AN OVERVIEW OF APOPTOSIS AND AMYLOIDOSIS

Introduction

 

Necrosis Types & Morphology

Necrosis is a form of cell death that occurs due to various factors, such as injury, infection, toxins, or lack of blood supply. It is different from apoptosis, which is a controlled and programmed cell death. Morphologically, necrosis is characterized by distinct changes in affected cells and tissues. These changes can vary depending on the type of necrosis, but some common features include:

1. Cell swelling: Cells undergoing necrosis often show swelling, known as oncosis. This is caused by the influx of water and ions into the cell, leading to an enlarged and hydropic appearance.
2. Loss of plasma membrane integrity: The cell membrane loses its integrity, leading to leakage of cellular contents into the surrounding tissue. This can trigger an inflammatory response.
3. Disruption of organelles: Organelles within the cell may become damaged or fragmented.
4. Inflammatory response: Necrosis typically induces inflammation in the surrounding tissue, as cellular debris and released intracellular contents can activate the immune system.

Types of necrosis with examples:

1. Coagulative Necrosis: Coagulative necrosis is the most common type of necrosis and is often caused by ischemia (lack of blood supply) due to, for example, arterial blockage. The affected tissue becomes firm and pale. The cell outlines remain intact for a period of time, creating a coagulated appearance. Over time, the dead tissue is broken down and eventually replaced by scar tissue. Coagulative necrosis occurs in organs like the heart, kidney, and spleen.
2. Liquefactive Necrosis: Liquefactive necrosis is characterized by the transformation of the affected tissue into a liquid, often seen in bacterial or fungal infections. The tissue is soft and appears as a pus-filled area, forming an abscess. The process results in the formation of a cystic cavity containing cellular debris and inflammatory cells. The brain is particularly susceptible to liquefactive necrosis.
3. Caseous Necrosis: Caseous necrosis has a cheese-like, granular appearance and is typically observed in tuberculosis infections. It occurs when the immune system walls off the affected tissue, forming a soft and friable mass with a characteristic yellowish-white appearance.
4. Fat Necrosis: Fat necrosis happens when adipose (fat) tissue undergoes necrosis. This type is commonly seen in breast tissue after trauma or injury to the breast. The dead fat cells release fatty acids, which combine with calcium to form chalky white deposits, called fat saponification.
5. Gangrenous Necrosis: Gangrenous necrosis refers to the death of a large area of tissue, often in the extremities, due to severe ischemia and subsequent bacterial infection. There are two main types of gangrenous necrosis: a. Dry gangrene: This occurs when the blood supply is impaired, leading to tissue dryness and blackening. It is commonly seen in conditions like peripheral arterial disease. b. Wet gangrene: This occurs when the affected tissue becomes infected, leading to tissue liquefaction. The area appears swollen, foul-smelling, and may have a dark color.

These are some of the main types of necrosis, each with distinct morphological characteristics and underlying causes. Understanding the different types of necrosis is essential for diagnosing and managing various pathological conditions.

 

Morphology and Mechanism of Apoptosis:

Apoptosis, also known as programmed cell death, is a tightly regulated process essential for maintaining tissue homeostasis and eliminating damaged or unnecessary cells without causing inflammation. It plays a crucial role in various physiological processes during development, immune response, and tissue turnover.

Morphology of Apoptosis: The morphological changes observed during apoptosis include:

1. Cell Shrinkage: The cell undergoes a reduction in size due to the condensation of cytoplasm and organelles.
2. Nuclear Changes: The nucleus undergoes chromatin condensation, resulting in the formation of discrete, dense masses known as pyknotic bodies. This is in contrast to the clumped and marginated chromatin observed in necrosis.
3. Membrane Blebbing: The plasma membrane forms irregular, rounded protrusions known as blebs, which eventually separate from the cell, forming apoptotic bodies.
4. Apoptotic Bodies: The fragmented cell breaks into smaller membrane-bound apoptotic bodies containing cellular components. These apoptotic bodies are then phagocytosed by neighboring cells or macrophages, preventing the release of harmful cellular contents.
5. Lack of Inflammation: Apoptosis is a non-inflammatory process, unlike necrosis, which can trigger inflammation.

