Cell Injury and Cellular adaptations, Wound healing - Robbins Pathology - Chapter 1

This chapter provides an overview of general pathology, starting with the basics. The focus is on cell injury and its types: reversible and irreversible. Additionally, it covers two types of cell death: necrosis and apoptosis.

This chapter discusses cell injury and its types. When cells are subjected to stress, they initially try to adapt. However, if the stress continues or increases, the cells become injured. Cell adaptation failure leads to cell injury which can be reversible or irreversible. Reversible cell injury occurs when there is minimal damage and the cell has a chance of returning to normal function. Irreversible cell injury occurs when the damage is severe and results in either necrosis or apoptosis.

Reversible Cell Injury - The most common cause of cell injury is hypoxia, which leads to a decrease in oxygen availability for the cell. - Hypoxia can be caused by ischemia, which is a decrease in blood supply due to occlusion of blood vessels. - Mitochondrial dysfunction occurs as a result of hypoxia and leads to decreased ATP production through oxidative phosphorylation. - Sodium-potassium ATPase pump fails when there is no ATP, causing an accumulation of sodium ions inside the cell and subsequent influx of water.

Hydropic Change - Cellular swelling or hydropic change is the first visible morphological change in reversible cell injury. It occurs due to excessive water entering the cells. - Swelling not only affects the cytoplasm but also organelles like mitochondria and endoplasmic reticulum (ER). - Loss of microvilli on the surface membrane and formation of cytoplasmic blebs are observed during cellular swelling.

Understanding Myelin Figures Myelin figures are electron microscopic features characterized by a laminated appearance in the cytoplasm. They are formed when excessive water enters the cell, causing swelling and damage to cell membranes and organelles. These damaged membranes release phospholipids that form concentric walls or laminations known as myelin figures.

Key Events in Reversible Cell Injury - In reversible cell injury, there is a decrease in ATP levels leading to hydropic change. - Anaerobic respiration occurs due to lack of oxygen, resulting in increased lactic acid production. - Clumping of chromatin within the nucleus is observed. - Swelling of endoplasmic reticulum leads to detachment of ribosomes and decreased protein synthesis.

When cells are irreversibly damaged, it means they cannot be repaired. This occurs when there is severe membrane damage and the cell membrane can no longer undergo repair. The key difference between reversible and irreversible cell injury is the presence of severe membrane damage. When the cell membrane is damaged, calcium starts to enter the cell as a result. Calcium acts as an enzyme activator.

Severe Membrane Damage and Calcium Influx When there is severe membrane damage, calcium influx into the cell increases. This calcium activates phospholipases, which break down the cell membrane and mitochondrial membranes. The presence of severe membrane damage and mitochondrial damage indicates irreversible cell injury.

"Large Amorphous Flocculent Densities" in Mitochondria "Large amorphous flocculent densities" refer to calcium deposits in mitochondria. These deposits are a hallmark of irreversible cell injury.

Effects of Calcium on Proteins and Nucleus Calcium not only activates phospholipases that break down the cell membrane but also proteases that degrade cytoskeletal proteins within the cells. Additionally, it activates nucleuses leading to breakdown of nuclear DNA.

Nuclear Changes in Irreversible Cell Injury In irreversible cell injury, the nucleus undergoes condensation (hypnosis), fragmentation (carrier axis), and dissolution (carolysis). These nuclear changes occur after the cell has decided irreversible damage. Clumping of chromatin is also observed as a nuclear change.

"Myelin Figures" in Reversible and Irreversible Cell Injury "Myelin figures" are seen in both reversible and irreversible cell injury. They refer to structures that can be observed under microscopic examination.

Determining Irreversibly Damaged Cells Cell membrane damage, mitochondrial damage, and the presence of large flocculent mitochondrial densities indicate irreversibly damaged cells. Calcium deposition within mitochondria contributes to this process.

Types of Cell Death Different tissues contain different types of cells that may undergo various forms of cell death depending on their specific characteristics.

Necrosis: Pathological Cell Death Necrosis is a form of cell death that occurs when cells are exposed to external stress, leading to irreversible injury and the death of the cell. It is always pathological and considered a passive process as it does not involve ATP or programmed mechanisms. The most common type of necrosis is coagulative necrosis, where the architecture of the cells remains preserved despite their death.

"Coagulative Necrosis": Preserved Architecture "Coagulative Necrosis" refers to a type of necrotic cell death where tissue architecture remains intact even after cellular demise. This phenomenon can be observed in various organs such as the heart, kidneys, spleen, and other solid tissues affected by infarction (loss of blood supply). Coagulation or denaturation proteins play a crucial role in preserving cellular structure during this process.

Ghost Cells: Empty but Preserved In cases of coagulative necrosis, ghost cells may appear - empty structures without nuclei inside them. These ghost cells retain their architectural boundaries while lacking any internal components due to protein denaturation caused by coa

In this chapter, we explore a condition called liquefaction necrosis that affects the brain. This occurs when a specific area of the brain becomes infected and damaged, resulting in tissue architecture loss. Under microscopic examination, it is difficult to identify neurons due to the lack of preserved tissue architecture. The affected area undergoes complete dissolution through liquefication.

