Cellular Response, Adaptation, and Reversible Cell Injury PDF

Cellular Responses and Adaptations to Stress  Cellular Response to Stress Normal cell needs special conditions “environment” to function properly. Cells try to adapt to surrounding stimuli or changes → so it can survive. The normal condition or the standard environment that the...

Cellular Responses and Adaptations to Stress  Cellular Response to Stress Normal cell needs special conditions “environment” to function properly. Cells try to adapt to surrounding stimuli or changes → so it can survive. The normal condition or the standard environment that the cell looks to live in is called: (Homeo-stasis). Homeo : home or environment. Stasis: stable or standing still or fixed. Things that might change around the cell: PH, Temp., Electrolytes level, Glucose.  Cellular Responses  Adaptation: hypertrophy, hyperplasia, atrophy, metaplasia.  Injury: reversible and irreversible (cell death).  Intracellular accumulation, calcification  Cellular Adaptations Reversible changes in size, number, phenotype, metabolic activity or function in response to changes in their environment. Adaptation can be both physiologic (we want to happen) and/or pathologic (disease).  Hypertrophy Muscle  Hypertrophy Heart: left ventricle hypertrophy (Pathological).  Hypertrophy Uterus  Hypertrophy: Hypertrophy is an increase in cell size resulting in increase in the size of the organ. Alone in nondividing cells (cardiac myocytes or skeletal muscles). Coexisting with hyperplasia in dividing cells (skin or GI tract cells). Physiologic vs pathologic.  Hypertrophy  Caused by increased functional demand (workload) or stimulation by hormones or growth factors.  Mechanism: increased production of cellular structural proteins and organelles.  There is a limit for hypertrophy.  The most common stimulus for hypertrophy of muscle is increase workload (Bodybuilders)  Subcellular organelle may undergo selective hypertrophy. (drugs causing smooth ER hypertrophy).  Hyperplasia: Increased number of cells resulting in increased mass of the organ or tissue. Takes place in cells capable of dividing. Mechanism: - it is the result of growth factor-driven proliferation of mature cells. - In some cases by increased output of new cells from tissue stem cells.  Hyperplasia Physiological Hyperplasia (hormonally induced or compensatory), Examples: – Female breast in puberty & lactation (Hormonal). – Compensatory hyperplasia in partial liver resection.  Pathological – Hyperplasia of the endometrium (excessive hormone stimulation) and prostate hyperplasia. – Infection by papillomavirus (skin warts). Pathologic hyperplasia can be a fertile soil for development of malignancy. ATROPHY  Atrophy Atrophy muscle fibers.  Atrophy Brain  Atrophy Undescended testis  Atrophy  Reduced size of cell, tissue or organ due to loss of cell substance (size and number).  Two types:  Physiologic : - During normal development (Thyroglossal duct). - Involuting gravid uterus.  Pathologic: - Decreased workload (Disuse atrophy) - Loss of innervation (Denervation atrophy) - Diminished blood supply - Inadequate nutrition - Loss of endocrine stimulation (Loss of estrogen).  Atrophy  Mechanisms: - Decreased protein synthesis and increased protein degradation. - Degradation of cellular protien caused by Ubiquitin- proteasome pathway: Ubiquitin ligases activated → attach small peptide ubiquitin to cellular protien → target these protiens for degradation in Proteasomes. - Increased Autophagy (self eating) : The starved cell eats its own component in an attempt to find nutrients and survive.  Metaplasia  Metaplasia is a “reversible” change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type.  New epithelium is better in dealing with the current stress or irritation. But at the same time:  Persistence of factors causing metaplasia may lead to progression into malignant transformation.  Most common epithelial metaplasia is columnar to squamous (Respiratory tract).  Metaplasia Replacement of ciliated columnar epithelium by stratified squamous epithelium in the respiratory tract of a smoker.  Metaplasia Squamous to Columnar epithelium in esophagus (Barrett esophagus).  