Color Atlas of Pathophysiology 3rd Edition PDF

Flexibok ^ Color Atlas of Pathophysiology Stefan Silbernagl Florian Lang Illustrations by Ruediger Gay Astried Rothenburger basic sciences 3rd Edition...

Flexibok ^ Color Atlas of Pathophysiology Stefan Silbernagl Florian Lang Illustrations by Ruediger Gay Astried Rothenburger basic sciences 3rd Edition tV:*? * v7 V *. L.. ** 1 I. - - if. 1 \> r>v V ft y -..v- - A v - * -- ;> SETV* , tl: - ONT pry ' * V /1 1 & V **.. f J V is t. ' J V / r Download From: AghaLibrary.com fiThieme  At a Glance 2 1 Fundamentals 24 2 Temperature, Energy 30 3 Blood 70 4 Respiration, Acid- Base Balance 100 5 Kidney, Salt and Water Balance 146 6 Stomach, Intestines, Liver 190 7 Heart and Circulation 258 8 Metabolic Disorders 282 9 Hormones 324 10 Neuromuscular and Sensory Systems 388 Further Reading 391 Index Download From: AghaLibrary.com  Color Atlas of Pathophysiology 3 rd Edition Stefan Silbernagl, MD Professor Institute of Physiology University of Wurzburg Wurzburg, Germany Florian Lang, MD Professor Institute of Physiology University of Tubingen Tubingen, Germany 195 color plates by Rudiger Gay and Astried Rothenburger Thieme Stuttgart New York Delhi Rio de Janeiro Download From: AghaLibrary.com  Library of Congress Cataloging-in-Publication Data This book is an authorized translation of the is available from the publisher 4th German edition published and copyrighted 2013 by Georg Thieme Verlag, Stuttgart, Germany. Translator: Geraldine O’Sullivan, Dublin, Ireland Title of the German edition: Taschenatlas Pathophysiologie Illustrator: Atelier Gay + Rothenburger, Sternenfels, Germany Important Note: Medicine is an ever-changing sci- ence undergoing continual development. Research 4th German edition 2013 and clinical experience are continually expanding 2 nd English edition 2010 our knowledge, in particular our knowledge of 1st Chinese edition 2012 (Taiwan ) proper treatment and drug therapy. Insofar as this 3rd French edition 2015 book mentions any dosage or application, readers 2 nd Czech edition 2012 may rest assured that the authors, editors, and 1st Greek edition 2002 publishers have made every effort to ensure that 1st Indonesian edition 2007 such references are in accordance with the state of 2 nd Japanese edition 2011 knowledge at the time of production of the book. 1st Korean edition 2013 Nevertheless, this does not involve , imply, or ex- 1st Polish edition 2011 press any guarantee or responsibility on the part of 2 nd Portuguese edition (in preparation) the publishers in respect of any dosage instructions 1st Romanian edition 2011 and forms of applications stated in the book. Every 1st Russian edition (in preparation) user is requested to examine carefully the manu- 1st Spanish edition 2010 facturers’ leaflets accompanying each drug and to 2 nd Turkish edition 2010 check, if necessary in consultation with a physician or specialist, whether the dosage schedules men- © 2016 Georg Thieme Verlag KG tioned therein or the contraindications stated by the manufacturers differ from the statements made Thieme Publishers Stuttgart in the present book. Such examination is particular- Rudigerstr. 14, 70469 Stuttgart, Germany ly important with drugs that are either rarely used + 49 [ 0 ] 711 8931 421 or have been newly released on the market. Every [email protected] dosage schedule or every form of application used is entirely at the user’sown risk and responsibility. Thieme Publishers New York The authors and publishers request every user to 333 Seventh Avenue , New York, report to the publishers any discrepancies or inac- NY 10001, USA curacies noticed. If errors in this work are found + 1-800-782-3488 after publication, errata will be posted at www. [email protected] thieme.com on the product description page. Thieme Publishers Delhi A-12, Second Floor, Sector-2, Noida-201301 Uttar Pradesh, India + 911204556600 [email protected] Thieme Publishers Rio, Thieme Publica oes Ltda. Some of the product names, patents, and registered Edificio Rodolpho de Paoli, 25° andar ^ designs referred to in this book are in fact registered Av. Nilo Pe anha, 50 - Sala 2508 trademarks or proprietary names even though spe- ^ Rio de Janeiro 20020-906 Brasil cific reference to this fact is not always made in the + 55 21 3172 2297/ + 55 21 3172 1896 