Cellular Adaptations and Injury - Lectures 2-3 PDF

CELLULAR ADAPTATIONS CELL INJURY CELL DEATH! Dariusz Grzanka, PhD! Pathology! Rudolph Virchow 1821-1902 The Father of Modern Pathology!  Core of Pathology 1.Etiology 2.Pathogenesis 3.Morphologic Changes 4.Functional Consequences!  Patho...

CELLULAR ADAPTATIONS CELL INJURY CELL DEATH! Dariusz Grzanka, PhD! Pathology! Rudolph Virchow 1821-1902 The Father of Modern Pathology!  Core of Pathology 1.Etiology 2.Pathogenesis 3.Morphologic Changes 4.Functional Consequences!  Pathogenesis! Recovery! pathomechanism! Etiology! Sympt Def.! Scar! oms! Disease! Sympt Death! oms! Compila tion ! Etiology is the study of disease causation Greek “aitologia”- giving a reason Pathogenesis the sequence of events that give rise to the manifestations of disease step by step development of a disease and the chain of events leading to that disease Morphologic Changes structural alterations induced in the cells and tissues by the disease Functional Consequences clinical manifestation of the disease  Pathogenesis! Recovery! pathomechanism! Etiology! Sympt Def.! Scar! oms! Disease! Sympt Death! oms! Compila tion ! whiteheads, blackheads, and inflamed red growths (papules, pustules, and cysts)! Acne vulgaris!  Acne vulgaris! Complications of acne! Scars! Homeostasis is a state of balance in the body, organ, tissue, cell physiologic, metabolic capability to adopt to some changes in their internal and external environments normal cell is in steady state able to handle physiologic demand according to its adaptive capacity ! Homeostasis cells can alter their functional state in response to modest stress and maintain their homoeostasis Cellular Adaptation occurs when excessive physiologic stresses or pathologic stimuli result in a new but altered state that preserves the viability of the cell.! Adapt - to conform to changes in environment – internal and external ! To accommodate, to adjust, to fit, to accept – concession or yielding ! Survival strategy – in response to physiological or pathological demands ! Most cells have the inherent plasticity - ! Survival of the fittest or the adaptable! Homeostasis excessisve stress or adverse pathologic stimuli Adaptation Reversible injury Irreversible injury --> Cell death  Homeostatic imbalance! Inability to adapt Cellular Response ( exceeded limits of Cellular adaptations adaptive response, point (reversible changes) of no return” - cell injury): hypertrophy Cell death hyperplasia atrophy Necrosis metaplasia Coagulative Liquefative dysplasia Intracellular accumulations (in various Apoptosis organelles), degeneration– water Others ( np. Autophagy, mitotic (hydropic degeneration), proteins (hyaline catastrophe)! ! deg.), fat (steatosis), calcifications etc. Cellular Adaptations!  REVERSIBLE = INJURY IRREVERSIBLE = DEATH SOME INJURIES CAN LEAD TO DEATH IF PROLONGED and/or SEVERE enough! Necrosis !  REVERSIBLE CHANGES! REDUCED oxidative phosphorylation ATP depletion Cellular “SWELLING”!  IRREVERSIBLE CHANGES! MITOCHONDRIAL IRREVERSIBILITY IRREVERSIBLE MEMBRANE DEFECTS LYSOSOMAL DIGESTION! INJURY CAUSES (REVERSIBLE)! THE USUAL SUSPECTS! But…WHO are the THREE WORST?! INJURY CAUSES (REVERSIBLE)! Hypoxia, (decreased O2) PHYSICAL Agents CHEMICAL Agents INFECTIOUS Agents Immunologic Genetic Nutritional! CAUSES OF CELL INJURY!  INJURY MECHANISMS (REVERSIBLE)! DECREASED ATP - MITOCHONDRIAL DAMAGE INCREASED INTRACELLULAR CALCIUM INCREASED FREE RADICALS INCREASED CELL MEMBRANE PERMEABILITY!  CONTINUUM! REVERSIBLE à IRREVERSIBLEà T! DEATHà i m EMà e! LIGHT MICROSCOPYà GROSS APPEARANCES! Ischemic injury! See also Ch. 1, p. 14, Fig. 1-17!  Calcium homeostasis! Calcium in cell injury!  Cellular swelling (slide 134)! is the first manifestation of almost all forms of injury to cells. It is a difficult morphologic change to appreciate with the light microscope; ! ! it may be more apparent at the level of the whole organ.!  Hydropic degenerate ! Mitochondria Swelling  What is Death? What is Life?! DEATH is – IRREVERSIBLE MITOCHONDRIAL DYSFUNCTION – PROFOUND MEMBRANE DISTURBANCES LIFE is……..???! Apoptosis or Type I cell-death.! ! ! ! Autophagic or Type II cell-death. (Cytoplasmic: characterized by the formation of large vacuoles which eat away organelles in a specific sequence prior to the nucleus being destroyed.)