Mechanism of Apoptosis: Apoptosis is primarily regulated by a family of proteins known as caspases, which are proteolytic enzymes that initiate and execute the apoptotic process. The two main pathways that lead to caspase activation are:

1. Extrinsic Pathway (Death Receptor Pathway):
   • External signals, such as cytokines or ligands, bind to specific death receptors on the cell surface.
   • This binding leads to the recruitment and activation of caspase-8, forming the death-inducing signaling complex (DISC).
   • Caspase-8 activates downstream caspases, such as caspase-3, initiating the apoptotic cascade.
2. Intrinsic Pathway (Mitochondrial Pathway):
   • Internal cellular stressors, such as DNA damage, nutrient deprivation, or growth factor withdrawal, trigger the intrinsic pathway.
   • This results in the release of cytochrome c and other pro-apoptotic proteins from the mitochondria into the cytoplasm.
   • Cytochrome c forms a complex called the apoptosome with Apaf-1 (apoptotic protease-activating factor 1) and procaspase-9, activating caspase-9.
   • Caspase-9 then activates downstream caspases, like caspase-3, leading to apoptosis.

Both pathways eventually converge to activate executioner caspases, such as caspase-3 and caspase-7, which cleave numerous cellular proteins, leading to cell dismantling and death.

Causes of Apoptosis with Examples:

1. Cellular Damage and DNA Fragmentation: Cells damaged by radiation, chemotherapy, or toxins undergo apoptosis to prevent the propagation of harmful mutations. For example, ultraviolet radiation can cause DNA damage in skin cells, leading to apoptosis as a protective mechanism against potential cancer development.
2. Viral Infections: Some viruses can trigger apoptosis to facilitate their release and spread to neighboring cells. For instance, Human Immunodeficiency Virus (HIV) induces apoptosis in CD4+ T cells, which are critical for immune function.
3. Developmental Processes: Apoptosis plays a vital role in shaping tissues and organs during development. For example, apoptosis in the webbing between fingers and toes ensures the formation of separate digits during embryonic development.
4. Hormone Withdrawal: Certain cells require specific hormones for survival. When these hormones are withdrawn, apoptosis is initiated. An example is the regression of the uterine lining during menstruation when progesterone levels drop.
5. Immune Cell Regulation: Activated immune cells, such as T cells and B cells, undergo apoptosis after fulfilling their function to avoid excessive immune responses. This prevents autoimmune diseases and maintains immune balance.
6. Tumor Suppression: Apoptosis helps eliminate cells with potential cancer-causing mutations, acting as a natural defense against tumor formation. If apoptosis is inhibited, it can contribute to tumor growth.

Remember that while apoptosis is essential for maintaining tissue integrity and proper functioning, an imbalance in apoptosis regulation can lead to various diseases, including neurodegenerative disorders, autoimmune diseases, and cancer.

 

Theories of Aging

 

Ischemia and Hypoxia: O2 Response

Ischemia and hypoxia are both conditions that involve a lack of oxygen supply to tissues, but they have distinct characteristics and implications for cellular responses.

Ischemia: Ischemia refers to a reduction or complete blockage of blood flow to a particular tissue or organ, leading to a decreased oxygen supply to the cells. It can be caused by various factors, such as blood clots, narrowed blood vessels, or other obstructions in the blood flow.

Hypoxia: Hypoxia, on the other hand, specifically denotes a condition where there is an inadequate amount of oxygen reaching the cells, regardless of the cause. Hypoxia can result from various factors, including reduced oxygen levels in the air, impaired lung function, or issues with oxygen-carrying capacity in the blood.

Time course of molecular events in response to lack of oxygen:

1. ATP Depletion: When oxygen supply is compromised, cellular respiration is impaired, leading to reduced ATP (adenosine triphosphate) production, the primary energy source for cells. ATP levels decrease rapidly within minutes of oxygen deprivation.
2. Anaerobic Metabolism: In an attempt to compensate for the lack of oxygen, cells switch to anaerobic metabolism, converting glucose into lactic acid to generate limited ATP. However, this process is much less efficient and results in lactic acid accumulation, causing cellular acidosis.
3. Ion Pump Failure: ATP is crucial for maintaining the ion gradients across the cell membrane. ATP depletion leads to the failure of ion pumps, particularly the sodium-potassium pump, disrupting cellular homeostasis and causing cellular swelling.
4. Increased Glycogenolysis: Cells attempt to mobilize glycogen stores to provide additional energy in the absence of oxygen.

