is used to transform nutrients into energy in the form of ATP. Reproduction: Tissue growth occurs as cells enlarge and reproduce themselves. Not all cells are capable of continuous division. Communication: Communication is vital for cells to survive as a society of cells. Appropriate communication allows the maintenance of a dynamic steady state. Eukaryotic Cell  Eukaryotic Cell Nucleus: The nucleus, which is surrounded by the nucleoplasm and generally is located in the center of the cell, is the largest membrane-bound organelle. Two pliable membranes compose the nuclear envelope. The nuclear envelope is pockmarked with pits, called nuclear pores, which allow chemical messages to exit and enter the nucleus. The outer membrane is continuous with membranes of the endoplasmic reticulum.  Eukaryotic Cell Nucleus: The nucleus contains: the nucleolus (a small dense structure composed largely of RNA), most of the cellular DNA, and the DNA-binding proteins (i.e., the histones) that regulate its activity. The primary functions of the nucleus are cell division and control of genetic information. Other functions include the replication and repair of DNA and the transcription of the information stored in DNA.  Eukaryotic Cell Cytoplasm: The cytoplasm is an aqueous solution (cytosol) that fills the cytoplasmic matrix. The cytosol represents about half the volume of a eukaryotic cell. It contains thousands of enzymes involved in intermediate metabolism and is crowded with ribosomes making proteins The organelles suspended in the cytoplasm are enclosed in biological membranes, so they can simultaneously carry out functions requiring different biochemical environments.  Eukaryotic Cell Cytoplasm: Many of these functions are directed by coded messages carried from the nucleus by RNA. The functions include synthesis of proteins and hormones and their transport out of the cell, isolation and elimination of waste products from the cell, performance of metabolic processes, breakdown and disposal of cellular debris and foreign proteins (antigens), and maintenance of cellular structure and motility. The cytosol is a storage unit for fat, carbohydrates, and secretory vesicles.  Cytoplasmic Organelles Ribosomes: RNA protein complexes Synthesized in nucleolus Sites for cellular protein synthesis Endoplasmic reticulum Network of tubular channels (cisternae) that extend throughout the outer nuclear membrane. Specializes in synthesis, folding, and transport of protein and lipid components of most organelles. A new role is sensing cellular stress.  Cytoplasmic Organelles Golgi complex: Network of smooth membranes and vesicles located near nucleus. Responsible for processing and packaging proteins onto secretory vesicles that break away from the complex and migrate to various intracellular and extracellular destinations, including plasma membrane.  Cytoplasmic Organelles Golgi complex: Best-known vesicles are those that have coats largely made of the protein clathrin. Proteins in the complex bind to the cytoskeleton, generating tension that helps organelle function and keep its stretched shape intact. The complex is a refining plant and directs traffic.  Cytoplasmic Organelles Lysosomes: Sac-like structures that contain enzymes for digesting most cellular substances to their basic form, such as amino acids, fatty acids, and carbohydrates (sugars). Cellular injury leads to the release of lysosomal enzymes that cause cellular self-destruction. A new function of lysosomes is signaling hubs of a sophisticated network for cellular adaptation.  Cytoplasmic Organelles Peroxisomes: Similar to lysosomes in appearance but contain several oxidative enzymes (e.g., catalase, urate oxidase) that produce hydrogen peroxide; reactions detoxify various wastes  Eukaryotic Organelles Mitochondria: Contain metabolic machinery needed for cellular energy metabolism. Enzymes of respiratory chain (electron- transport chain), found in inner membrane of mitochondria, generate most of cell's adenosine triphosphate (ATP) (oxidative phosphorylation). Have a role in osmotic regulation, pH control, calcium homeostasis, and cell signaling.  Eukaryotic Organelles Cytoskeleton “Bone and muscle” of cell. Composed of a network of protein filaments, including microtubules and actin filaments (microfilaments); forms cell extensions (microvilli, cilia, flagella). Intermediate filaments bridge the cytoplasm from one cell junction to another strengthening and supporting the sheet of epithelium. Membrane skeleton of the erythrocytes  Hereditary spherocytosis (HS) Spectrin, a cytoskeletal structure within the erythrocyte, is in turn bound to ankyrin and thereby plays an important role in maintenance of the biconcave shape of the erythrocyte. Hereditary spherocytosis (HS) is a congenital hemolytic disorder, wherein a genetic mutation coding for a structural membrane protein (ankyrin) phenotype leads to a spherical shaping of erythrocytic cellular morphology which are prone to repture.  