! ! ! Necrotic cell death or Type-III! Apoptosis! APOPTOSIS Physiologic (or programmed) cellular death occurs when a cell within an organism dies through activation of an internal suicide program! Events in apoptosis! APOPTOZA! Autophagy! NECROSIS! NECROSIS Necrosis is the sum of the morphologic changes that follow cellular death in living tissue or organs. NECROSIS Two Processes in Basic Morphologic Changes in Necrosis 1.Denaturation of Proteins 2.Enzymatic Digestion of organelles and other cytosolic components NECROSIS Events that will Lead to NECROSIS 1.Mitochondrial vacuolization 2.Extensive damage to plasma membrane 3.Lysosomal swelling 4.Enzymatic leakage in cytoplasm 5.Enzymatic activation NECROSIS Fate of NECROSIS 1.Autolysis Digestion by lysosomal enzymes of the dead cells themselves 2.Heterolysis Digestion by lysosomal enzymes of immigrant leukocytes NECROSIS Types of Necrosis 1.Coagulation Necrosis 2.Liquefaction Necrosis 3.Caseous Necrosis 4.Fat Necrosis 5.Gangrenous NECROSIS Types of Necrosis 1.Coagulation Necrosis The most common pattern of necrosis Characterized by denaturation of cytoplasmic proteins with preservation of the framework of the coagulated cell Heart, Kidneys, Liver, other solid organs! NECROSIS Types of Necrosis 3.Caseous Necrosis Characteristic of tuberculous lesions and appears grossly as soft, friable, “cheesy” material! NECROSIS Types of Necrosis 4.Fat Necrosis Necrosis in adipose tissues induced by the action of lipases. Generate chalky white areas (fat saponification)! 1. Liquefaction Necrosis - brain stroke!  ! 1. Liquefaction Necrosis - brain stroke  NORMAL CORTEX MARTWICA (ROZPŁYWNA?)! "red neurons" MARTWICA (ROZPŁYWNA?)! Brain encephalomalacia! Liquefaction Necrosis - late phase of brain stroke, lots of macrophages ! Abscess !  ! Liver abscess: Liquifactive necrosis N. Ghatak MD !  ! Myocardial Infarction- Necrosis  ! Splenic Infarction - Coagulative necrosis  ! Renal Infarction - Coagulative  ! Renal Infarction - Coagulative necrosis Caseous necrosis Tuberculosis ! hilar lymphnode Extensive Caseous necrosis ! Tuberculosis  ! LANGHANS GIANT CELL Caseous NECROSIS !  ! Caseous necrosis - Tuberculosis  Fat necrosis -- gross! FAT NECROSIS - ENZYMATIC, BALSER'S TYPE !  ! Fat Necrosis - Peritoneum.  GANGRENE! GANGRENE ("gangrenous necrosis") is not a separate kind of necrosis at all, but a term for necrosis that is advanced and visible grossly. If there's mostly coagulation necrosis, (i.e., the typical blackening, desiccating foot that dried up before the bacteria could overgrow), we call it DRY GANGRENE. If there's mostly liquefactive necrosis (i.e., the typical foul- smelling, oozing foot infected with several different kinds of bacteria), or if it's in a wet body cavity, we call it WET GANGRENE.!  ! Gangrene - Diabetic foot  ! Gangrene - Amputated Diabetic foot  ! Gangrene Intestine - Thrombosis. ADAPTATION!  Steam cells! Tissue renewal and adaptation!  Continuous steady state! Differentiated cells; with capacity to divide when needed ! Stem Cell Conditionally Continuously Dividing Dividing Hepatocyte Skin Pancreatic Acinar Intestinal Mucosa Renal Tubular Cells Respiratory Epithelium Bone Marrow (HSC) Uterine epithelium CELL TYPES Non Dividing Skeletal and cardiac Muscle Neuron! “Other people come and we fade away” Tennyson “ We fade away and the other people come” V. S. Naipaul  Cell Signals! Cells give and receive signals – Cells respond to multiple intracellular and extracellular signals They respond by increasing or decreasing the cell number and /or cell size The signals can be: Mitogens, Morphogens or Motogens. !  Cell Signals! Hormone + Receptor ! Transcription! ENDOCRINE! PARACRINE! AUTOCRINE!  