Tissue Necrosis in the Brain and Pancreas The brain and pancreas are tissues that have a high amount of hydrolytic enzymes. When these cells undergo death, the enzymes dissolve the cell architecture, resulting in a loss of tissue preservation.

"Cheesy" Appearance of Lung Tissue Necrosis In lung tissue undergoing necrosis, there is an area that appears like cottage cheese or has a waxy cheesy appearance. This morphological change indicates necrotic changes in the lung tissue.

Cassius necrosis is characterized by a cottage cheese-like appearance. It is a combination of coagulative and liquefactive necrosis. This type of necrosis is associated with infections like tuberculosis (TB), histoplasmosis, and coccidioidomycosis.

Fat necrosis occurs when fat cells undergo death, typically in areas with high amounts of fat such as the breasts and buttocks. Trauma or injury to these areas can lead to damage and subsequent death of adipocytes. As a result, fatty acids are released and bind with calcium, leading to the formation of white deposits known as chalky white appearance.

In acute pancreatitis, the pancreatic parenchyma undergoes liquefaction necrosis while the peripancreatic fat undergoes fat necrosis. The deposition of calcium in the peripancreatic fat leads to a chalky white appearance known as saponification.

Fibrinoid necrosis is a type of tissue damage characterized by the deposition of fibrin-like material in areas of necrosis. This pink-colored glossy material can be observed during examination.

In vasculitis conditions, such as autoimmune polyarthritis nodosa, necrotizing vasculitis occurs where the blood vessels undergo necrosis due to immune-mediated damage. The walls of the blood vessels show pink fibrin-like material.

Fibrinoid Necrosis When fibrino necrosis color material is deposited, it is known as fibrinoid necrosis. This type of necrosis can occur in conditions like rheumatic heart disease.

"Ash off Bodies" in Rheumatic Heart Disease "Ash off bodies", also known as astral bodies, are pathognomonic indicators of rheumatic heart disease. They are an example of fibrinoid processor.

- Coagulative necrosis occurs in all solid organs like the heart and kidneys. - Liquefactive necrosis happens in organs with a higher presence of enzymes, such as the brain and pancreas. - Caseous necrosis is observed in fungal infections.

In a case of trauma to the breast, such as during a road traffic accident, fat necrosis can occur. This happens when the fatty acids in the breast tissue undergo saponification and calcium deposits form. Additionally, fibrino-necrosis may be observed in vasculitis conditions.

There are two important types of gangrene: dry gangrene and wet gangrene. Dry gangrene is commonly seen in the limbs, while wet gangrene is more often observed in the bowels or intestines due to arterial occlusion. Dry gangrenes occur when blood supply to an area is gradually cut off, resulting in coagulative necrosis.

- Dry gangrene is characterized by a dry and mummified appearance, indicating coagulative necrosis. - Wet gangrene, on the other hand, has a more liquidy appearance and is associated with liquefactive necrosis along with infections. - The presence of a clear line of demarcation distinguishes dry gangrene from wet gangrene. Infections are less likely to develop in dry gangrene compared to wet gangrene.

Zincus degeneration, also known as hyaline necrosis or zincerosis, refers to the death of skeletal muscles due to acute infectious conditions. This type of necrosis is characterized by a glassy or waxy appearance in the affected muscles. It is a form of coagulative necrosis where the tissue architecture remains preserved. Zincus degeneration commonly occurs in infections like typhoid and serine's hepatitis, particularly affecting skeletal muscles such as rectus abdominis.

Muscle degeneration is an important topic that involves different types of necrosis, including reversible and irreversible cell injury. In this chapter, we will explore the process of cell death and various forms of necrosis.

Apoptosis: Programmed Cell Death Apoptosis is a programmed cell death that can occur in both physiological and pathological conditions. Unlike necrosis, apoptosis is an active process that is properly planned by the cell using ATP. It does not cause inflammation because the cell membrane remains intact and cellular contents do not leak out.

Differences Between Apoptosis and Necrosis - In necrosis, a group of cells die due to stress or arterial occlusion, while apoptosis usually affects single cells. - During necrosis, the size of the affected cells increases due to cellular swelling before bursting. In contrast, during apoptosis, cell size decreases over time. - Necrosis is a passive process without any use of ATP; however, apoptosis requires ATP for its execution. - After necrotic cell death occurs, there will be inflammation as damaged membranes lead to leakage of cellular contents. On the other hand,

Physiological vs Pathological Apoptosis - Physiological examples include embryogenesis (separation of digits), shedding endometrial cells during menstruation (hormone-dependent), and deletion

Apoptosis: The Intrinsic Pathway In every cell, there are stress sensors that detect the level of stress. When cells experience high levels of stress, these sensors activate pro-apoptotic factors which initiate apoptosis. These factors include Bax, BCL-XL, and p53.

