Cellular Adaptations, Cell Injury and Cell Death PDF

ATTENDANCE Have you checked in? Please remember to check into the session via Osler! 15/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 1  Cellular adaptations,...

ATTENDANCE Have you checked in? Please remember to check into the session via Osler! 15/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 1  Cellular adaptations, cell injury and cell death Assistant Professor Joan Roehl 15/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 2  Acknowledgement of Country Bond University acknowledges the Kombumerri people, the traditional Owners and Custodians of the land on which the University now stands. We pay respect to Elders past, present and emerging. Copyright Warning. This material has been reproduced and communicated to you by or on behalf of Bond University in accordance with section 113P of the Copyright Act 1968 (Act). The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. 15/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 3  Week Learning Outcomes Week 6, Science and Scholarship LO 9  Describe the types and mechanism of cell injury, processes of cellular adaptation to these injuries and cell death (Forum) 15/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 5  Session Learning Outcomes During this session you will learn to  … identify the regenerative capacity of different cell/tissue types  … know causes and outcomes of cell stress/injury  … describe the process of cellular adaptation to stress  … differentiate types of cell damage (reversible vs. irreversible injury)  … describe the process of cell/tissue death (apoptosis and necrosis) 15/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 6 Regenerative capacity of different cell/tissue types WHAT ARE THE DIF F ERENCES BETWEEN LABILE, STABLE AND P ERMANENT TIS S UES? CRICOS Provider Code: 00017B TEQSA: PRV12072  Regenera t ive ca pa cit y of differ ent cell/ t is s ue t ypes 30 trillion cells in the human body – most are differentiated ‘end’ cells – which make up the tissues of our body Ability of tissues to repair themselves determined (in part) by their proliferative capacity Cell populations may be divided based on their regenerative/proliferative capacity as follows: Labile, stable, and permanent cells/tissues 15/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 8 Regenerative capacity of different cell/tissue types Labile tissue (continuously dividing cells) Cells constantly lost and replaced Haematopoietic cells of bone marrow - making white and red blood cells; most epithelia e.g., skin, gut, respiratory airways; gonads Stable tissue (quiescent – only divide when stimulated to replace injured cells) Have limited regenerative capacity, replicate slowly Hepatocytes, renal tubular cells, endothelial cells, smooth muscle cells Permanent tissue (normally only divide in foetus – terminally differentiated) Very limited regenerative capacity – injury results in scar Most neurons, cardiac muscle, skeletal fibres CRICOS Provider Code: 00017B TEQSA: PRV12072 9 Regenerative capacity - Labile cell populations Constantly divide Constant loss of end cells Vulnerable to agents preventing or disrupting cell division Stem cells present in tissues that differentiate Bone marrow Small intestine Testis Skin CRICOS Provider Code: 00017B TEQSA: PRV12072 Regenerative capacity - Stable cell populations The cells are not constantly dividing but may divide in response to cell injury and loss Kidney Liver Adipose tissue CRICOS Provider Code: 00017B TEQSA: PRV12072 Regenerative capacity - Permanent cell populations Cells (generally) cannot divide – injury results in scar Neurons Skeletal muscle Cardiac muscle *Modern concepts of neurobiology neurons not so permanent but very limited cellular recovery in adults. CRICOS Provider Code: 00017B TEQSA: PRV12072  Renal tubule cells Hepatocytes Respiratory epithelium Endothelial cells Skeletal muscle Cardiac muscle cells Most neurons Skin epithelium Haematopoietic stem cells Gut epithelium Labile Stabile Permanent CRICOS Provider Code: 00017B TEQSA: PRV12072 13 Introduction: Cellular response to stress and noxious stimuli WHAT HAP P ENS TO CELLS IF THEY BECOME STRES S