Brief Summary
This YouTube video by PW MedEd provides a comprehensive overview of cell injury, necrosis, and apoptosis. It begins with a review of previous concepts, then explains the different types of necrosis (coagulative, liquefactive, caseous, fibrinoid, and fat), detailing their mechanisms and examples. The video then transitions to apoptosis, covering its physiological and pathological aspects, the extrinsic and intrinsic pathways, and diagnostic methods.
- Types of Necrosis: Coagulative, Liquefactive, Caseous, Fibrinoid, and Fat.
- Apoptosis: Programmed cell death with extrinsic and intrinsic pathways.
- Diagnostic Methods: H&E staining, DNA agarose gel electrophoresis, and TUNEL assay.
Introduction and Review
The session starts with greetings and a quick recap of the previous class, which covered reversible and irreversible cell injury, as well as necrosis. The instructor poses questions to the students to refresh their understanding of key concepts such as the role of hypoxia in cell injury, the accumulation of sodium in reversible cell damage, and the accumulation of calcium in irreversible cell injury. Myelin figures and amorphous densities of mitochondria are found in both reversible and irreversible cell injury. Necrosis typically appears pink under microscopy.
Types of Necrosis: Coagulative and Liquefactive
The lecture transitions to discussing the five types of necrosis: coagulative, liquefactive, caseous, fibrinoid, and fat. Regardless of the type, necrosis generally appears pink under microscopy. Coagulative necrosis is the most common type and typically occurs in infarcts of solid organs, excluding the brain. Gangrene, a gross term for greenish-black tissue, includes dry gangrene (a form of coagulative necrosis) and wet gangrene (infected dry gangrene, which involves liquefactive necrosis). Liquefactive necrosis primarily involves lipid degradation through enzyme activation and is commonly seen in brain infarcts and acute pancreatitis. In coagulative necrosis, tissue architecture is maintained, and "ghost cells" are present, while in liquefactive necrosis, tissue architecture is lost.
Why Liquefactive Necrosis Occurs in the Brain
The instructor explains why liquefactive necrosis is more common in the brain compared to other organs. The brain is rich in fat, requiring lipid degradation rather than protein degradation. This process involves enzyme activation, particularly lipase, which can originate from lysosomes within the cell (autolysis) or from white blood cells (heterolysis). While brain biopsies are rare, the concept is applicable in cases of acute pancreatitis, where lipase activation leads to liquefactive necrosis. Abscesses, characterized by a collection of white blood cells, also exhibit liquefactive necrosis due to the presence of lytic enzymes.
Gangrene: Dry vs. Wet
The discussion clarifies the difference between dry and wet gangrene. Dry gangrene is essentially coagulative necrosis without blood supply, resulting in a black discoloration. Wet gangrene, on the other hand, is dry gangrene complicated by a superadded infection and pus formation (suppuration), leading to liquefactive necrosis. Abscesses are defined as pus-filled enclosed spaces, while ascites refers to fluid accumulation in the abdomen.
Caseous Necrosis
Caseous necrosis is characterized by a chalky white appearance and is strongly associated with tuberculosis (TB). While caseous necrosis is primarily a gross term, microscopy reveals pink-colored necrotic tissue with granularity. Granulomas, a key feature of TB, are also observed microscopically. The instructor emphasizes that TB should always be the primary consideration when caseous necrosis is identified.
Fibrinoid Necrosis
Fibrinoid necrosis is defined as fibrin-like necrosis, primarily occurring in vessel walls. It is associated with conditions that damage blood vessels, such as vasculitis, systemic lupus erythematosus (SLE), malignant hypertension, and rheumatic heart disease. The instructor explains that fibrinoid necrosis is essentially vessel wall necrosis, characterized by a pink color with blue areas under microscopy, indicating necrosis in the vessel wall.