Plasma Membrane Membranes surround the cell or enclose an intracellular organelle and are exceedingly important to normal physiologic function Because they control the composition of the space, or compartment, they enclose. Membranes can allow or exclude various molecules, and because of selective transport systems, they can move molecules in or out of the space  Plasma Membrane Functions Cellular Mechanism Membrane Functions Structure Usually thicker than membranes of intracellular organelles Containment of cellular organelles Maintenance of relationship with cytoskeleton, endoplasmic reticulum, and other organelles Maintenance of fluid and electrolyte balance (ion channels) Outer surfaces of plasma membranes in many cells are not smooth; they are also studded with cilia or even smaller cylindrical projections called microvilli; both are capable of movement Protection Barrier to toxic molecules and macromolecules (proteins, nucleic acids, polysaccharides) Barrier to foreign organisms and cells Activation of cell Hormones (regulation of cellular activity) Mitogens (cellular division) Antigens (antibody synthesis) Growth factors (proliferation and differentiation)  Plasma Membrane Functions Cellular Mechanism Membrane Functions Storage Storage site for many receptors Transport (e.g., sodium [Na+] pump) Diffusion and exchange diffusion Endocytosis (pinocytosis, phagocytosis) Exocytosis (secretion) Active transport Cell-to-cell Communication, anchors (integrins), and attachment at junctional interaction complexes Symbiotic nutritive relationships Release of enzymes and antibodies to extracellular environment Relationships with extracellular matrix  Plasma Membrane Membrane Composition: The basic structure of cell membranes is the lipid bilayer, composed of two opposing leaflets and proteins.  Plasma Membrane Membrane Composition: Different membranes have varying percentages of lipids and proteins. Intracellular membranes may have a higher percentage of proteins than do plasma membranes, presumably because most enzymatic activity occurs within organelles.  Plasma Membrane Membrane Composition: The membrane organization is achieved through noncovalent bonds that allow different physical states called phases (solid gel, fluid liquid–crystalline, and liquid-ordered). These phases can change under physiologic factors, such as temperature and pressure fluctuations. Carbohydrates are mainly associated with plasma membranes, in which they are chemically combined with lipids, forming glycolipids, and with proteins, forming glycoproteins  Plasma Membrane Membrane Composition: The outer surface of the plasma membrane in many types of cells, is not smooth but dimpled with flask- shaped invaginations known as caveolae (“tiny caves”). Caveolae are thought to serve as a storage site for many receptors, provide a route for transport into the cell and may act as the initiator for relaying signals from several extracellular chemical messengers into the cell's interior.  Membrane Composition Lipids: Each lipid molecule is said to be polar, or amphipathic, which means that one part is hydrophobic (uncharged, or “water hating”) and another part is hydrophilic (charged, or “water loving”). The membrane spontaneously organizes itself into two layers because of these two incompatible solubilities. The hydrophobic region (hydrophobic tail) of each lipid molecule is protected from water, whereas the hydrophilic region (hydrophilic head) is immersed in it.  We make cool things with Liposome A suspension of phospholipids (glycerophospholipids or sphingomyelins). Closed, self-sealing solvent-filled vesicles that are bounded by only a single bilayer. Serve as models of biological membranes. Hold promise as vehicles for drug delivery since they are absorbed by many cells through fusion with the plasma membrane  Membrane Composition Lipids: The bilayer serves as a barrier to the diffusion of water and hydrophilic substances, while allowing lipid-soluble molecules, such as oxygen (O2) and carbon dioxide (CO2), to diffuse through the membrane readily. A major component of the plasma membrane is a bilayer of lipid molecules— glycerophospholipids, sphingolipids, and sterols (e.g., cholesterol).  Membrane Composition Lipids: The most abundant lipids are phospholipids. Phospholipids have a phosphate-containing hydrophilic head connected to a hydrophobic tail. Phospholipids and glycolipids form self- sealing lipid bilayers. Lipids along with protein assemblies act as “molecular glue” for the structural integrity of the membrane.  Membrane proteins associate with the lipid bilayer in different ways Proteins: A. Transmembrane proteins that extend across the bilayer and exposed to an aqueous environment on both sides of the membrane. B. Proteins are located almost entirely in the cytosol and associated with the cytosolic half of the lipid bilayer. C. Proteins that exist outside the bilayer and are attached to the membrane by one or more covalently attached lipid groups. D. Proteins are bound indirectly to one or the other bilayer membrane face and held in place by their interactions with other proteins.  