ED? CRICOS Provider Code: 00017B TEQSA: PRV12072  NORMAL CELL REVERSIBLE (homeostasis) INJURY Stress Injurious Mild, stimulus transient ADAPTATION CELL INJURY Inability to adapt Severe, progressive IRREVERSIBLE INJURY CELL NECROSIS DEATH APOPTOSIS Adapted from Kumar et al.: Robbins & Cotran Pathologic Basis of Disease. CRICOS Provider Code: 00017B TEQSA: PRV12072  Kumar et al.: Robbins & Cotran Pathologic Basis of Disease. CRICOS Provider Code: 00017B TEQSA: PRV12072  NORMAL CELL REVERSIBLE (homeostasis) INJURY Stress Injurious Mild, stimulus transient ADAPTATION CELL INJURY Inability to adapt Severe, progressive IRREVERSIBLE INJURY CELL NECROSIS DEATH APOPTOSIS Adapted from Kumar et al.: Robbins & Cotran Pathologic Basis of Disease. CRICOS Provider Code: 00017B TEQSA: PRV12072 Adaptations to cellular growth and differentiation HOW DO CELLS/ TIS S UES RES P OND TO HOMEOSTATIC CHANGES (STRES S )? CRICOS Provider Code: 00017B TEQSA: PRV12072 Adaptations – an overview Reversible changes in size, number, phenotype, metabolic activity, or function of cells in response to environmental changes through an active process: What does “active” Atrophy: decrease in cell size and cell number process mean? Hypertrophy: increase in cell size Hyperplasia: increase in cell number Metaplasia: change in cell type Dysplasia Stressors include: Change in hormonal stimulation Changed demand or nutrient supply Irritation Understanding Pathophysiology, Craft et al, 2011, Fig 4-6 CRICOS Provider Code: 00017B TEQSA: PRV12072 At r ophy Atrophy is a decrease in the size of an organ/tissue due to a decrease in cell size and cell number. A tissue that is undergoing atrophy is composed of cells that are undergoing autophagy and/or apoptosis Prefix meaning “absence of” A – trophy Suffix meaning “growth” Causes: Decreased workload (disuse atrophy) Loss of innervation (denervation atrophy) Decreased blood supply (=ischaemia) Inadequate nutrition (=marasmus) (cachexia) Loss of endocrine stimulation Pressure CRICOS Provider Code: 00017B TEQSA: PRV12072 Autophagy Active or passive? Atrophy often accompanied by increased autophagy Cell “eats itself” in response to stress (reduced nutrients) Delivery of cytoplasmic materials to the lysosome for degradation Implicated in many physiologic states and pathologic processes Can trigger cell death Kumar et al: Robbins & Cotran Pathologic Basis of Disease, 9th Edition. CRICOS Provider Code: 00017B TEQSA: PRV12072 Atrophy – example: senile atrophy of the brain gyri sulci A – normal young adult brain. B – atrophy of brain of an 82-year old CRICOS Provider Code: 00017B TEQSA: PRV12072 with cerebrovascular disease – note narrowed gyri and widened sulci. Atrophy – example: meningioma Meningioma: benign, slow-growing tumour of the meninges CRICOS Provider Code: 00017B TEQSA: PRV12072 Hyper t r ophy Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells (increase in cell size). Prefix meaning “increased” Hyper – trophy Suffix meaning “growth” Causes: Increased workload Increased hormonal stimulation Cardiac muscle cells and skeletal muscles only have a limited capacity for division, so they respond to increased metabolic demands mainly by undergoing hypertrophy. CRICOS Provider Code: 00017B TEQSA: PRV12072 Hyper t r ophy – exa m ple: ca r dia c hyper t r ophy Normal heart vs. cardiac hypertrophy. a Cross section of a normal heart in a perinatal death: the right ventricular free wall thickness is 3.5 mm, the left ventricular is 5 mm, and the septum 5.5 mm. b Cross section of a normal adult heart: the right ventricular free wall thickness is 2 mm, the left ventricular is 12 mm, and the septum 13 mm. c Cross section of hypertrophic heart in an adult: the right ventricular free wall thickness is 7 mm, the left ventricular is 21 mm, and the septum 22 mm. d Histology of a showing hypercellularity which is normal for a perinatal myocardium (high number of cardiac myocyte/myocardial area) (bar = 100 micron). e Histology of b with diameter of cardiac myocytes within normal values (mean diameter 12 micron) (bar = 100 micron). f Histology of c with cardiac myocyte hypertrophy (mean diameter 20 micron) (bar = 100 micron) Cardiac hypertrophy at