Metaplasia Mechanism: reprogramming of stem cells to differentiate along new pathway Signals generated by cytokines, growth factors and extracellular matrix promote expression of genes toward a new differentiation.  Cell Injury Stress (if severe, prolonged or damaging) leads to Injury. Stress Reversible Injury Irreversible Irreversible Injury (cell death), Necrosis or Apoptosis  Mechanisms of cell injury The cellular response to injurious stimuli depends on: - Nature of the injury - Duration - Severity. The consequences of injurious stimuli depend on: the type, status, genetic makeup and adaptability of the injured cell. The principal targets of cell injury are:  Biochemical mechanisms Depletion of ATP: The major causes of ATP depletion are: - Reduced supply of oxygen and nutrients - Mitochondrial damage - The actions of some toxins (Cyanide).  Mitochondrial damage Mitochondria are sensitive to hypoxia, chemical toxins and radiation. Consequences of mitochondrial damage: - Formation of mitochondrial permeability transition pore loss of membrane potential, failure of phosphorylation and ATP depletion necrosis. - Release of cytochrome c into the cytosol that activate apoptosis.  Influx of calcium and loss of calcium homeostasis Ca present intracellularly in mitochondria and ER. Injury will lead to increase cytosolic Ca. Increased intracellular Ca may induce apoptosis by direct activation of caspases.  Accumulation of oxygen derived free radicals (Oxidative stress) Free radicals: - Chemical species that have a single unpaired electron in the outer orbital. - Unstable atoms, react with inorganic and organic chemicals (proteins, lipids, carbohyd.) - The damage caused by free radical is determined by their rates of production and removal. - Excess free radical called Oxidative stress.  Reactive oxygen species (ROS) One of the oxygen derived free radicals. Produced normally in small amounts in all cells during the reduction-oxidation reactions during mitochondrial respiration and energy generation, and removed by defence mechanisms. Produced in neutrophils and macrophages, for destroying ingested microbes and other substances.  Generation of free radicals increased under several circumstances: Absorption of radiant energy: UV light and X- rays. Enzymatic metabolism of exogenous chemicals or drugs: Carbon tetracloride. Inflammation: Free radical produced by leukocytes.  Removal of free radicals Superoxide dismutases (SODs) Glutathione(GSH) peroxidases. Catalase Endogenous or exogenous antioxidants: Vitamins (A, E and C). Pathological effects of free radicals Lipid peroxidation in membranes: - Oxidative damage of the double bonds in the polyunsaturated fatty acids resulting in formation of peroxides which are unstable and lead to membrane damage. Cross linking and other changes in proteins. DNA damage. Defects in membrane permeability Increased membrane permeability leading ultimately to overt membrane damage is a constant feature in all forms of cell injury except Apoptosis. Causes include: - Ischemia, microbial toxins, lytic complement components, physical and chemical agents.  Consequences of membrane damage Most important sites of membrane damage: - Mitochondrial membrane: Decrease ATP. - Plasma membrane: loss of osmotic balance, influx of fluids, and loss of cellular contents. - Lysosomal membrane: leakage of their enzymes into cytoplasm (Ribonuclease (Rnases), DNases, glucosidases, other).  Damage to DNA and proteins Cells, usually, have mechanisms to repair DNA damage If the damage is severe the cells initiate a suicide program results in cell death by Apoptosis. Accumulation of misfolded proteins triggers Apoptosis.  Morphologic alterations in cell injury Reversible injury Generalized swelling of the cell (Hydropic change or vacuolar degeneration): failure of energy-dependent “ion pumps” in the plasma membrane result in disturbances in ionic and fluid homeostasis. It is usually the first manifestation.  Plasma membrane alterations: blebs, blunting or loss of villi and loosening of intercellular attachments. Mitochondrial changes: swelling and appearance of small amorphous densities. Nuclear alterations: nuclear chromatin clumping.