text. Therefore, the appearance of a name without designation as proprietary is not to be construed as Cover design: Thieme Publishing Group a representation by the publisher that it is in the Typesetting by Ziegler + Muller, public domain. Kirchentellinsfurt, Germany This book, including all parts thereof, is legally pro- tected by copyright. Any use, exploitation or com- Printed in India by Manipal Technologies, mercialization outside the narrow limits set by Karnataka copyright legislation, without the publisher’s con- sent, is illegal and liable to prosecution. This ap- ISBN 9783131165534 5 4321 plies in particular to photostat reproduction, copy- ing, mimeographing or duplication of any kind, Also available as an e-book: translating, preparation of microfilms, and electro- elSBN 9783131490636 nic data processing and storage. Download From: AghaLibrary.com  Preface to the Third Edition Pathophysiology describes the mechanisms The third edition of the Atlas would again which lead from the primary cause via indivi- have been inconceivable without the great dual malfunctions to a clinical picture and its commitment, amazing creativity and outstand - possible complications. Knowledge of these ing expertise of the graphic designers, Ms. mechanisms serves patients when the task is Astried Rothenburger and Mr. Rudiger Gay. We to develop a suitable therapy, alleviate symp- would like to extend our warmest gratitude to toms, and avert imminent resultant damage them for their renewed productive co-opera- caused by the disease. tion. Our thanks also go to our publishers, in Our aim in writing this Atlas of Pathophysiol- particular Ms. Angelika Findgott, Ms. Annie ogy was to address students of medicine, both Hollins, Ms. Joanne Stead , and Mr. Martin prior to and during their clinical training, and Teichmann for their exceptional skill and en- also qualified doctors as well as their co-work- thusiasm in editing and producing the 3 rd edi- ers in the caring and therapeutic professions tion of the Atlas. Ms. Katharina Volker once and to provide them with a clear overview in again did a great job during the updating of words and pictures of the core knowledge of the subject index, Ms. Tanja Loch during proof- modern pathophysiology and aspects of patho- reading. biochemistry. We hope that readers continue to find in this The book begins with the fundamentals of Atlas what they are looking for, that they find the cell growth and cell adaptation as well as the text and pictures understandable, and that disorders of signal transduction, cell death, tu- they enjoy using this book throughout their mor growth, and aging. It then covers a wide studies and their working life. range of pathomechanisms affecting tempera - tur balance, diseases of the blood , lungs, kid- Wurzburg and Tubingen, Germany neys, gastrointestinal tract, heart and circula- June 2015 tion, metabolism including endocrinal ab- normalities, skeletal muscle, the senses, and Stefan Silbernagl and Florian Lang the peripheral and central nervous system. Fol- lowing a short review of the fundamentals of physiology, the causes, course, symptoms, and arising complications of disease processes are described along with the pathophysiological basis of therapeutic intervention. The book has met the interest of numerous readers and thus a third edition has become necessary. The new edition provided us with the opportunity to critically review the former edition and to include new knowledge. We continue to appreciate any critical comments and ideas communicated to us from the reader- stefan.silbernagl@ mail.uni-wuerzburg.de ship. florian.lang@ uni-tuebingen.de V Download From: AghaLibrary.com  Contents Fundamentals S. Sllbernagl and F. Lang 2 Cell Growth and Cell Adaptation... 2 Abnormalities of Intracellular Signal Transmission... 6 PI3-Kinase-Dependent SignaiTransduction... 10 Necrotic Cell Death ··· 12 Apoptotic Cell Death... 14 Development ofTumor Cells... 16 Effects ofTumors... 18 Aging and Life Expectancy ··· 20 Temperature, Energy S. Silbernagl 24 2 Fever... 24 Hyperthermia, Heat Injuries... 26 Hypothermia, Cold Injury... 28 Blood S. Silbernagl 30 3 Overview.. · 30 Erythrocytes... 32 Erythropoiesis, Anemia... 32 Erythrocyte Turnover: Abnormalities, Compensation, and Diagnosis.. · 34 Megaloblastic Anemia Due to Abnormalities in DNA Synthesis... 