autopsy - Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Normal-heart-vs-cardiac-hypertrophy-a-Cross-section-of-a-normal-heart-in-a- CRICOS Provider Code: 00017B TEQSA: PRV12072 perinatal_fig5_350188027 [accessed 16 Feb, 2022] Hypertrophy – example: uterine hypertrophy Physiologic hypertrophy of the uterus during pregnancy. A, Gross appearance of a normal uterus (right) and a pregnant uterus (left). B, Small spindle-shaped uterine smooth muscle cells from a normal uterus, compared with C, large plump cells from the pregnant uterus, at the same magnification. CRICOS Provider Code: 00017B TEQSA: PRV12072 Hyper pla s ia Hyperplasia is the increase in cell number. Prefix meaning “increased” Hyper – plasia Suffix meaning “development” Causes: Increased hormonal/growth factor stimulation Hyperplasia can only take place if the tissue contains cells capable of dividing. While hyperplasia is distinct from cancer, cancerous proliferations may eventually arise. CRICOS Provider Code: 00017B TEQSA: PRV12072 Hyper pla s ia – exa m ple: benign pr os t a t ic hyper pla s ia CRICOS Provider Code: 00017B TEQSA: PRV12072 Met a pla s ia Change from one differentiated cell type into another, sometimes less differentiated, cell type. E.g. most common epithelial metaplasia: columnar to squamous Prefix meaning “change” Meta – plasia Suffix meaning “development” Associated with changes in cellular environment resulting in activation/suppression of genes e.g. epithelium of airways of chronic smokers e.g. oesophageal epithelium in GORD (Barrett oesophagus) Influences that predispose to metaplasia, if persistent, can initiate malignant transformation. CRICOS Provider Code: 00017B TEQSA: PRV12072 Met a pla s ia – exa m ple: conduct ive r es pira t or y epit helium in r es pons e t o s m oking Metaplasia of ciliated columnar (left) to squamous epithelium (right) in a bronchus Adaptation is useful in this example as it allows cell survival, however, what functions are lost? CRICOS Provider Code: 00017B TEQSA: PRV12072 Met a pla s ia – exa m ple: Ba r r et t oes opha gus / GORD Gastroesophageal reflux disease (GORD). Metaplasia of stratified squamous to columnar epithelium in oesophagus CRICOS Provider Code: 00017B TEQSA: PRV12072  Liver cells compensating for loss after removal of part of the liver Wasting of skeletal muscles due to disuse or malnutrition Shrinking of the brain due to ageing Barret's oesophagus Muscle 'gains' due to weightlifting Benign enlargement of the prostate Changes in the airway epithelium due to smoking Smaller kidney due to poor blood supply Heart cells enlarge due to high blood pressure Uterine cells get bigger to accommodate growing foetus Atrophy Hypertrophy Hyperplasia Metaplasia CRICOS Provider Code: 00017B TEQSA: PRV12072 32 Overview of cell injury and death WHAT HAP P ENS TO CELLS IF THEY BECOME INJ URED? CRICOS Provider Code: 00017B TEQSA: PRV12072  NORMAL CELL REVERSIBLE (homeostasis) INJURY Stress Injurious Mild, stimulus transient ADAPTATION CELL INJURY Inability to adapt Severe, progressive IRREVERSIBLE INJURY CELL NECROSIS DEATH APOPTOSIS Adapted from Kumar et al.: Robbins & Cotran Pathologic Basis of Disease. CRICOS Provider Code: 00017B TEQSA: PRV12072  Lack of blood supply = ischaemia Causes and mechanisms of cell injury Lack of oxygen = hypoxia Oxygen deprivation (= hypoxia) Nutritional imbalances Physical injury Free radical and reactive oxygen species Chemical injury Infectious agents Immunologic reactions Genetic derangements Nature of injury, duration, severity Cell type, state, adaptability Different agents (biological, chemical, physical) can injure the various structural and functional components of the cell. Some cells with specific function are selectively prone to certain types of injury. CRICOS Provider Code: 00017B TEQSA: PRV12072  Microscopic features NORMAL CELL REVERSIBLE Cellular swelling (homeostasis) INJURY Fatty change … Stress Injurious Mild, stimulus transient ADAPTATION CELL INJURY Inability to adapt Severe, progressive IRREVERSIBLE INJURY CELL NECROSIS DEATH APOPTOSIS Adapted from Kumar et al.: Robbins & Cotran Pathologic Basis of Disease. CRICOS Provider Code: 00017B TEQSA: PRV12072 Reversible