Membrane Composition Proteins: Proteins directly attached to the membrane bilayer can be removed by dissolving the bilayer with detergents called integral membrane proteins. The remaining proteins that can be removed by gentler procedures that interfere with protein–protein interactions but do not dissolve the bilayer are known as peripheral membrane proteins. Proteins exist in densely folded molecular configurations rather than straight chains; thus most hydrophilic units are at the surface of the molecule, and most hydrophobic units are inside.  Endoplasmic Reticulum, Protein Folding, and Endoplasmic Reticulum Stress Protein folding in the endoplasmic reticulum (ER) is critical for humans. Most secreted proteins fold and are modified in an error-free manner, but ER or cell stress, mutations, or random (stochastic) errors during protein synthesis can decrease the folding amount or the rate of folding. Pathophysiologic processes, such as viral infections, environmental toxins, and mutant protein expression, can perturb the sensitive ER environment.  Endoplasmic Reticulum, Protein Folding, and Endoplasmic Reticulum Stress These perturbations cause the accumulation of immature and abnormal proteins in cells, leading to ER stress. Fortunately, the ER is loaded with protective ways to help folding, for example, protein so-called chaperones that facilitate folding and prevent the formation of off-pathway types. Misfolded proteins not repaired in the ER are observed in some diseases and can initiate apoptosis, or cell death. Specific diseases include Alzheimer’s disease, Parkinson’s disease, prion disease, amyotrophic lateral sclerosis, diabetes mellitus, and sepsis.  The functions of membrane proteins Recognition and binding units (receptors) for substances moving into and out of the cell Pores or transport channels for various electrically charged particles. Specific enzymes that drive active pumps to maintain the concentration of certain ions against its concentration gradient (Na/K) Cell surface markers, such as glycoproteins which identify a cell to its neighbor Cell adhesion molecules (CAMs), or proteins that allow cells to hook together and form attachments of the cytoskeleton for maintaining cellular shape (makes cells stronger) Catalysts of chemical reactions (e.g., conversion of lactose to glucose  Protein regulation in a cell: proteostasis The cellular protein pool is in constant change or flux. Proteostasis is a state of cell balance of the processes of protein synthesis, folding, and dehydration. It is vital to health. This adaptable system depends on how quickly proteins are made, how long they survive, or when they are broken down. The proteostasis network comprises: ribosomes (makers); *protein synthesized by ribosomes* chaperones (helpers); and two protein breakdown systems or proteolytic systems— Lysosomes *digests proteins* and the ubiquitin–proteasome system (UPS).  Protein regulation in a cell: proteostasis These systems regulate protein homeostasis under a large variety of conditions, including variations in nutrient supply, the existence of oxidative stress or cellular differentiation, changes in temperature, and the presence of heavy metal ions and other sources of stress. Malfunction or failure of the proteostasis network is associated with human diseases.  Membrane Composition Carbohydrates: The short chains of carbohydrates contained within the plasma membrane are mostly bound to membrane proteins (glycoproteins) and lipids (glycolipids). Long polysaccharide chains attached to membrane proteins are called proteoglycans. All of the carbohydrate on the glycoproteins, proteoglycans, and glycolipids is located on the outside of the plasma membrane and the carbohydrate coating is called the glycocalyx.  The function of membrane carbohydrates The glycocalyx helps protect the cell from mechanical damage. Lubrication that assists the mobility of other cells, such as leukocytes, to squeeze through the narrow spaces. specific cell-to-cell recognition and adhesion. *FUNCTION OF CARB* Intercellular recognition is an important function of membrane oligosaccharides; for example, the transmembrane proteins called lectins, which bind to a particular oligosaccharide, recognize neutrophils at the site of bacterial infection. This recognition allows the neutrophil to adhere to the blood vessel wall and migrate from the blood into the infected tissue to help eliminate the invading bacteria.  Cellular adaptation Cells adapt to their environment to avoid injury. An adapted cell is neither normal nor injured; its status falls somewhere between these two states. Adaptations are reversible changes affecting the size, number, phenotype, metabolic activity, or function of cells. Adaptive responses have limits; additional stress can compromise essential cell functions leading to cell injury or death.  