36 Anemias Due to Disorders of Hemoglobin Synthesis... 38 Iron Deficiency Anemia.. · 40 Hemolytic Anemias... 42 Malaria... 44 Immune Defense.. · 46 Inflammation... 52 Hypersensitivity Reactions (Allergies) ···56 Autoimmune Diseases.. · 60 Immune Defects.. 62 Hemostasis and Its Disorders ··· 64 Respiration, Add-Base Balance F. Lang 70 4 Overview... 70 Ventilation. Perfusion... 72 Diffusion Abnormalities... 74 Distribution Abnormalities.. · 76 Restrictive Lung Diseases... 78 Obstructive Lung Diseases... 80 VI Pulmonary Emphysema.. · 82 Pulmonary Edema.. · 84 Download From: AghaLibrary.com  Pathophysiology of Breathing Regulation 86 — Acute Respiratory Distress Syndrome 88 —— —— — Hypoxia 90 Hyperoxia, Oxidative Stress 92 Development of Alkalosis 94 Development of Acidosis 96 Effects of Acidosis and Alkalosis 98 — Kidney, Salt and Water Balance F. Lang 100 Overview 100 — Abnormalities of Renal Excretion 102 — Pathophysiology of Renal Transport Processes 104 Abnormalities of Urinary Concentration 108 — — — Polycystic Kidney Disease 110 Abnormalities of Glomerular Function 112 — — — —— Disorders of Glomerular Permselectivity, Nephrotic Syndrome 114 Interstitial Nephritis 116 Acute Renal Failure 118 Chronic Renal Failure 120 Renal Hypertension 124 Kidney Disease in Pregnancy 126 Hepatorenal Syndrome 128 —- — - Urolithiasis 130 Disorders of Water and Salt Balance 132 —— — —— Abnormalities of Potassium Balance 134 Abnormalities of Magnesium Balance 136 Abnormalities of Calcium Balance 138 Abnormalities of Phosphate Balance 140 Pathophysiology of Bone 142 — Stomach, Intestines, Liver S. Silbernagl 146 — Function of the Gastrointestinal Tract 146 Esophagus 148 — Nausea and Vomiting 152 —— — Gastritis ( Gastropathy ) 154 Ulcer 156 — — Disorders after Stomach Surgery 160 Diarrhea 162 Maldigestion and Malabsorption 164 Constipation and ( Pseudo- )Obstruction 168 — — —— Chronic Inflammatory Bowel Disease 170 Acute Pancreatitis 172 — Chronic Pancreatitis 174 Cystic Fibrosis 176 — Gallstone Disease ( Cholelithiasis ) 178 — VII Download From: AghaLibrary.com  — Jaundice ( Icterus ) and Cholestasis — 182 —— Portal Hypertension 184 Fibrosis and Cirrhosis of the Liver 186 Liver Failure ( see also p. 184 ff.) 188 Heart and Circulation S. Silbernagl 190 — Overview 190 Phases of Cardiac Action ( Cardiac Cycle ) 192 —— The Electrocardiogram ( ECG ) 198 Abnormalities of Cardiac Rhythm 200 —— Origin and Spread of Excitation in the Heart 194 Mitral Stenosis 208 — — Mitral Regurgitation 210 Aortic Stenosis 212 — — Aortic Regurgitation 214 — Defects of the Tricuspid and Pulmonary Valves; Circulatory Shunts — 216 — Arterial Blood Pressure and Its Measurement 220 — —— Hypertension 222 Pulmonary Hypertension 228 Coronary Circulation 230 Coronary Heart Disease 232 Myocardial Infarction 234 - — Heart Failure 238 Pericardial Diseases 244 - — Edema 250 — — Circulatory Shock 246 Atherosclerosis 252 — Nonatherosclerotic Disturbances of Arterial Bloodflow; Venous Diseases 256 Metabolic Disorders S. Silbernagl 258 — Overview 258 Disorders of Amino Acid Metabolism 258 — Disorders of Carbohydrate Metabolism; Lipidoses — — 260 Energy Homeostasis, Obesity 266 Eating Disorders 270 - — Abnormalities of Lipoprotein Metabolism 262 — Gout 272 Iron Metabolism, Hemochromatosis 274 —— — —— Copper Metabolism , Wilson’s Disease 276 arAntitrypsin Deficiency 276 Dysproteinemias 278 Heme Synthesis, Porphyrias 280 VIII Download From: AghaLibrary.com  Hormones F. Lang 282 General Pathophysiology of Hormones 282 — Abnormalities of Endocrine Regulatory Circuits 284 — Antidiuretic Hormone 286 — Prolactin 286 — Somatotropin — 288 Adrenocortical Hormones: Enzyme Defects in Production 290 — Adrenocortical Hormones: Causes of Abnormal Secretion 292 Excess Adrenocortical Hormones: Cushing’s Disease — 294 — Deficiency of Adrenocortical Hormones: Addison’s Disease 296 — Causes and Effects of Androgen Excess and Deficiency 298 Female Sex Hormone Secretion — 300 — Effects of Female Sex Hormones 302 — Intersexuality 304— Causes of Hypothyroidism, Hyperthyroidism, and Goiter Effects and Symptoms of Hyperthyroidism 308 306 — — Effects and Symptoms of Hypothyroidism 310 — Causes of Diabetes Mellitus 312 — Acute Effects of Insulin Deficiency ( Diabetes Mellitus) 314 — Late Complications of Prolonged Hyperglycemia (Diabetes Mellitus) — 316 Hyperinsulinism, Hypoglycemia 318 Histamine, Bradykinin, and Serotonin - 320 — - Eicosanoids 322 Neuromuscular and Sensory Systems F Lang. 324 ^ — Overview 324 Pathophysiology of Nerve Cells 326 — Demyelination 328 — Disorders of Neuromuscular Transmission 330 Diseases of the Motor Unit and Muscles 332 — — Lesions of the Descending Motor Tracts 336 — Diseases of the Basal Ganglia 338 — Lesions of the Cerebellum 342 — Abnormalities of the Sensory System 344 — Pain - 346 Diseases of the Optical Apparatus of the Eye 348 — Diseases of the Retina 350 — Abnormalities of the Visual Pathway and Processing of Visual Information 352 — Hearing Impairment 354 — Vestibular System, Nystagmus 356 — Olfaction, Taste 356 — Disorders of the Autonomic Nervous System 358 — IX Lesions of the Hypothalamus 360 —  — — The Electroencephalogram ( EEG ) 362 —— Epilepsy 364 Sleep Disorders 366 — Consciousness 368 Aphasia 370 — Disorders of Memory 372 —— — Alzheimer’s Disease, Dementia 374 Depression 376 Schizophrenia 378 — Dependence, Addiction 380 — — Cerebrospinal Fluid , Blood-Brain Barrier 382 Cerebrospinal Fluid Pressure, Cerebral Edema 384 — Disorders of Cerebral Blood Flow, Stroke 386 Further Reading 388 Index 391 X  ForJakob Stefan Silbernagl For Viktoria and Undine, Karl, Philipp, Lisa Florian Lang 1 1 Fundamentals. S Silbernagl and F Lang. Cell Growth and Cell Adaptation In the middle of the 19 th century Rudolf Vir- some division and migration to the poles) fol - chow first conceived his idea of cellular pathol- lowed by the telophase (formation of nuclear ogy, i.e., that disease is a disorder of the physio- envelope). Cytokinesis begins in the late stage logical life of the cell. The cell is the smallest of the anaphase with development of the cleav- unit of the living organism ( Wilhelm Roux ), age furrow in the cell membrane. After this a i.e., the cell ( and not any smaller entity ) is in a new phase begins. position to fulfill the basic functions of the Cells with a short life-span, so-called labile organism, namely metabolism, movement, re- cells, continually go through this cell cycle, production and inheritance. The three latter thus replacing destroyed cells and keeping the processes are made possible only through cell total number of cells constant. Tissues with la - division , although cells that can no longer bile cells include surface epithelia such as those divide can be metabolically active and are in of the skin, oral mucosa, vagina and cervix, epi- part mobile. thelium of the salivary glands, gastrointestinal With the exception of the germ cells, whose tract, biliary tract, uterus and lower urinary chromosome set is halved during meiotic divi- tract as well as the cells in bone marrow. The sion ( meiosis), most cells divide after the chro- new cells in most of these tissues originate mosome set has first been replicated, i.e., after from division of poorly differentiated stem cells mitosis ( so-called indirect division of the nu- (-> p. 30 ff.). One daughter cell (stem cell ) usu- cleus ) followed by division of the cell ( cytokine- ally remains undifferentiated , while the other sis). In this process, every cell capable of mitosis becomes differentiated into a cell which is no undergoes a cell or generation cycle ( -> A) in longer capable of dividing, for example, an which one mitosis ( lasting ca. 0.5 - 2 h ) is al- erythrocyte or granulocyte ( -> A ). Spermato- ways separated from the next one by an inter- genesis, for example, is also characterized by phase ( lasting 6 -36 h, depending on the fre- such differentiated cell division. quency of division ). Most importantly, the cell The cells of some organs and tissues do not cycle is governed by certain cycle phase-specif- normally proliferate (see below ). Such stable ic proteins, the cyclines. They form a complex or resting cells enter a resting phase , the G0 with a protein kinase, called cdc2 or p34cdc2, phase, after mitosis. Examples of such cells are which is expressed during all phases. When cy- the parenchymal cells of the liver, kidneys, and tokinesis is completed ( = end of telophase ; pancreas as well as connective tissue and mes- -» A), cells that continually divide ( so-called la- enchymal cells (fibroblasts, endothelial cells, , bile cells; see below ) enter the G