Reversible Injury: During the initial stages of oxygen deprivation, the cell may undergo reversible injury, where cellular damage is not severe, and the cell has the potential to recover once the oxygen supply is restored. This phase typically lasts for a short period, ranging from minutes to a few hours.

Irreversible Injury: If oxygen deprivation persists for an extended period, irreversible injury occurs, leading to cell death. Irreversible injury is characterized by severe cellular damage beyond the point of recovery, and even if oxygen is restored, the cell cannot survive. Irreversible injury may result in apoptosis (programmed cell death) or necrosis (uncontrolled cell death).

Key events distinguishing reversible from irreversible injury:

1. Mitochondrial Dysfunction: Reversible injury often involves mild mitochondrial dysfunction, which can be restored upon reperfusion. In contrast, irreversible injury leads to significant and widespread mitochondrial damage, causing a complete loss of cellular respiration and ATP production.
2. Membrane Damage: Reversible injury may cause mild disturbances in the cell membrane, allowing for potential repair. Irreversible injury leads to severe membrane damage, leading to cellular lysis and leakage of cellular contents.
3. DNA Damage: Prolonged oxygen deprivation can result in DNA damage, which is often irreversible and contributes to cell death.
4. Cellular Acidosis: The accumulation of lactic acid is reversible in the early stages of injury, but prolonged acidosis can lead to irreversible damage to cellular structures and enzymes.

In summary, both ischemia and hypoxia involve oxygen deprivation to cells, but ischemia is characterized by a lack of blood flow, while hypoxia is characterized by insufficient oxygen delivery. The time course of molecular events in response to lack of oxygen determines whether the cell undergoes reversible or irreversible injury. Reversible injury may be restored if oxygen is supplied promptly, while irreversible injury leads to cell death due to severe and irreversible damage to cellular structures and functions.

 

Cell Injury Organelle Alterations

 

Cell Injury: Free Radicals vs Chemicals

Cell injury can occur through various mechanisms, two of which are free radical-induced injury and chemical-induced injury. Let’s compare and contrast these two types of cell injury in terms of their biochemical and molecular mechanisms:

1. Free Radical-Induced Cell Injury: Free radicals are highly reactive molecules that contain unpaired electrons, making them unstable and capable of damaging cellular components. They are produced during normal metabolic processes or in response to external factors such as radiation, pollution, or toxins. The major type of free radicals involved in cell injury are reactive oxygen species (ROS), including superoxide radicals (O2-), hydroxyl radicals (OH-), and hydrogen peroxide (H2O2). Biochemical Mechanisms: Free radicals cause cell injury primarily through oxidative stress. Oxidative stress occurs when there is an imbalance between the production of free radicals and the cell’s ability to neutralize them using antioxidants. Free radicals can damage lipids, proteins, and nucleic acids, leading to cell membrane disruption, enzymatic inactivation, and DNA damage. Molecular Mechanisms: The molecular mechanisms of free radical-induced cell injury involve lipid peroxidation, protein oxidation, and DNA damage. Free radicals attack polyunsaturated fatty acids in the cell membrane, leading to lipid peroxidation and membrane destabilization. They can also oxidize essential proteins, altering their structure and function, and cause mutations in DNA, leading to potential genetic abnormalities and cell death.
2. Chemical-Induced Cell Injury: Chemicals can cause cell injury through various mechanisms, depending on the specific chemical’s properties and target tissues. Chemicals that can induce cell injury include environmental toxins, drugs, heavy metals, and industrial chemicals. Biochemical Mechanisms: The biochemical mechanisms of chemical-induced cell injury can vary widely depending on the specific chemical involved. Some chemicals directly damage cellular components through covalent binding, disrupting their function. Others may interfere with essential cellular processes, alter ion channels, or impair enzymatic pathways. Molecular Mechanisms: The molecular mechanisms of chemical-induced cell injury depend on the chemical’s properties and targets. For example, some chemicals may disrupt ion channels, leading to changes in membrane potential and calcium signaling, which can trigger cell death pathways. Others may inhibit critical enzymes, interfere with DNA replication, or induce apoptosis (programmed cell death).