Cell Injury, Inflammation & Repair (PHIDG 1501 Lecture Notes) PDF

PHIDG 1501 - Integrated Sequence 1 Cell Injury Inflammation Repair (3 lecture hours) Recommended Reading: Robbins Basic Pathology, 10th Edition (2018) Cell Injury  Learning Objectives Describe in general terms the underlying princip...

PHIDG 1501 - Integrated Sequence 1 Cell Injury Inflammation Repair (3 lecture hours) Recommended Reading: Robbins Basic Pathology, 10th Edition (2018) Cell Injury  Learning Objectives Describe in general terms the underlying principles of cell injury Describe in detail the following cell injury- related concepts, definitions and terms: Homeostasis, Adaptation, Hypertrophy, Hyperplasia, Atrophy, Metaplasia Describe in general and in detail all possible mechanisms of cell injury Describe in detail morphological changes associated with cell injury  “Homeostasis” The intracellular milieu of cells is tightly regulated to keep it fairly constant. This state is referred to as homeostasis. “Intracellular milieu”: Concentration of anions and cations Concentration of enzymes Activity of enzymes Concentration of wide variety of proteins pH of cytosol and cell organelles  “Cellular Adaptation” As cells encounter physiologic stress (increased workload) or pathologic stress (nutrient deprivation, injuries) they undergo adaptation Goal of cellular adaption is to preserve viability and function “Cellular Injury” If the adaptive capability is exceeded cellular injury develops Overview: The principal adaptive responses 1) “Hypertrophy”: Increase in cell size 2) “Hyperplasia”: Increase in cell number Hypertrophy and Hyperplasia can occur together resulting in an enlarged organ 3) “Atrophy”: Decrease in cell size 4) “Metaplasia”: Change in cell type 1) Hypertrophy In cells incapable of dividing like striated muscle cells No new cells, only bigger cells enlarged by increased amount of structural proteins and organelles Pathological & physiological hypertrophy https://www.abcam.com/content/cardiac-hypertrophy Compare volume of LV 2) Hyperplasia In cells capable of replication (smooth muscle cells) a) Physiologic hyperplasia: Hormonal hyperplasia: Proliferation of glandular epithelium of the female breast during puberty and pregnancy. Stimuli: Hormones Compensatory hyperplasia: Growth of residual tissue after removal / loss of part of an organ (liver!) Stimuli: Growth factors secreted by the remnant hepatocytes & nonparenchymal liver cells b) Pathologic hyperplasia: Stimuli: Excess hormones or growth factors Endometrial hyperplasia Overgrowth of endometrial tissue. Bleeding. Caused by excess of estrogen over progesterone Digitate human papillomavirus wart Excess of viral growth factors All hyperplastic process remains controlled. When hormonal or growth factor stimulation abates, hyperplasia disappears 3) Atrophy Shrinkage cell size linked to loss of cell substance Diminished function, but not dead Entire tissue/organ can diminish in size Possible causes for atrophy: Loss of innervation Pathologic cause Decreased workload Reduced blood supply Inadequate nutrition Physiologic cause Loss of endocrine stimulation (menopause) Aging (senile atrophy) 4) Metaplasia Reversible change in which one adult cell type is replaced by another adult cell type Cells sensitive to a particular stress are replaced by cells better able to withstand adverse environment Example: “Squamous change” in respiratory epithelium in Trachea and Bronchi of habitual smokers (see Figure next slide) “squamous cells” = Flat scale-like cells “stratified squamous epithelium”= Multiple layers of flat scale-like cells  Stratified squamous epithelium has a better chance of survival Important protective mechanisms lost: No mucus secretion No ciliary clearance of particulate matter  Cell adaptations to stress SUMMARY Hypertrophy: Increased cell and organ size, often in response to increased workload, induced by mechanical stress and by growth factors; occurs in tissues incapable of cell division Hyperplasia: Increased cell numbers in response to hormones and other growth factors; occurs in tissues whose cells are able to