cell injury – cellular/cloudy swelling Whenever cells are incapable of maintaining ionic and fluid homeostasis Result of failure of energy- dependent ion pumps in plasma membrane CRICOS Provider Code: 00017B TEQSA: PRV12072 Reversible cell injury – fatty change (steatosis) Occurs in hypoxic injury and various forms of toxic or metabolic injury Manifested by the appearance of lipid vacuoles in the cytoplasm Seen mainly in cells involved in/dependent on fat metabolism  hepatocytes (liver) and myocardial cells CRICOS Provider Code: 00017B TEQSA: PRV12072  NORMAL CELL REVERSIBLE (homeostasis) INJURY Stress Injurious Mild, stimulus transient ADAPTATION CELL INJURY Inability to adapt Severe, progressive IRREVERSIBLE INJURY CELL NECROSIS DEATH APOPTOSIS Adapted from Kumar et al.: Robbins & Cotran Pathologic Basis of Disease. CRICOS Provider Code: 00017B TEQSA: PRV12072 Irreversible cell injury – apoptosis vs. necrosis WHAT IS THE P ROCES S OF CELL DEATH? CRICOS Provider Code: 00017B TEQSA: PRV12072 Apopt os is Apoptosis = programmed cell death (or “cell suicide”) Removal of cells beyond physiological function or Apoptosis during digit development damaged beyond repair Physiology: Embryonic development Eliminates unwanted, old cells e.g. breakdown of endometrium of uterus during menstruation Functioning of immune cells Pathology: Defective apoptosis may lead to cancer HIV induces increased apoptosis of immune cells Some viruses inhibit apoptosis of cells they infect Immune cell induces CRICOS Provider Code: 00017B TEQSA: PRV12072 apoptosis in cancer cell Apopt os is Cell shrinks Condensation of cytoplasm and nucleus Formation of apoptotic bodies Phagocytosis of apoptotic bodies By macrophages and neutrophils No inflammation or scarring Intact cell membranes, preservation of organelles, cell shrinkage CRICOS Provider Code: 00017B TEQSA: PRV12072 Necr os is Necrosis = cell/tissue death due to severe injury Ischaemia, chemical, thermal … Unregulated cell death – passive process Damage to cell membranes Cell contents leak out causing neighbouring cells to undergo necrosis Lysosomal enzymes digest the cell (lysis) Acute inflammation occurs CRICOS Provider Code: 00017B TEQSA: PRV12072 Necr os is in t is s ues CRICOS Provider Code: 00017B TEQSA: PRV12072 Necr os is in t is s ues – Coa gula t ive necr os is Architecture of dead tissue is preserved for a span of at least some days Firm texture, pale areas (cells not lysed for days) Occurs in almost all tissues (except brain) Commonly result from hypoxia caused by severe ischaemia (localised area: infarct) Can become gangrenous due to bacterial infection Gangrene Coagulative necrosis. A – A wedge- shaped kidney infarct (yellow). B – Microscopic view of the edge of the infarct, with normal kidney (N) and CRICOS Provider Code: 00017B TEQSA: PRV12072 necrotic cells in the infarct (I) Necr os is in t is s ues – Liquefa ct ive necr os is Dead cells digested resulting in liquid viscous mass Creamy, yellow pus (presence of leukocytes) e.g. brain Commonly results from ischaemic injury in brain or from localised microbial infections CRICOS Provider Code: 00017B TEQSA: PRV12072 Necr os is in t is s ues – Ca s eous necr os is TB lesions in lungs fragmented or lysed cells and amorphous granular debris enclosed within a distinctive inflammatory border (granuloma) Dead cells digested Soft, ‘cheesy’ material e.g. lung CRICOS Provider Code: 00017B TEQSA: PRV12072 Session checklist  What are the differences between labile, stable, and permanent tissues?  What are the three possible outcomes of cell stress/injury?  Describe the four types of cell/tissue adaptations. Identify some causes of these adaptations. What factors determine whether cellular adaptations are possible? Are adaptations passive or active, reversible or not?  Describe the differences between apoptosis and necrosis.  Understand these terms: atrophy, hypertrophy, hyperplasia, hypertrophy, metaplasia, autophagy, apoptosis, necrosis. CRICOS Provider Code: 00017B TEQSA: PRV12072  bond.edu.au Assistant Professor Joan Roehl Faculty of Health Sciences and Medicine Bond University, Gold Coast, Australia 15/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 50