Fat Necrosis: Traumatic vs. Enzymatic
Fat necrosis is divided into traumatic and enzymatic types. Traumatic fat necrosis results from physical injury to fat-rich areas like the breast, gluteal region, or abdomen. Repeated injections, such as insulin, can cause lipodystrophy, an abnormal atrophy of fat tissue. Enzymatic fat necrosis, on the other hand, is associated with acute pancreatitis, where lipase leaks out and destroys fat in the omentum and peripancreatic tissue. Chronic conditions can lead to calcification in necrotic areas due to the accumulation of calcium.
Apoptosis: Introduction and Physiological Aspects
The lecture transitions to apoptosis, or programmed cell death, which plays a critical role in both physiological and pathological processes. Physiological examples include embryological development, cell death of skin and hair, and the death of excess inflammatory cells after an infection. Self-reacting lymphocytes also undergo apoptosis to prevent autoimmune disorders. The instructor highlights that apoptosis is a painless process, unlike necrosis.
Pathological Causes of Apoptosis
Pathological causes of apoptosis include DNA mutations, viral infections, and intracellular protein accumulation. These processes are often painless, making early detection challenging. Conditions like Alzheimer's and Parkinson's disease involve intracellular protein accumulation that leads to cell death via apoptosis.
Apoptosis: Initiator and Execution Phases
Apoptosis involves two main phases: the initiator phase and the execution phase. The initiator phase has two pathways: the extrinsic pathway (cell membrane-mediated) and the intrinsic pathway (mitochondria-mediated). The extrinsic pathway involves the FAS receptor, while the intrinsic pathway is triggered by DNA mutations. Both pathways converge on the execution phase.
Extrinsic Pathway of Apoptosis
The extrinsic pathway begins with a normal cell having an FAS receptor. When the cell is infected by a virus, lymphocytes bind to the FAS receptor, activating downstream pathways. This activation leads to the conversion of procaspase 8/10 to active caspase 8/10, which triggers the execution phase. Some viruses produce a protein called FLIP to block this activation, preventing cell death.
Intrinsic Pathway of Apoptosis
The intrinsic pathway is mitochondria-mediated and involves several proteins located in the outer mitochondrial membrane. These proteins are categorized as anti-apoptotic, pro-apoptotic, and sensors of cell stress. In a normal cell, BCL2 blocks the exit of cytochrome C, essential for ATP production. When DNA mutation occurs, sensors of cell stress activate, leading to the destruction of BCL2 and activation of BAX and BAK. Cytochrome C is released, leading to the formation of an apoptosome, which activates caspase 9.
Execution Phase of Apoptosis
The execution phase is initiated by caspase 8, 9, or 10, which activate more caspases (3 and 6) and endonucleases. Caspases are proteases that cleave proteins after aspartic acid residues. Endonucleases cause DNA fragmentation at palindromic sites. Unlike necrosis, apoptosis does not involve phospholipases, so the cell membrane remains intact, preventing inflammation.
Cellular Changes and Apoptotic Bodies
During apoptosis, the cell shrinks, and the cytoplasm becomes darker pink due to protein precipitation. The nucleus condenses and becomes smaller and darker (though the term "pyknotic" is not typically used). The cell fragments into membrane-bound particles called apoptotic bodies, which may or may not contain nuclear material. These apoptotic bodies are then phagocytosed by macrophages in a process called efferocytosis, which does not involve inflammation.
Efferocytosis and Diagnostic Methods for Apoptosis
Efferocytosis involves macrophages engulfing apoptotic bodies without releasing cytokines, thus preventing inflammation. This process is facilitated by "eat me" signals, such as phosphatidylserine and thrombospondin, which flip to the outer aspect of the cell membrane. Diagnostic methods for apoptosis include H&E staining, DNA agarose gel electrophoresis, and TUNEL assay. The TUNEL assay stains the cut ends of DNA, while annexin staining identifies phosphatidylserine on the outer aspect of apoptotic bodies. DNA agarose gel electrophoresis reveals a "step ladder" pattern in apoptotic cells, indicating DNA fragmentation.
Conclusion
The lecture concludes by mentioning necroptosis and pyroptosis, which are not covered in detail but are available in recorded lectures. The instructor emphasizes the importance of critical thinking and questioning concepts to enhance understanding.