Cellular adaptation The most significant adaptive changes in cells include the following: Atrophy—decrease in cell size Hypertrophy—increase in cell size Hyperplasia—increase in cell number Metaplasia—reversible replacement of one mature cell type by another, less mature cell type or a change in cell phenotype Dysplasia—or deranged cellular growth, is not considered a true cellular adaptation but rather an atypical hyperplasia  Cellular adaptation Physiologic atrophy: During childhood, the thymus decreases in size. Age-related atrophic changes to the gonads occur secondary to decreases in hormonal stimulation Pathologic atrophy to muscle will occur when a limb is placed in a cast. This form of atrophy, known as disuse atrophy, also occurs with prolonged bed rest or other immobilization. Physiological hypertrophy: is enlargement secondary to aerobic exercise or a “runner's heart.” Pathological hypertrophy: LVH occurs secondary to hypertension.  Cellular adaptation Two types of physiologic (normal) hyperplasia occur: compensatory hyperplasia and hormonal hyperplasia: Compensatory hyperplasia: If the cancerous region of the liver is removed, the remaining cells will undergo hyperplasia. Hormonal hyperplasia occurs in organs that respond to endocrine hormonal stimulation. Physiologic hormonal hyperplasia: during the follicular phase of the menstrual cycle, estrogen secretion by the ovary results in hyperplasia and endometrial proliferation Pathologic hormonal hyperplasia: the endometrial changes that are due to hormonal imbalances.  Cellular adaptation The most significant adaptive changes in cells include the following: Dysplasia: An abnormal changes in the shape and organization of cervical cells. Metaplasia: In smoker the stratified squamous epithelial cells replace the normal columnar ciliated cells.  Cellular injury Injury to cells and the extracellular matrix (ECM) leads to injury of tissues and organs and ultimately determines the structural patterns of disease. Cellular injury occurs when the cell is unable to maintain homeostasis. The injury may be reversible (the cell can recover) or irreversible (cellular death). Loss of function results from cell and ECM injury and cell death. Table 1. Types of progressive cell injury and responses Type Responses Adaptation Atrophy, hypertrophy, hyperplasia, metaplasia Active cell injury Immediate response of “entire” cell Reversible Loss of ATP, cellular swelling, detachment of ribosomes, autophagy of lysosomes Irreversible “Point of no return” structurally when severe vacuolization of mitochondria occurs and Ca++ moves into the cell Necrosis Common type of cell death with severe cell swelling and breakdown of organelles Apoptosis, or programmed Cellular self-destruction for elimination of unwanted cell populations cell death Autophagy Eating of self, cytoplasmic vesicles engulf cytoplasm and organelles, recycling factory Chronic cell injury Persistent stimuli response may involve only specific organelles or cytoskeleton (subcellular alterations) (e.g., phagocytosis of bacteria) Accumulations or Water, pigments, lipids, glycogen, proteins infiltrations Pathologic calcification Dystrophic and metastatic calcification  Cellular injury Cellular injury may occur secondary to a variety of factors: Chemical agents, Lack of sufficient oxygen (hypoxia), Free radicals, Infectious agents, Physical and mechanical factors, Immunologic reactions, Genetic factors, and Nutritional imbalances.  Cellular injury The extent of the cellular injury is a function of cell type, level of differentiation, and adaptive mechanisms of the cell. Also important is the nature, severity, and duration of the injury. Fully differentiated, mature cells are more susceptible to injury than are cell precursors.  Cellular injury Stages of cellular adaptation, injury, and death The normal cell responds to physiologic and pathologic stresses by adapting (atrophy, hypertrophy, hyperplasia, metaplasia). Cell injury occurs if the adaptive responses are exceeded or compromised by injurious agents, stress, and mutations. The injury is reversible if it is mild or transient, but if the stimulus persists, the cell suffers irreversible injury and eventually death.  Cellular injury Two individuals exposed to an identical stimulus may incur varying degrees of cellular injury. Individual differences, including genetics, nutritional status, and immunologic competency, can profoundly influence the extent of cell injury. The precise “point of no return” with respect to cell death remains unclear. Once changes to the nucleus have occurred or cell membranes are disrupted, or both, irreversible injury and cell death are inevitable.  