Homeostasis and Cellular Adaptation

Homeostasis and Cellular Adaptation

• Homeostasis is a state of balance within the body's organs, tissues, and cells where the body's physiologic and metabolic capabilities adapt to internal and external environmental changes. A normal cell is in a steady state, able to handle physiologic demands based on its adaptive capacity.
• Cellular adaptation occurs when cells are exposed to excessive physiological stresses or pathological stimuli, resulting in an altered state that preserves cell viability.
• Adaptations allow cells to conform to environmental changes to adjust and accommodate internal and external stimuli. Cells possess inherent plasticity to survive, adapting to environmental pressures.

Cellular Responses to Stress

• Cellular responses to stress can include:
  • Hypertrophy: Increase in cell size
  • Hyperplasia: Increase in cell number
  • Atrophy: Reduction in cell size
  • Metaplasia: Change in the type of a cell
  • Dysplasia: Abnormal hyperplasia, potentially a precursor to cancer
  • Intracellular accumulations (e.g., water, proteins, fats, calcifications)
  • Cellular degeneration (damage to cellular components)

Cell Injury and Death

• If adaptation limits are exceeded, cell injury occurs, leading to cell death.
• Cell death can manifest in these ways:
  • Necrosis: Premature cell death, various types (coagulative, liquefactive, caseous, fat, gangrenous)
  • Apoptosis: Programmed cell death (a natural process, type I)
  • Autophagy (type II): Cellular self-digestion and repair
  • Mitotic catastrophe (type of cell death)

Injury Mechanisms and Cell Death

• Injury causes (reversible): Hypoxia (low oxygen), physical agents, chemical agents, infectious agents, immunologic factors, genetic factors, and nutritional factors
• Injury mechanisms (reversible): Decreased oxidative phosphorylation, ATP depletion, cellular swelling, increased intracellular calcium, increased free radicals, increased cell membrane permeability
• A continuum exists from reversible changes to irreversible changes to cellular death.

Morphological Changes and Cell Death

• Cellular swelling is an initial hallmark of most cell injuries.
• Cellular death involves irreversible mitochondrial dysfunction and profound membrane disturbances.

Types of Cell Death

• Necrosis (type III): Cellular damage, often due to infection or trauma
• Apoptosis (programmed cell death): A regulated, essential type of cell death.
• Autophagic cell death: Cellular self-digestion, a sort of repair process.

Necrosis

• Necrosis is the collection of morphologic changes following cell death in living tissue or organs.
• Key processes include protein denaturation and enzymatic breakdown of organelles.
• Causes that can trigger necrosis: mitochondrial vacuolization, extensive plasma membrane damage, lysosomal swelling, leakage of cytoplasmic/lysosomal enzymes, and activation of certain enzymes within the cell.
• Outcomes of necrosis include autolysis (digestion by the cell's own enzymes) and heterolysis (digestion by enzymes from immune cells).

Types of Necrosis

• Coagulative, Liquefactive, Caseous, Fat, and Gangrenous necrosis.

Examples of Tissue Necrosis

• Coagulative: Kidney, heart, liver tissue
• Liquefactive: Brain tissue (e.g., brain stroke), liver abscess
• Caseous: Tuberculosis lesions
• Fat: Adipose tissue
• Gangrenous: Advanced necrosis, often visible (dry or wet)

Cellular Adaptation Examples

• Hyperplasia: Increased cell number in response to physiological or pathological stimuli (e.g., breast during pregnancy, liver after partial resection, psoriasis, goiter)
• Hypertrophy: Increased cell size (e.g., heart muscle in response to hypertension)

Atrophy

• Atrophy is the decrease in cell size, organelles, protein synthesis (macromolecules), often associated with increased protein degradation. Types include reduction in cell size and/or decreased cell number; hypoplasia represents reduced proliferation and increased loss. Examples include Alzheimer's disease and reduced skeletal muscle in disuse atrophy.

Cellular Accumulations

• Lipid accumulation (e.g., steatosis in the liver)
• Protein accumulation (e.g., certain genetic disorders, alpha-1-AT deficiency)
• Glycogen storage disorders
• Pigments (exogenous/endogenous)
  • Exogenous: Carbon, Tattoos
  • Endogenous: Lipofuscin (wear and tear pigment), Melanin, Hemosiderin (iron)
• Calcification (Dystrophic or metastatic)

Cellular Signaling

• Cells communicate and respond to internal and external signals (hormones, growth factors, etc.) affecting cell number and size. Signals can include: Mitogens, Morphogens, and Motogens.