Cell Signals! Endocrine: hormones, peptides produced by endocrine cells, released into circulation. Act on distant target organ/cells Paracrine: peptides produced and released by one group of cells act on adjacent groups of cells Autocrine: peptides released by the cell act on the same cell Intracrine/Metacrine: molecules / transcription factors/metabolites produced within the cell act on the same cell intracellularly ! GROWTH FACTORS: CONCEPTS ! CELLS MAY CONTAIN CELL SURFACE AND CYTOSOLIC/NUCLER RECEPTORS! CELL SURFACE WITH MORE THAN ONE RECEPTOR: THUS, CELL IS THE TARGET FOR MULTIPLE SIGNALS! GROWTH FACTORS CAN BE MULTI- FUNCTIONAL: ELICIT MORE THAN ONE RESPONSE! GROWTH FACTORS CAN BE ONCOGENIC! GROWTH FACTORS ! Hepatocyte Growth Factor (HGF) and its receptor c- Met: HGF is mitogenic, motogenic and morphogenic ! Epidermal Growth Factor (EGF) and its receptor c-erb B1: mitogenic and differentiating! Fibroblast Growth Factor (FGF)- acidic and basic ! Vascular Endothelial Growth Factor (VEGF)! Transforming Growth Factor β (TGFβ)!  Cellular Adaptations! Hyperplasia: increase in the number of cells. Hypertrophy: increase in the size of cells. Atrophy: reduction in the size of cells. Metaplasia: change in differentiation from one cell type to another. Dysplasia: abnormal hyperplasia. Cancer: cellular autonomy and uncontrolled growth. Slide – Adaptation diagram! Slide – Adaptation diagram! Cellular Adaptation Hyperplasia increase in the number of cells in an organ or tissue. occurs in cells capable of dividing! Cellular Adaptation Hyperplasia Physiologic Hormonal Compensatory Pathologic!  MORE CELLS PHYSIOLOGICAL! (PROLIFERATION)! BREAST: (PUBERTY, STEM CELL PREGNANCY, COMPARTMENT LACTATION) UTERUS: CONDITIONALLY- PREGNANCY! DIVIDING NON-DIVIDING CELLS: NO! HYPERPLASIA! COMPENSATORY! PATHOLOGICAL! KIDNEY (NEPHRECTOMY) PSORIASIS LIVER (PARTIAL GOITER ! HEPATECTOMY)!  HYPERPLASIA! CONDITIONALLY DIVIDING: MORE OF THE SAME! RENEWING TISSUES: !  ! BPH - Benign Prostatic Hyperplasia. Endometrial Hyperplasia!  GOITER! LOW IODINE TSH FOLLICULAR ENDEMIC AREAS CELL PROLIFERATION / HYPERTROPHY!  SCAR, KELOID! TGFβ Overexpression, polyclonality of fibroblasts !  Keloid – most extreme example of scar! Mr. Gordon- former slave from Louisiana – 1800s’! Hyperplasia. A. Normal adult bone marrow. B. Hyperplasia of the bone marrow. Cellularity is i ncreased, fat is decreased. C. Normal epidermis. D. Epidermal ! hyperplasia in psoriasis, shown at the same magnification as in C. The epidermis is thickened, owing to an increase in the number of s quamous cells  HYPERTROPHY! No change in cell number Reversible increase in cell size Hypertrophy is the rule in non-dividing cells – since they can not divide Myocardium, skeletal muscle, neurons Increase amount of DNA, RNA, protein Increased synthesis, reduced loss Hypertrophy! Do you want muscles? Or do you want to look muscular?!  plastic models illustrating the different densities and consequent volume differences of fat and muscle tissue!  When you have achieved a "normal" degree of leanness, building a beautiful body has little to do with losing weight, it's all about modulating the ratio of lean to fat mass!  "building a bigger metabolic engine" and not starving the latter away on a low-calorie diet, is the cornerstone of maintainable reductions in body fat levels!  Sketch of a mammalian skeletal muscle fiber - myonucleus (turqouis), mitochondria (blue), sarcoplasmic rectilium (buff), tubules (orange), myofibrils (pinkish)!  If you picture a muscle fiber as a number of balloons which are held together by an elastic net, then the myonuclei would be within the individual balloons!  Pathway A - hypertrophy via satellite cell recruitment and increases in the number of myonuclei per muscle fiber,! Pathway B - hypertrophy via increases in myonuclear domain size within an existing muscle fiber, and! Pathway C - hyperplasia, which would be the increase in muscle size by cell division and thusly an increase in the number of muscle fibers! sarcoplasmic hypertrophy - which focuses more on increased muscle glycogen storage! ! myofibrillar hypertrophy - which focuses more on increased myofibril size!  Fiber composition of bodybuilders, recreational lifters, endurance rowers and sedentary control; determined via myosin heavy chain (MHC) isoform content of the triceps brachii muscle !  TESTOSTERONE?! plastic models illustrating the different densities and consequent volume differences of fat and muscle tissue! Relative free testosterone and free estradiol levels in men from the NHANES study; data expressed relative to serum levels of "lean" men with