Lecture 01: Cell Adaptation, Injury, & Death PDF

January 10, 2025 LECTURE 01: CELL ADAPTATION, INJURY, & DEATH I.​ INTRODUCTION Cellular Adaptation, Injury, Death ​ Cell adaptation...

January 10, 2025 LECTURE 01: CELL ADAPTATION, INJURY, & DEATH I.​ INTRODUCTION Cellular Adaptation, Injury, Death ​ Cell adaptation ○​ Reversible structural and functional response to changes that allow the cell to survive (continue to function) ​ Stimulus (Physiologic or Pathologic) ○​ Hormones can induce cellular adaptation, physiologically ○​ If stimulus is removed, it will go back to its original state ​ Cellular Adaptation ○​ Not necessarily pathologic; sometimes a normal process ○​ Reversible ○​ → Healthy cell ​ Cellular Injury ○​ Adaptive limits exceeded ○​ → Healthy cell (reversible) ​ Cell Death ○​ Severe (intensity) and/or Persistent (time) ○​ Irreversible II.​ CELLULAR ADAPTATION Cellular Adaptation: Healthy Cell ​ If there is an increase in demand for the function of the cell, they either: ○​ (1) Increase in organelles (Hypertrophy) ​ Preferred by muscles (as it saves energy) ○​ (2) Increase number of cells (Hyperplasia) ​ Occurs when there is damage to muscle fibers ​ If there is no need for those cells, they either: ○​ (1) Decrease in number and/or size (Atrophy) ○​ (2) Degrade molecules to recycle the biochemical substrates (Autophagy) ​ If there is a need in change of function: ○​ (1) Metaplasia ​ Increase in size and/or number ○​ Sometimes both hypertrophy and hyperplasia occur simultaneously ○​ Hypertrophy ​ Increase in cell volume/size ​ Increase in organelles or necessary components within cytoplasm or cell ○​ Hyperplasia ​ Increase in number of cells ​ Decrease ○​ Atrophy ​ Decrease in number and/or size ​ Opposite of hypertrophy and hyperplasia ​ Usually brought about by autophagy ○​ Autophagy ​ degradation of molecules to recycle the biochemical substrates ​ Metaplasia ○​ Change in phenotype ​ If cell is in need of another function Hypertrophy ​ Increase in cell volume or size due to increased synthesis of intracellular components to keep up with the functional demand ​ G0 and G1 → stage of cell cycle where there is protein synthesis Example of Hypertrophy: Skeletal muscles ​ Skeletal muscles ○​ Develop from myoblast ​ Myoblasts fuse and form muscle fibers → muscle cells ​ Satellite cells — serve as reservoir ○​ Differentiate to produce precursor cells → new muscle fibers ○​ When there is a need to …???? ​ A ​ Easier to increase cell size than make new cell ​ A ​ A ​ Hyperplasia comes in when there is damage/injury ○​ But muscles prefer hypertrophy because it is energy-saving Example of hypertrophy: Cardiac muscle cells ​ Cardiac muscle cells → contrast of skeletal muscle cells (?) ○​ Cannot undergo mitosis ○​ Cells do not increase; contractile proteins increase ○​ Cardiac muscles are branching ​ Hypertension ○​ Blood vessels are contracted → resistance ○​ To overcome resistance, cardiac muscles need to increase contractile protein ​ Don’t undergo mitosis; only increase contractile proteins (actin and myosin) ​ Result in thickening of ventricular walls ​ Lumen is significantly decreased because ventricle walls are thickened ○​ Allows to overcome increasing pressure ​ However, it is space occupying condition ​ Patients with cardiomegaly have increased risk for ischemic heart because of the ventricle wall enlargement ○​ Give vasodilators to address this ​ Vasodilates blood vessels ​ Relieves hypertension ​ Dilates blood vessel ​ Lessens burden of the heart ​ a Hyperplasia ​ Increase in the number of cells in response to a stimulus ​ Mitosis occurs ○​ One daughter cell stays as stem cells ○​ One daughter cell differentiates ○​ Some can still proliferate Example of Hyperplasia ​ Blood vessel obstruction ○​ When there is lipid accumulation → obstruction ○​ Vascular Endothelial growth