Cellular injury General mechanisms of cell injury Regardless of the cause of injury, a host of biochemical events result in cell injury and death. Such events include; Adenosine triphosphate (ATP) depletion, Damage from oxygen-derived free radicals, and Alterations in calcium level. Injury to cell components includes; Membrane damage, Protein folding defects, Mitochondrial compromise, and DNA damage. Table 2. Common themes in cell injury and cell death. Theme Comments ATP depletion Loss of mitochondrial ATP and decreased ATP synthesis; results include cellular swelling, decreased protein synthesis, decreased membrane transport, and lipogenesis, all changes that contribute to loss of integrity of plasma membrane Reactive oxygen Lack of oxygen is key in the progression of cell injury in ischemia; activated oxygen species (↑ROS) species (Superoxide, H2O2, OH−) destroy cell membranes and structure. Ca++ entry Normally intracellular cytosolic calcium concentrations are very low; ischemia and certain chemicals cause an increase in cytosolic Ca++ concentrations; sustained levels of Ca++ continue to increase with damage to plasma membrane; Ca++ causes intracellular damage by activating many enzymes Mitochondrial It can be damaged by increases in cytosolic Ca++, ROS; two outcomes of mitochondrial damage damage are loss of membrane potential, which causes depletion of ATP and eventual death or necrosis of cell, and activation of another type of cell death (apoptosis) Membrane damage Early loss of selective membrane permeability found in all forms of cell injury, lysosomal membrane damage with release of enzymes causing cellular digestion Protein misfolding, Proteins may misfold, triggering unfolded protein response that activates corrective DNA damage responses; if overwhelmed, response activates cell suicide program or apoptosis; DNA damage (genotoxic stress) also can activate apoptosis  Cellular injury The most common forms of cell injury include (1) ischemic and hypoxic injury, (2) ischemia-reperfusion injury, (3) oxidative stress or accumulation of oxygen- derived free radicals-induced injury, and (4) chemical injury.  Cellular injury Ischemic and hypoxic injury Hypoxia, the lack of sufficient oxygen within cells, is the most common cause of cellular injury. Hypoxia can result from many circumstances, such as; Reduced oxygen content in the ambient air, Loss of hemoglobin, Decreased red blood cell (RBC) production, Respiratory and cardiovascular diseases, and Poisoning of the cellular oxidative enzymes (cytochromes).  Cellular injury Ischemic and hypoxic injury Hypoxia negatively impacts normal physiologic processes: differentiation, angiogenesis, proliferation, erythropoiesis, and overall cell viability.  Ischemic and hypoxic injury The role of reactive oxygen species (ROS) in cell injury Mitochondria are the primary consumers of oxygen. Hypoxia triggers the mitochondrial complex to produce reactive oxygen species (ROS). ROS can promote oxidative stress, which can damage cells (Adapted from Kumar V et al, editors: Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Elsevier.)  Cellular injury Ischemic and hypoxic injury Arteriosclerosis and thrombus can result in localized tissue ischemia. Progressive hypoxia, caused by gradual arterial narrowing, is better tolerated than acute anoxia caused by an acute obstruction or a thrombus. An acute obstruction in a coronary artery can result in a rapidly evolving myocardial infarction (“heart attack”) if the blood supply is not restored. Gradual onset of ischemia, however, usually results in myocardial adaptation.  Cellular injury Ischemic and hypoxic injury Ischemia-induced reduction in ATP levels causes a failure of the plasma membrane's sodium–potassium (Na+-K+) pump and sodium–calcium (Na+-Ca++) exchange mechanisms. Sodium and calcium influx into and accumulate in the cell. Potassium (K+) diffuses out of the cell. Without the pump mechanism, sodium and water can freely enter the cell resulting in cellular swelling and dilation of the ER.  Cellular injury Ischemic and hypoxic injury With dilation, ribosomes detach from the rough ER, reducing protein synthesis. If hypoxia persists, the entire cell becomes markedly swollen. These disruptions are reversible if oxygen (O2) is restored. If oxygen is not restored, vacuolation occurs within the cytoplasm. The damaged outer membrane causes lysosomes to swell; marked swelling occurs to the mitochondria.  Cellular injury Ischemic and hypoxic injury With continued hypoxia, cell death rapidly follows as calcium accumulates within the cell, essential metabolic processes cease, and cell membranes become dysfunctional. Influx of calcium into the cell activates enzymes that trigger apoptosis. Restoration of blood flow and oxygen can result in an additional injury known as ischemia–reperfusion injury.  