divide Atrophy: Decreased cell / organ size, as a result of decreased nutrient supply or disuse; associated with decreased synthesis and increased degradation Metaplasia: Change of phenotype of differentiated cells, often response to chronic irritation that makes cells better able to withstand the stress; usually induced by altered differentiation pathway of tissue stem cells; may result in reduced function or increased propensity for malignant transformation  Overview Cell Death 9th Conference on Targeting Mitochondria, Berlin, Germany, October 2018 “Chaotic” “Programmed Cell Death Cell Death” Necrosis Apoptosis Running out of ATP … switches into necrosis  Fragmentation, no lysis “Clean” phagocytosis of apoptotic bodies Cell lysis… Inflammation  Causes of Cell Injury & Death Oxygen Deprivation Interferes with OXPHOS Most common cause of hypoxia: Ischemia Chemical Agents Reactive Oxygen Species (ROS) O2. OH. other free radicals More about ROS later… Infectious agents Viruses, bacteria, fungi, other pathogens Immunologic Reactions Autoimmune and allergic reactions Genetic Defects Deficiency of functional proteins Physical agents Trauma, radiation, extreme temperatures  Morphology of Reversible Cellular Injury: 2 major features Cellular swelling Fatty change (steatosis) Appearance of lipid-filled vacuoles Failure of ATP-dependent ion pumps in cytoplasm Loss of ionic and fluid homeostasis Impairment of lipid metabolism Normal kidney Swelling of some Histological section mouse liver tubules with epithelial cells viable epithelial causes narrowing Severe steatosis: White vesicles cells of tubules  Morphology of Necrosis on Cellular Level P.Santhi, Indian Pediatrics 2000; 37: 1017 Increased pink staining with Hematoxylin & Eosin (H&E) due to 1) Increased eosinophilia Less RNA Increase denatured protein 2) Myelin figures Karyolysis: DNA degradation 3) Calcification Pyknosis: Shrinkage of nucleus 4) Nuclear changes: Karyorrhexis: Fragmentation of nucleus  Subcellular Responses to Injury / Stress Induction of distinctive alterations involving only (!) subcellular organelles 1) Autophagy Lysosomal digestion of cell’s own components Residual bodies may contain undigested debris (pigments like ink from tatoos) Survival mechanism in times of nutrient deprivation  2) Induction (Hypertrophy) of Smooth ER Drugs metabolized by P450 enzyme system in liver P450 enzyme system localized in smooth ER. Protracted drug use leads to adaptation: Increase of SER Consequence: Need to increase dose  3) Mitochondrial Alterations Changes in size, shape, number (Exercise increases number of mitochondria) Mitochondrial network, constantly undergoing fusion and fission R. Medda et al. J Struct. Biology 156 (2006) 517 Microtubular network  4) Cytoskeletal Abnormalities Cytoskeleton - elaborate array of protein fibers, that help maintain cell shape, provide mechanical strength and aid in chromosome separation © migration.files.wordpress.com 3 Types: Microtubules Actin filaments Intermediate filaments Cells constantly remodel their intracellular scaffolding in response to environmental stress Membrane stability depends on cytoskeleton Drugs binding to microtubules prevent proliferation = Anticancer drugs  Mechanism of Cell Injury OVERVIEW of most important targets  ATP depletion Lack of oxygen and nutrients Direct mitochondrial damage Toxins (like cyanide) For formation of 50% of ATP in Initiation Complex brain used for for Translation sodium pump 2 GTP! 3 Na+ out 2 K+ in Osmotic gain of water Cytosolic Ca 10,000 x < Extracellular Ca (or mitochondria / ER) When ATP dependent calcium transporters fail: Increased cytosolic Ca leads to activation of enzymes Cellular injury by oxidative stress Sources of ROS NADPH Oxidases NO Synthase Xanthin Oxidase Blue: ROS Neutralization “leaky” pathways respiratory chain license: CC BY-NC-ND 3.0  ROS Paradigm Shift Hydrogenperoxide and other ROS serve as physiological 2nd Messengers for multitude of biochemical pathways! V. Weissig & D. Guzman-Villanueva, Expert Opin. Drug Deliv. (2015) 12(11) 1-8 Nanocarrier-based antioxidant therapy: promise or delusion?