factor ​ Involved in formation of new blood vessels ○​ In blood vessels: Newly formed blood vessels (Tunica intima/media/adventitia ) ​ Tunica media is not well-developed yet in the image ​ Not that resistant to pressures ​ Prone to rupture ​ Physiologic hyperplasia in the endometrium (menstrual cycle) ○​ Estrogen smth ​ It becomes pathologic if there is too much estrogen Hyperplasia (Pathologic: Thyroid) ​ When there is too much estrogen, it becomes pathologic Eg: Thyroid ​ High thyroid hormone (T3 and T4) → Pituitary gland detects that you havve high thyroid hormone thus will stop it ○​ If lacking (e.g., iodine deficiency), no basic components to produce thyroid hormones ​ Send signals to pituitary gland to produce thyroid-stimulating hormones ○​ The branching is the increase in the number of cells ○​ Histologic slide: ​ Makes them appear like short columnar despite being supposedly cuboidial because of the crowding of the cells undergoing hyperplasia Atrophy ​ Reduction in size and number of the cells ○​ Opposite of hypertrophy and hyperplasia ​ Nature will always choose a path with less consumption of energy/resources ○​ Spontaneous reactions proceed with release of free energy (exergonic) ○​ Endergonic reactions proceed only if free energy can be gained ​ Rationale ○​ Not economic to maintain cells that we don’t need anymore ○​ Choosing paths that take lesser energy and resources ​ Importance of O ○​ Used in the ETC in order for energy to move forward Example of Atrophy ​ Skeletal muscles ○​ After some time, muscles become smaller again ​ Body detects that there is no need to increase contractile proteins because they are not stimulated via work out (Disuse atrophy) ○​ Decrease in number/size but do not necessarily die ○​ No stimulus/workload → atrophy Types of Atrophy ​ Disuse atrophy (decreased workload) ○​ E.g., 1-month gym absence of a frequent body builder ​ Denervation atrophy (loss of innervation) ○​ E.g., Motor endplates ​ Found in skeletal muscles ​ Terminal axons innervating skeletal muscles ​ If axon is transected, then you don’t have acetylcholine that will initiate electrical activity of skeletal muscles that open Ca+ channels → contraction ​ No muscle contraction = no need for the muscles = atrophy ​ Diminished blood supply ○​ Patients who undergo stroke, the specific blood vessels that are affected undergoes atrophy ○​ Abnormal: Decreased gyri sized and increased sulci ​ Inadequate nutrition ○​ Not enough nutrients for cells to produce proteins for cell function ○​ Inadequate nutrients = inadequate materials to produce cells ​ Loss of endocrine stimulation ○​ Decrease in TSH production (???) ​ Pressure  ○​ Connected to diminished blood supply ○​ Also space occupying ​ E.g., growing embryo of mom with myoma ​ Baby competes with the space of the embryo because of ???? myoma??? Autophagy ​ Atrophy result from decreased protein synthesis or increased protein degradation (through autophagy or ubiquitin-proteasome) ○​ Protein-degradation occurs mainly by ubiquitin-proteasome pathway ​ (almost all) ○​ Not exclusive, both can happen at the same time in one system ​ Ubiquitin-proteasome pathway ○​ Proteins fold via action of chaperone (links high energy and low energy reactions to cause folding) ○​ If folding is hampered (e.g., UV, reactive oxygen species) → misfolding of proteins ​ Recognized by ubiquitin-proteosome ​ Function of human ubiquitin: to link and target the misfolded proteins to proteasome for protein degradation ​ If misfolded proteins cannot be guided, undergoes apoptosis (degradation of protein) ○​ This process acts as a solution to misfolded proteins Autophagy → Jeano ​ The digestion of organelles within the cell ​ Similar to ubiquitin-proteosome pathways, there are ??? that initiate ?? ○​ Initiating complexes bind to proteins no longer needed to degrade