Cellular injury Ischemia-reperfusion injury Restoration of blood flow and oxygen to ischemic tissues can increase recovery of cells reversibly injured, but paradoxically result in an additional injury known as ischemia–reperfusion injury and cause cell death. Reperfusion is a serious complication and an important mechanism of injury in instances of tissue transplantation and other ischemic syndromes (e.g., hepatic, intestinal, renal). Redrawn from Damjanov I: Pathology for the health professions, ed 3, St Louis, 2006, Saunders.  Cellular injury Several mechanisms are proposed for reperfusion injury, including the following: Oxidative stress: Reoxygenation induces oxidative stress by generating high ROS and nitrogen species. Increased intracellular calcium concentration: Intracellular and mitochondrial calcium accumulates within the cell during acute ischemia. Inflammation: Ischemic injury promotes inflammation. Dead cells stimulate immune cells to release cytokine-mediated danger signals, thus initiating an inflammatory response. Complement activation: Complement activation may exacerbate damage that has occurred secondary to reperfusion injury.  Cellular injury Free radicals and reactive oxygen species—oxidative stress Free radicals are an important mechanism of cellular injury, especially injury caused by ROS. This form of injury is called oxidative stress. Reactive oxygen species (ROS) are reactive molecules from molecular oxygen formed as a natural oxidant species in cells during mitochondrial respiration and energy generation. Oxidative stress is caused by increased reactive species, depletion of antioxidant defense, or both.  Cellular injury Free radicals and reactive oxygen species—oxidative stress Oxidative stress results in the detrimental oxidation of different molecules, including proteins, lipids, nucleic acids, and others. Oxidative stress can activate several intracellular signaling pathways because ROS can regulate enzymes and transcription factors. Free radicals are generated in a variety of conditions, including; chemical and radiation injury, ischemia–reperfusion injury, cellular aging, and microbial destruction by phagocytes.  Cellular injury Free radicals and reactive oxygen species—oxidative stress A free radical is an electrically uncharged atom or group of atoms with an unpaired electron. Having one unpaired electron makes the molecule unstable; the molecule becomes stabilized either by donating or by accepting an electron from another molecule. The free radical has the potential to form a damaging chemical bond with proteins, lipids, and carbohydrates found within the cell membrane. Free radicals are highly reactive. They have low chemical specificity—that is, they can react with most molecules in their proximity.  Cellular injury Free radicals also cause several damaging effects, such as the following: 1. Lipid peroxidation—the destruction of polyunsaturated lipids, which leads to membrane damage and increased permeability. 2. Protein alteration—a process whereby polypeptide chains become fragmented, leading to protein loss, protein misfolding, and alters protein–protein interaction. 3. DNA damage—results in mutations. 4. Mitochondrial effects—mitochondria can become damaged by ROS, compromising available energy for the cell.  Cellular injury Free radicals and reactive oxygen species—oxidative stress The toxicity of certain drugs and chemicals can be attributed to free radicals. The drug/chemical may be converted to a free radical or it may generate oxygen-derived metabolites. Free radicals have been either directly or indirectly linked with a growing number of diseases and disorders: Atherosclerosis, diabetes, cataract, Ischemic brain injury, Reduced cognitive performance (Alzheimer’s disease), and Cancer  Cellular injury Free radicals and reactive oxygen species—oxidative stress The body has various mechanisms to eliminate free radicals. As an example, the oxygen free radical superoxide may spontaneously decay into oxygen and hydrogen peroxide. https://xula0- my.sharepoint.com/personal/badam_xula_edu/Documents/PA%20Program/501 Table 3. Methods contributing to inactivation or termination of free radicals 1%20Basic%20Science%20I/Lecture%20slides/Edited/PDF%20files/Antioxidan t%20Nutrients%20and%20free%20radicals.pdf Method Process Antioxidants Endogenous or exogenous; either blocks synthesis or inactivates (e.g., scavenges) free radicals; includes vitamin E, vitamin C, cysteine, glutathione, albumin, ceruloplasmin, transferrin, γ-lipoacid, others Enzymes Superoxide dismutase, which converts superoxide to hydrogen peroxide (H2O2); Catalase (in peroxisomes) decomposes H2O2; Glutathione peroxidase decomposes hydroxyl radical (OH−) and H2O2  Cellular injury Chemical or toxic injury Mechanisms of cell stress from chemical agents include oxidative stress, ER stress, heat shock response, DNA damage response, mental stress, inflammation, and osmotic stress. Chemicals are classified under these types of cell stress mechanisms. Xenobiotics (from Greek Xenos, “foreign”; bios, “life”) are compounds and chemicals that have toxic, mutagenic, or carcinogenic properties.  