PATH*3610 Principles of Disease: Cell degeneration and Death PDF

PATH*3610 Principles of Disease General Pathology Pathology of Organ Systems PATH*3610 Principles of Disease Cell degeneration and Death Major Principle of Disease Definitions are ◼ Literal ◼ Specific ◼ Use prefixes and suffixes and the Latin or...

PATH*3610 Principles of Disease General Pathology Pathology of Organ Systems PATH*3610 Principles of Disease Cell degeneration and Death Major Principle of Disease Definitions are ◼ Literal ◼ Specific ◼ Use prefixes and suffixes and the Latin or Greek meanings Disease Pathology - Pathos (suffering) and - ology (the study of) Lesion = structural change Cause Etiology (the study of the cause) Pathogenesis = how a lesion develops Cause – mechanisms - lesion General Pathology Cellular Injury and Adaptation Cell Death  Degeneration - Cell death ◼ Burn ◼ Ulcer ◼ Pus de "down from, away from" + genus (genitive generis) "birth, descent" Stimulus/insult and injury. ◼ Stimulus vs injury – depends on outcome ◼ Outcome depends on ◼ Duration ◼ Severity ◼ Physiological state. ◼ Stimulus causes adaptation – reversible ◼ Injury causes ◼ Degeneration – reversible – (injury) ◼ Death – irreversible – (injury) Adaptation to a stimulus ◼ Hypertrophy ◼ All cells ◼ Cells get bigger ◼ Atrophy is the opposite - ◼ Hyperplasia ◼ More cells ◼ Labile and stable cells atrophia – ‘not fed’; -plasia – to form.  Response to stimulus or injury? ◼ Permanent (post-mitotic, terminally differentiated) cells ◼ Neurons, cardiac myocyte, skeletal myocyte ◼ Stable cells (resting) ◼ Fibroblasts, smooth muscle cell, some epithelial cells (liver, kidney) ◼ Labile cells (Stem cells) ◼ Epithelial cells of skin, stomach, intestine ◼ Bone marrow progenitors/stem cells ◼ Target of cytotoxic chemotherapy Myo – muscle; cytos – cell; progenitor – ancestor or parent; toxic – capable of causing death Response vs healing ◼ Response of cells is ◼ Hyperplasia ◼ Hypertrophy ◼ No response – maintanence ◼ Healing of tissue is ◼ Regeneration or ◼ Not regeneration (Plan B; see later). Principles of Healing by Regeneration ◼ System - no ◼ Organ – no in mammals ◼ Primary tissue ◼ Supporting tissue (fibrous tissue) ◼ Blood vessels ◼ Other cells ◼ Primary tissue – yes with exceptions ◼ Similar cells together (and their product) ◼ Cell - yes Cell cycle ◼ G0 - Resting G2 G1 - Presynthetic S X ◼ ◼ S - DNA synthesis ◼ G2 - premitotic X M ◼ M - mitotic Cell division G1 G0 Cell cycle regulation ◼ Growth factors (GF) (+ and -) ◼ Epidermal growth factor (EGF) ◼ Transforming growth factor (TGF) β ◼ Insulin like growth factor (IGF) ◼ Fibroblast growth factor (FGF) ◼ Vascular endothelial growth factor (VEGF)  Cell cycle regulation ◼ Hormones, Growth factors and Cytokines ◼ Inherent characteristics ◼ Embryonic stem cells ◼ pluripotent ◼ Adult stem cells ◼ Restricted differentiation pattern Cytos – cell; kine – movement; growth factor – cell growth and differentiation; hormone – stimulates at a distance Cell Death – the terminology quagmire  Terminology of death and dying Common terminology Disease terminology ◼ Dead ◼ Dead ◼ Cell death, tissue death ◼ Death ◼ Necrosis ◼ Type of death Accidental cell death ◼ Traumatic death Regulated cell death Cell Death – the terminology Accidental cell death Regulated cell death  Cell Death: the mechanisms ◼ Accidental cell death ◼ Instantaneous and catastrophic and severe. ◼ Trauma, freezing, burns, infarct ◼ Regulated cell death ◼ Lethal trigger ◼ Involves genetically encoded molecular machinery. ◼ 12 molecular subroutines or programs. Which occurs depends on cell, injury, time, severity, physiological state. ◼ involves initiation and execution phases. ◼ Programmed cell death ◼ Physiologic/embryologic/postembryologic cell death ◼ Differentiation processes – cornification of skin Cornification – process of making cornified cells of epidermis Cell Death ◼ About 40 billion cells die in your body each day. ◼ Efficiently and silently removed by macrophages by a process of efferocytosis – the silent removal of cell corpses! Efferocytosis