organelles to recycle products to produce new molecules ○​ A ○​ A ○​ A ​ A ​ A ​ A Metaplasia ​ Reversible change from one differentiated cell type to another cell type ○​ Perform new function more capable for adapting to the environment ​ Most common metaplasia is columnar to squamous metaplasia (or simply squamous metaplasia) ○​ Unlike esophagus (squamous → columnar) ○​ Common likely because of smoking (cells are not equipped to resist toxic substances found in cigarettes) ​ Neither of the increase/decrease mechanisms ​ Another pathway that cells can take to adapt to environment Example of Metaplasia ​ Stratified squamous mucosa ○​ One layer, BV are more vessels ​ With columnar/squamous metaplasia ○​ Because of the acidity, acid regurgitates into the esophagus ○​ Stem cells in the basal squamous mucosa, differentiates into intestinal mucosa ​ Becomes columnar cells ​ Now has presence of many goblet cells ○​ A ​ Slide (upper right): Squamous cell lung carcinoma ○​ Infiltration in the basement membrane ​ Squamous cells enter the stroma ​ Metaplasia is not malignant itself, but as time goes by ​ Accumulate mutation that allow them to invade the stroma ​ a ​ Example of Metaplasia ​ Small cell carcinoma (neuroendocrine cells) → Squamous cell carcinoma (basal type) ​ A ​ I wanna kms what the fuck ○​ Bruh buti nag voice record ako ○​ A ○​ A ​ A ​ A ​ A ​ III.​ CELLULAR INJURY Cellular injury ​ When cell can no longer adapt ​ Initially it is reversible ○​ However, if stimulus is so severe, where the cell cannot keep up ​ It undergoes irreversible injury → cell death ​ If survived, it become malignant cells ​ Malignancy is the other end point not just cell death ​ Cellular swelling ​ Fatty change ​ Intracellular accumulations Cellular swelling ​ Two features are consistently seen in reversibly injured cells: ○​ Cellular swelling ○​ Lipid accumulation ​ Usually caused by failure of ATP-dependent Na-K pumps ○​ Failure of sodium-potassium pumps ​ Derangement in cellular ??? ​ Left: normal tubular cells ​ Right: larger in volume ○​ Pale staining due to presence of water ○​ Proteins are still present; however ​ Water inside will not uptake stain anymore Example of Cellular swelling ​ Summary of how Na-K pump achieve function and the crossing over of different solutes etc. ​ ​ Partial polarities allow interaction ○​ H+ interacts with I- Fatty change ​ Two features are consistently seen in reversibly injured cells: ○​ Cellular swelling ○​ Lipid accumulation ​ Occurs when lipid metabolic pathway/s is/are disrupted ​ Ex: cardiac muscle: skeletal cells ○​ ??? ○​ No longer adapt to stimulus then it disrupts metabolic pathway and lipid accumulates ○​ Brown pigmentation due to??? ​ A ​ A ​ A Fatty change ​ Most prominent in organs that are actively involved in lipid metabolism such as liver ○​ Liver involved mainly for lipid metabolism ​ Injury will accumulate lipids ​ Lipid is a neutral molecule = clear stain, appears as large droplets ○​ A ​ A ​ A ​ A Intracellular accumulations ​ Manifestation of metabolic derangement ○​ Lipids ○​ Proteins → hyaline change ○​ Glycogen ○​ Pigments (exogenous or endogenous) ​ Endogenous → ​ Exogenous ​ Carbon pigment (harmless)from the environment that are not degraded ○​ Incidental finding during autopsy or biopsy ​ May be harmless or may cause further injury Example of Intracellular accumulations ​ Abnormal metabolism ○​ RBC ​ Normally produce hemoglobin a (2 alpha 2 beta) ​ If there is an abnormality in the production of hemoglobin, there is an adaptation ​ Reduced betaglobin = increased alphaglobin (more degrative?? Than beneficial) ○​ Alphaglobulin aggregates are not effective ​ Interferes with liquid components? ○​ Degraded in the spleen ○​ → Resulting in anemia ○​ Response of bone marrow is to produce RBC ​ Defect in protein folding, transport ​ Lack of enzymes ○​ Can degrade/metabolize molecules ​. ​ ​ Ingestion of indigestible materials ○​ Carbon pigments ○​ Silicone ??? ○​ A ​ A ​ A ​ A Intracellular accumulations ​ Defect in protein synthesis ○​ Alpha-secretase — supposed to cleave protein ○​ b-Secretase takes over if a-Secretase fails ​ Produce b-monomer ○​ Accumulation of amylate fibrase? → macroscopic __ ​ Interferes with the interconnection of the neurons ○​ A ○​ A ​ A ​ A ​ A Intracellular accumulations ​ Lipid accumulation due to lack of enzymes ○​ Undergo beta oxidation ​ No enzyme to deal with betaoxidatiev lipids — causing it to accumulate ​ Macrophages will phagocytose it but not degrade it thus accumulating ​ Aka heart failure cells ​ Ingestion of indigestible materials ○​ When you have indigestible endogenous material ○​ “Coal miners pneumonosis(?)” ​ Coal particles are inhaled causing: ​ Accumulation of coal particles ​ Body can’t degrade it so it will wall the particles off ​ Fbiroblast block part where coal particles accumulate? ​ Some of the alveoli are significantly enlarged or damaged because of the increase in air pressure ​ Becomes pathologic since it affects the function of the specific organ ​ Space occupying and compress alveoli ​ Some walls are damaged due to increase in pressure  ​ It becomes pathologic if it affects the function of a specific organ IV.​ CELL DEATH Cell Death ​ Apoptosis ​ Necrosis ​ Necroptosis Cell Death ​ Removal of damaged, unneeded, and aged cells is essential during development and maintenance of homeostasis ○​ Apoptosis has no inflammatory reaction, while necrosis have inflammatory reaction ​ [A] Morphologic ○​ Apoptosis → programmed cell death ○​ Necrosis → accidental cell death ​ [B] Biochemical ○​ Apoptosis ○​ Necroptosis ○​ Pyroptosis ○​ Ferroptosis ○​ Cuproptosis ​ Cell death subtypes: ○​ Regulated Cell Death ​ Molecules control the occurrence  ​ Programmed Cell Death ​ Apoptosis ​ Important during embryologic development ○​ Accidental Cell Death ​ Necrosis ​ Cell death doesn’t necessarily mean pathologic Cell Death ​ Cell death can be influenced either by: ○​ Genetics ​ Lack genetics or genes to promote cell death ○​ Environmental ​ Lack stimulus to promote cell death Apoptosis ​ Tightly regulated suicide program that can either be physiologic or pathologic ○​ Physiologic: During development ○​ Pathologic: Force induces apoptosis ​ Plasma membrane remains intact → phagocytosed before contents leak out = minimal inflammatory reaction ○​ No inflammatory reaction because it is organized(?) / because of organelles ​ No spillage of anything that can induce inflammatory reaction ​ Either deprived of survival signals (anti-apoptotic) or receive pro-apoptotic signals ​ Caspase (cysteine in the active site, cleaves proteins after aspartic residues) ○​ Induces apoptosis through cascade of caspases until the final caspase induce membrane fragmentation ​ Intrinsic pathway: Involve mitochondria ​ Extrinsic pathway doesn’t necessarily involve mitochondria ○​ The receptors can activate caspases ​ At the center: Initiation caspases ○​ Caspase → cysteine in active site, cleaves proteins after aspartic residues ○​ Aspartic residue: part of cleavage ○​ Once cleaved, activates caspase proteins ​ All will induce apoptosis Apoptosis: Intrinsic Pathway ​ Intrinsic pathway: ○​ Translocation of either BAX or BAK proteins ​ Pores that attaches to the outer membrane ○​ Once pores form at outer membrane → release Cytochrome C ​ Mitochondrial outer membrane permeabilization? (MOMP) ​ Degrade ??? ○​ Something is inhibited ○​ Lead to apoptosis ○​ Activation of Pyroptosis ​ Pyro– increase in temperature (reduces fever) ​ NIK molecule (induce nuclear factor kappa B) → attach to specific gene segments ​ Nuclear factor kappa B – in charge of expression of other something ​ Huchkiliphoma WHAT THE FUCK ○​ Mitochondrial