The Role of Cytochrome C "Cytochrome C" is a substance present in the mitochondria's inner membrane. Under normal conditions, it remains within the mitochondria and does not enter the cytoplasm. However, during times of cellular stress when anti-apoptotic factors like bcl2 decrease due to activation by stress sensors such as Puma or McQs (stress sensor proteins), cytochrome c leaks into the cytoplasm where it binds with Apaf-1 to form an apoptosome complex.

Execution Phase and Clearance Once caspases 8 and 10 are activated through either extrinsic or intrinsic pathways respectively along with caspase 9 from intrinsic pathway initiation phase; executioner caspases including Caspase-3/6/7 become active leading to phospholipid breakdown causing damage to organelle membranes while endonucleases fragment DNA resulting in cell death via apoptosis.The fragmented cells called apoptotic bodies express 'eat me' signals on their surface such as phosphatidylserine which attract macrophages for clearance.

Atrial Fibrillation and Stroke A 73-year-old man with paroxysmal atrial fibrillation presents with right-sided weakness and difficulty speaking. Atrial fibrillation increases the risk of stroke due to clot formation in the atria, which can travel to the brain and cause a stroke. Despite appropriate treatment, his symptoms fail to improve.

Apoptosis in Cancer Treatment A 46-year-old man with a slowly growing neck mass undergoes combination chemotherapy for cancer treatment. The tumor cells shrink significantly after chemotherapy-induced apoptosis, where cytochrome C leaks out of mitochondria triggering cellular changes.

Necroptosis: Combination of Necrosis and Apoptosis Necroptosis is a type of cell death that combines features of both necrosis and apoptosis. It can occur physiologically during growth plate formation or pathologically in conditions like pancreatitis, fatty liver disease, cytomegaloviral infection (CMV), Parkinsonism, Alzheimer's disease.

Apoptosis and Necroptosis In apoptosis, caspase activation is crucial. Caspase-8 is involved in inactive form. In necroptosis, RIP kinases along with pro-caspase-8 cause phosphorylation of MLKL leading to cell death.

Pyroptosis "Pyroplosis" refers to a type of cell death that involves the release of pyrogen (interleukin-1), causing fever. It occurs when bacterial antigens bind with toll-like receptors or enter cells directly, activating inflammasomes and producing gasdermin which damages the cell membrane.

Pionoptosis Pionoptisis is another type of programmed cell death caused by antigen binding with not-like receptors resulting in activation on inflammosome converting Pro-Caspace number one into active Caspace number one

Hypertrophy Hypertrophy refers to an increase in the size of a cell due to increased protein synthesis. This occurs when cells are subjected to stress, leading to elevated levels of transcription factors such as GATA4 and NFAT. Examples include muscle hypertrophy during exercise and organ hypertrophy in cases of outflow tract obstruction.

Hyperplasia Hyperplasia is characterized by an increase in the number of cells through mitosis. Certain types can increase the risk of cancer, such as endometrial hyperplasia caused by granulosa cell tumors producing excessive estrogen levels. Benign prostatic hyperplasia (BPH) does not pose a cancer risk but is stimulated by dihydrotestosterone (DHT). Drugs like finasteride and dutasteride inhibit 5-alpha reductase enzyme activity, reducing DHT levels.

Atrophy Atropy involves a decrease in both cell size and number due to activationof ubiquitin proteasome degradation pathway that destroys cellular components.The examples include wasting atropy from lackof muscle use,malnutrition atropy from inadequate nutrition,ischemic atropyfrom decreased blood supply,and denervationatropgyfrom loss or damage tonerve supply

Cellular Adaptations - Apoptosis is regulated by neurons called Alpha motor neurons, which innervate muscles and cause muscle contraction. - Damage to lower motor neurons can lead to denervation atrophy, resulting in decreased muscle size and function. - The ubiquitin proteasome degradation pathway plays a role in the decrease of cell size and number during atrophy.

Metaplasia - Metaplasia refers to the change of one cell type into another due to stress or stem cell reprogramming. - Examples include intestinal metaplasia caused by vitamin A deficiency, squamous metaplasia in smokers' lungs, and columnar metaplasia seen in Barrett's esophagus.

Dysplasia - Dysplasia is characterized by disorganized growth of cells with loss of differentiation. It is irreversible and considered a pre-cancerous stage. -Intracellular Accumulations: In certain pathological conditions such as iron accumulation (hemochromatosis), copper accumulation (Wilson's disease), glycogen accumulation (glycogen storage diseases) or calcium accumulations occur inside cells causing various disorders

Melanin and Stains Loss of dopaminergic neurons leads to a decrease in dopamine, resulting in the absence of melanin production. The stains used to identify melanin are Mason Fontana and HMV 45 for immunohistochemistry.

Iron Accumulation "Hemochromatosis" is a condition where iron accumulates inside cells, particularly renal tubules. Pearl stain or Prussian Blue can be used to identify iron deposits.