is Greek: to carry the dead to the grave  Cell Death – the terminology Some of the terminology is historical and contextural: ◼ Macroscopic descriptors ◼ Histological descriptors ◼ Molecular pathways and subroutines  Historical macroscopic (gross) appearance and descriptors of Cell death ◼ Coagulative – in olden times - dry gangrene ◼ Liquifactive - pus, abscess, ◼ Caseous Gangrene - localized death and decomposition of body tissue; caseous – like cheese "Necrosis" UGA Vet School Music Video (Taylor Swift "Tim McGraw" Parody)  Oversimplistic mechanism of death Ways cells die Swell Shrink Necrosis Apoptosis Necros (death) –osis (a process of) : Apo (away from) and ptosis (fall) Even more Terminology of Death ◼ Cell swelling ◼ Hydropic cell death = Oncotic necrosis ◼ Cell stays the same ◼ Coagulative necrosis ◼ Cell shrinks ◼ Apoptotic cell death  Cell Death: Microscopic/histological descriptors; cell swelling ◼ Cell Swelling ◼ Cellular (hydropic) swelling ◼ Plasma membrane and organelles injured, dysregulated ion and fluid homeostasis ◼ Fatty change Normal Liver with liver Fatty change Cell Death: Microscopic/histological descriptors; ‘Necrotic appearance’. ◼ Cell swelling (Oncotic necrosis) Normal hepatocytes Swollen hepatocytes  Cell Death: Microscopic/histological descriptors; ‘Necrotic appearance’ coagulation necrosis ◼ Dead cells look the same as normal cells  Cell Death: Microscopic/histological descriptors; Apoptotic appearance ◼ Apoptotic cells are shrunken and taken up by neighboring cells and macrophages Apoptosis is Greek. Apo (from) and Ptosis (falling) = falling off  Cell Death: Yet another classification! ◼ Type 1 (apoptotic) ◼ Cells shrink, nuclei condense and may fragment ◼ Caspase induced proteolysis ◼ Type II (autophagic) ◼ Cells vacuolated ◼ Autophagosomes formed (vacuoles) ◼ Fuse with lysosomes ◼ Type III (necrotic; aka oncosis, oncotic necrosis) ◼ Cells swell ◼ Loss of membrane function ◼ Enzyme release – basis for tests on serum Oncotic – condition of swelling  Cell Death: Mechanisms / Molecular pathways ◼ Accidental cell death ◼ Instantaneous and catastrophic and severe. ◼ Trauma, freezing, burns, infarct ◼ Regulated cell death ◼ Lethal trigger ◼ Involves genetically encoded molecular machinery. ◼ 12 molecular subroutines or programs. Which occurs depends on cell, injury, time, severity, physiological state. ◼ involves initiation and execution phases. ◼ Programmed cell death ◼ Physiologic/embryologic/postembryologic cell death ◼ Differentiation processes – cornification of skin Cornification – process of making cornified cells of epidermis Degeneration and Death of the Whole Body Aging Free radicles Reactive oxygen and nitrogen species (RONS) Death: Growing old gracefully ◼ Fountain of youth ◼ Philosophers stone (of Harry Potter) ◼ Bacta (of Star Wars, Mandalorian) ◼ Megavitamin therapy ◼ Facial strip/exfoliation ◼ Botox ◼ Plastic surgery Death: Aging theories ◼ Intrinsic cellular aging ◼ Chromosomal shortening – telomeres and telomerase ◼ Clock genes - nematodes ◼ Extrinsic cellular aging ◼ Lifetime of wear and tear ◼ Free radicals ◼ Reactive oxygen and nitrogen species (RONS) ◼ Reactive oxygen species like oxygen derived free radicals (ODFR) ◼ Reactive nitrogen species like nitric oxide ◼ Counteract RONS with antioxidants. Death: Free Radical Injury ◼ production vs scavengers ◼ Drugs and chemicals ◼ Inflammation ◼ Microbial injury ◼ Irradiation ◼ Aging  Death: Antioxidants and aging ◼ Drosophila ◼ alter oxidative pathways ◼ BMR and aging ◼ higher free radical formation ◼ Caloric restriction in spiders, guppies, rodents, and dogs. Inconclusive in primates ◼ Growth hormone – insulin like growth factor receptor 1 signaling Shimokawa I. Mechanisms underlying retardation of aging by dietary energy restriction. Pathol Int. 2023 Dec;73(12):579-592. doi: 10.1111/pin.13387. Epub 2023 Nov 17. PMID: 37975408. Death: Antioxidants ◼ ‘Natural’ ◼ Vitamin A, C and E ◼ Glutathione ◼ While theoretically beneficial, evidence suggests that Vit E supplements are not effective, and may harm.