DNA can leak out ​ Induce something ​ Activate stimulator of interferon genes — involved in activation of macrophage — for phagocytosis ​ This recruits macrophages towards site of apoptosis (ready to phagocytose) ​ Interferon genes are involved in activating macrophages ​ Macrophages have a role in apoptosis to phagocytose ○​ Release of double-stranded RNA ​ Product for mitochondrial dna ​ Mitochondrial permeable outer membrane ​ Why would dna go out even if membrane is intact? Apoptosis: Extrinsic Pathway ​ How does mtDNA get out when the inner membrane is intact during MOMP? ○​ Ongoing question putek Necrosis ​ Don't form vesicles ​ The cytoplasmic are not membrane bound ○​ Leaks out components within the cell → cell “bursts” ○​ Induces inflammatory reaction ​ Unlike apoptosis (no inflammatory reaction) ​ Ex: Ischemic heart disease ○​ decrease/obstruction of blood flow, cardiomycocytes undergo necrosis ○​ Initially no inflammatory reaction kasi lumalabas pa lang cellular components ○​ After 24hs, there’s a different reaction of the???? → inflammatory reaction ○​ [Re: systemic moving out:] Unang lalabas ang CK-MII sunod ang troponin ​ Therefore you’ll know that the condition is going on for quite some tie at the presence of troponin in CBC ​ Systemic moving out of the components ○​ Free flowing goes out first ​ Enzymes ​ Freely flowing in the cytoplasm ○​ The structural proteins follows ​ If degradation is matagal na pota Patterns of Necrosis ​ Morphologically ​ Not exclusive to each other ​ Coagulative ○​ Wherein you can still see the architecture/structure, it's still intact ​ Eventually will liquefy ○​ Seen for quite some time ○​ Architecture is preserved ​ Maintained by the structural skeleton ○​ Presumably, enzymes are neutralized during injury preventing proteolysis ​ Liquefactive ○​ Digestion → viscous liquid ○​ E.g., Absence of fibroblasts in brain ​ No protein factors that support structural integrity of the tissue thus, will liquefy directly ​ No longer undergo Coagulative necrosis ○​ Viscous ○​ Produces a cavity? ​ Macrophages surrounding area of liquefaction Patterns of Necrosis ​ Caseous ○​ “Cheeselike” ○​ Friable white areas of necrosis enclosed within a distinctive inflammatory border ​ Ex: tuberculosis ​ Tuberculosis bacilli ​ Macrophages increase ____ that digests and dissolves/degrades the area ​ To contain the enzymes, there are walling off by fibroblasts ​ Macrophages in the periphery, that are fused together ​ Also digest normal tissues ​ With lymphocytes and fibroblasts surrounded, respectively ​ Fat Necrosis ○​ Pancreatic enzyme leak out → liquefy adipocyte’s membrane ○​ Fatty acids combine with calcium to produce chalky-white lesions ​ Lesions = Digested lipids Patterns of Necrosis ​ Fibrinoid Necrosis ○​ An-Ab complexes + plasma proteins deposit in the vessel wall (fibrin-like: bright pink and amorphous) → inflammatory reaction ​ Inhibits smth??? ○​ Occur during antibody-antibody formation ○​ Due to leakage of coagulative factors Necroptosis ​ Recently discovered ​ Since viruses develop intracellularly, the mechanism to neutralize viruses is to kill the infected cell → induce apoptosis ○​ However, some viruses were able to adapt to pathways involved in apoptosis ○​ When tried to inhibit caspase 8, cell death still occurred even if its not suppose to occur ​ One of the adaptive mechanisms of the virus so the cell they use would not die ​ Virus inhibited caspase 8 to avoid apoptosis of its host cell ○​ With ○​ A ​ Called necroptosis because it is necrosis but pathway involves apoptosis* Summary ​ Normal cell (homeostasis) ○​ Stress → Adaptation ​ If unable to adapt → Cell Injury ○​ Injurious stimulus → Cell injury ​ If severe, progressive → Irreversible injury ​ Cell Death ○​ Necrosis ○​ Apoptosis ​ If mild, transient → Reversible injury → Normal cell Titl