Cellular injury Chemical or toxic injury Many xenobiotics are hepatotoxic. The liver is the initial contact site for many ingested compounds—xenobiotics, drugs, and alcohol— predisposing this organ to chemically induced injury. Many chemical compounds used in household cleaning, insect control, outdoor maintenance, or chemical manufacturing are potential carcinogens. The extent of chemically induced liver injury varies from minor liver injury to acute liver failure, cirrhosis, and liver cancer.  Cellular injury Chemical or toxic injury Hepatic detoxification occurs through enzyme-mediated biotransformation and antioxidant systems. Biotransformation is a process whereby enzymatic reactions convert one chemical into a less toxic or nontoxic compound. The liver has the highest supply of biotransformation enzymes of all organs and plays a key role in protecting the host from chemical toxicity.  Cellular injury Antioxidants Antioxidants are molecules that inhibit the oxidation of other molecules, thereby preventing the formation of free radicals. Antioxidants often terminate a chain reaction, which would otherwise result in free radical formation. Endogenous antioxidants are antioxidants produced by the body: Superoxide dismutase (SOD), Alpha lipoic acid (ALA), Catalase, Coenzyme Q 10 (CoQ10), and Glutathione peroxidase (GPX).  Cellular injury Chemical agents, including drugs Numerous chemical agents cause cellular injury. Minute amounts of some, such as arsenic and cyanide, can rapidly destroy cells and cause individual death. Chronic exposure to air pollutants, insecticides, and herbicides can cause cell injury. CCl4, alcohol, and social drugs can significantly alter cellular function and injure cellular structures. Over-the-counter (OTC) and prescribed drugs are important causes of cellular injury. The abuse and addiction to opioids, such as heroin, morphine, fentanyl, and other prescription pain relievers, are a serious global problem that affects all societies.  Cellular injury Infectious Injury The pathogenicity (virulence) of microorganisms lies in their ability to survive and proliferate within the host. The disease-producing potential of a microorganism is a function of its ability to (1) invade and destroy cells, (2) produce toxins, and (3) produce damaging hypersensitivity reactions.  Cellular injury Immunologic and inflammatory injury Cellular membranes are injured as a result of direct contact with immune or inflammatory-mediated responses, such as phagocytes and biochemical substances generated during an inflammatory response. Potentially injurious biochemical agents include; Histamine, Antibodies, Lymphokines, Complement system products, and Proteases.  Cellular injury Immunologic and inflammatory injury The complement system is responsible for several membrane alterations associated with immunologic injury. Membrane alterations can facilitate a rapid leakage of potassium out of the cell, along with an influx of water. Antibodies can bind and occupy receptor molecules on the plasma membrane, interfering with its function. Antibodies also can block or destroy cellular junctions, obstructing intercellular communication.  Cellular death With sufficient structural or physiologic damage, cell injury becomes irreversible and cells die. Historically, cell death has been attributed to either necrosis or apoptosis.  Cellular death Necrosis Necrosis is the sum of cellular changes occurring after local cell death. It is characterized by autolysis or autodigestion, a cellular self-digestion process. Cellular death is initiated long before any necrotic changes can be detected by light microscopy. Dense clumping of nuclear material and the progressive disruption of plasma and organelle membranes portend irreversible injury, and necrosis follows. Cellular death Necrosis As membrane integrity is lost, necrotic cell contents leak into the surrounding intracellular spaces, triggering an inflammatory response within the tissue. In the later stages of necrosis, when most organelles are disrupted, karyolysis (dissolution) occur. Pyknosis, a process where the nucleus shrinks into a small, dense mass of genetic material, occurs. Eventually, lysosomal enzymes break up the pyknotic nucleus called karyorrhexis. Karyorrhexis is the fragmentation of the nucleus into small particles or “nuclear dust.”  Cellular death Coa Apoptosis Apoptosis is an active process of cellular self-destruction, resulting in programmed cell death. It has been implicated in both normal and pathologic tissue changes. Cells die as a part of a normal physiologic process.  Cellular death Apoptosis Death by apoptosis also causes loss of cells in many pathologic states, including the following: Severe cell injury: When cell injury exceeds the capacity for repair mechanisms, cell signaling triggers apoptosis. Accumulation of misfolded proteins: This condition results from either genetic mutations or free radicals.  