Growth Factors

• Growth factors (GFs) are substances that stimulate cell growth. They often have receptors on cell surfaces and within cells, exerting various functions and potentially being oncogenic.

Cellular Metaplasia and Dysplasia

• Metaplasia: A reversible change in one cell type to another (e.g., lung cells in smokers, gastric mucosa in Meckel diverticulum, oesophagitis)
• Dysplasia: Abnormal development and potentially pre-cancerous cellular changes (e.g., Cervical dysplasia). Dysplasia can progress to malignant neoplasms.

Cellular Division and Non-Division

• Some cells divide continuously (stem cells, some epithelial cells)
• Some cells divide conditionally (liver, some epithelial)
• Some cells do not divide (neurons, skeletal muscle, cardiac muscle)

Cell Proliferation - Examples

• Physiological: Breast (during puberty, pregnancy, lactation), Uterus (during pregnancy), Kidney (after nephrectomy), Liver (after partial hepatectomy)
• Pathological: Psoriasis, Goiter, Benign Prostatic Hyperplasia (BPH), Endemic Goiter (low iodine)
• Non-dividing cells: neurons, skeletal and cardiac muscle

Hypertrophy

• Hypertrophy involves no change in cell number; a reversible increase in cell size, and it is common in non-dividing cells (myocardium, skeletal muscle, neurons).
• Key changes in hypertrophy include increased DNA, RNA, and protein; increased synthesis; and reduced loss.
• Hypertrophy pathways include satellite cell recruitment, myonuclear domain size increases, and, less commonly, hyperplasia (increased muscle numbers).
• Sarcoplasmic or myofibrillar hypertrophy occurs, increasing glycogen or myofibril sizes, respectively.
• Scarring or keloid formation is associated with excess TGFβ overexpression and fibroblast polyclonality.

Atrophy

• Atrophy involves a decrease in cell size, organelles, synthesis of macromolecules, and often increased protein degradation.
• There are reductions in cell size and/or cell numbers, and hypoplasia is represented by decreased proliferation and increased loss. Examples include Alzheimer's Disease and disuse atrophy.

Cellular Accumulations (Continued)

• Lipids: Steatosis (fatty change) is the accumulation of lipids within hepatocytes, potentially due to ethanol, drugs, or toxins. Accumulation can occur at any step from fatty acid entry into the cell to triglyceride removal. Cholesterol accumulation may be observed as needle-like clefts in tissues or in macrophages as "foamy macrophages".
• Proteins: Accumulation may be due to impaired metabolism, increased reabsorption in renal tubules, defective protein folding, or other factors. This can lead to toxicity in some neurodegenerative diseases.
• Glycogen: Glycogen accumulation can be normal or pathological (glycogen storage diseases).
• Pigments: Exogenous pigments (e.g., carbon, tattoos) and endogenous pigments (e.g., lipofuscin, melanin, hemosiderin).
• Calcifications: Dystrophic calcifications occur in nonviable tissue with normal serum calcium levels. Metastatic calcifications occur in normal viable tissues due to hypercalcemia.

Types of Necrosis (Continued)

• Coagulative necrosis: Characterized by denaturation of cytoplasmic proteins, preserving the cell's basic shape. Common in heart, kidneys, and liver.
• Caseous necrosis: Characteristic of tuberculous lesions, appears as a soft, friable, "cheesy" material.
• Fat necrosis: Necrosis in adipose tissue induced by lipases, generating chalky white areas (fat saponification).
• Liquefaction necrosis: Occurs primarily in the brain and other areas with high numbers of macrophages. In the brain, liquefication necrosis is a characteristic late-phase change observed in stroke.
• Gangrene: Advanced necrosis visible macroscopically, can be dry or wet (based on whether the necrosis is coagulative or liquefactive, respectively).

Metaplasia and Dysplasia

• Metaplasia: A reversible change where one mature adult cell type is replaced by another. This often occurs in response to abnormal environmental stimuli to better withstand the altered environment. This could occur in specialized tissues such as the esophagus or lungs. Loss of function or complications due to metaplastic functioning can occur.
• Dysplasia: Dysplasia can be a cellular precursor to cancer, exhibiting abnormal changes in cell numbers/size and cellular arrangement.

Cellular Signaling

• Hormone action: Hormones bind to receptors, which triggers a cascade of intracellular signaling pathways leading to transcription and cellular responses.
• Growth factors: Growth factors (GFs) stimulate cell growth, often with multiple receptors and multiple functions. GFs can be mitogenic, motogenic, morphogenic, and potentially oncogenic. Examples include: HGF, c-Met, EGF, c-erbB1, FGFs, VEGF, and TGFβs.