Cellular death Coa Apoptosis Death by apoptosis also causes loss of cells in many pathologic states, including the following: Infections: Apoptosis may result from the host's immune response to the presence of a virus infecting the cell. Obstruction in tissue ducts: Obstruction of blood flow to the organ results in pathologic atrophy, commonly noted in the pancreas, kidney, or parotid gland.  Cellular death Table 4. Features of necrosis and apoptosis. Feature Necrosis Apoptosis Cell size Enlarged (swelling) Reduced (shrinkage) Nucleus Pyknosis → karyorrhexis Fragmentation into nucleosome-size → karyolysis fragments Plasma membrane Disrupted Intact; altered structure, especially orientation of lipids Cellular contents Enzymatic digestion; may Intact; may be released in apoptotic bodies leak out of cell Adjacent Frequent No inflammation Physiologic or Invariably pathologic Often physiologic, means of eliminating pathologic role (culmination of irreversible unwanted cells; may be pathologic after some cell injury) forms of cell injury, especially deoxyribonucleic acid (DNA) damage  Cellular death Apoptosis Accumulation of misfolded proteins: Excessive accumulation of misfolded proteins in the ER leads to a condition known as endoplasmic reticulum stress (ER stress). ER stress culminates in cell death secondary to apoptosis. This mechanism has been linked to several degenerative diseases of the CNS and other organs. Amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson's disease, Alzheimer's disease, and Huntington's.  Cellular death The unfolded protein response, endoplasmic stress, and apoptosis.  Cellular death Apoptosis Initiation of apoptosis requires tightly regulated cell signaling. Key components involve proteases, enzymes that divide other proteins. Caspases are a family of aspartic acid–specific enzymes that trigger proteolytic activity in response to signals, which induce apoptosis. Specifically, activated caspases cleave other proteins within the system, initiating a series of sequential reactions known as the “suicide” cascade.  Cellular death Apoptosis The cascade results in rapid and contained cell death. Cells undergoing apoptosis release chemical factors, which recruit phagocytes. The phagocytes quickly engulf cellular remnants, reducing their potential to induce damaging inflammation.  Cellular death Coagu Apoptosis Caspase activation triggers two different but convergent pathways: the mitochondrial (intrinsic) pathway and the death receptor (extrinsic) pathway.  Cellular death Manifestations of cellular injury Cellular Manifestations: Accumulations Metabolic disturbances can result from cell injury, particularly where there is an excessive intracellular accumulation of biochemical substances. Most accumulations result from four types of mechanisms,  Cellular death Most accumulations result from four types of mechanisms: Insufficient removal of the normal substance because of altered configuration or transport. Example: steatosis, fatty changes in the liver. Accumulation of abnormal substance because of defects in protein folding, transport, or abnormal degradation. Such occurrences are usually secondary to gene mutation. Inadequate metabolism of an endogenous substance, usually because of a lack of a lysosomal enzyme. Example: storage diseases. Harmful exogenous materials. Example: heavy metals and mineral dust inhalation and ingestion or the presence of pathogenic microorganisms. Cellular death Coagulative necrosis Manifestations of cellular injury  Cellular death Autophagy The Greek term autophagy means “eating of self.” Autophagy is a “recycling factory” as well as a survival mechanism. It is a self-destructive process that delivers cytoplasmic contents to the lysosome for degradation. When cells are starved or nutrient deprived, autophagy initiates a “cannibalization response,” which digests the cell and recycles the contents. Autophagy can maintain cellular metabolism under conditions of starvation. Under conditions of stress, autophagy removes damaged organelles, thus enhancing the likelihood of survival.  Cellular death Autophagy Autophagy holds promise for formulating new therapeutic strategies in treating disease. Evidence also suggests that autophagy may be the last immune defense against infectious microorganisms that have invaded the intracellular environment. The “garbage collecting” and recycling functions, characterizing autophagy, becomes less efficient and less discriminating in aging individuals. Consequently, harmful agents accumulate and cause increased cell damage as people age.  Cellular death Autophagy Failure to clear protein products in neurons of the CNS has been linked with dementia. Similarly, failure to clear mitochondria, which generates ROS, can lead to nuclear DNA mutations and cancer. These processes may even partially define normal aging. Enhancing autophagy may decrease cancer incidence and prevent the development of particular degenerative diseases.