phase ( gap chondrocytes and osteocytes, and smooth phase 1), during which they grow to full size, muscle cells ). Special stimuli, triggered by redifferentiate and fulfill their tissue-specific functional demand or the loss of tissue ( e.g., tasks ( high ribonucleic acid [ RNA] synthesis, unilateral nephrectomy or tubular necrosis ; re- then high protein synthesis ). This is followed moval or death of portions of the liver ) or tis- by the S phase, which lasts about eight hours. sue trauma ( e.g., injury to the skin ), must occur During this phase the chromosome set is dou- before these cells re-enter the G, phase bled ( high DNA synthesis ). After the subse- ( -» A , B ). Normally less than 1 % of liver cells di- quent G2 phase , which lasts about one to two vide ; the number rises to more than 10 % after hours ( high protein and RNA synthesis; energy partial hepatectomy. storage for subsequent mitosis ; centriole divi- The conversion from the G0 phase to the GA sion with formation of the spindle), the next phase and , more generally, the trigger for cell mitosis begins. The prophase ( dedifferentiation proliferation requires the binding of growth of the cell, e.g., loss of microvilli and Golgi ap- factors ( GFs ) and growth -promoting hormones paratus ; chromosomal spiraling) is followed ( e.g. insulin ) to specific receptors that are usu- by the metaphase ( nuclear envelope disap- ally located at the cell surface. However, in the 2 pears, chromosomes are in the equatorial case of steroid receptors these are in the cyto- plane). Then comes the anaphase ( chromo- plasm or in the cell nucleus ( -> C). The GF re- i— A. Cell Cycle Interphase: 6 - 36 h Prophase G2 \ I S ase: S- phase. DNA replication ilir'atinn Gap phase 2: Protein and RNA synthesis, centriole division 1- 2h ' / Metaphase uu ^ Adapt ion 83 h Cell ' A Mitosis: M n / and ^ Cyto esis ^ Gap phase 1 1:; Growth, differentiation a , -?/ m Growth. Anaphase 1 — 2h -r - r f Ej y Gap phase 0: v Cell Liver, kidney, etc. 1.1 * © G1 y. Telophase Plate M GO $ Stimulation of cell division by: Ultimately no further cell division e. g. nephrectomy, e. g. subtotal tubular necrosis hepatectomy Erythrocytes I Liver 'ii X J KidneyJL\ f Nerve cells Granulocytes B. Compensatory Hyperplasia Metabolic overload, stress, cytokines, etc. pr Expression of Hormones a (norepinephrine, f / protooncogenes (c-fos, c-myk) f insulin, glucagon) * \ * Growth factors (TGFa, HGF, etc.) t ^ Renewed cell division 3  ceptors are activated (usually tyrosine kinase unable to divide. Such cells include, among activity; -> p. 7 f., A 10), which results in phos- others, nerve cells in adults. The capability of phorylation of a number of proteins. Lastly, the regeneration of an adult’s cardiac and skeletal signaling cascade reaches the nucleus, DNA muscle cells is also very limited (-> e.g., myo- synthesis is stimulated and the cell divides cardial infarction; p. 234). (-» p. 16). Adaptation to changed physiological or un- In addition to tissue- specific growth factors physiological demands can be achieved ( e.g., hepatic growth factor [HGF] in the liver), through an increase or decrease in the number there are those with a wider spectrum of ac- of cells ( hyperplasia or aplasia; -> D, E ). This can tion, namely epidermal growth factor (EGF), be triggered by hormones ( e.g., development of transforming growth factor (TGF-a), platelet- secondary sex characteristics and growth of derived growth factor ( PDGF), fibroblast mammary epithelium during pregnancy) or growth factor ( FGF) as well as certain cytokines can serve the process of compensation, as in such as interleukin 1 and tumor necrosis factor wound healing or after reduction of liver pa-.. (TNF) Growth inhibition ( -> p 16) occurs, for renchyma (-> B ). Cell size may either increase example, in an epithelium in which a gap has ( hypertrophy ), or decrease ( atrophy ) (-> E ). been closed by cell division, when neighboring This adaptation, too, can be triggered hormon- Fundametls cells come into contact with one another (con- ally, or by an increase or decrease in demand. tact inhibition ). Even compensatory growth in While the uterus grows during pregnancy by the liver stops (-> B) when the original organ both hyperplasia and hypertrophy, skeletal mass has been regained. TGF-0 and interferon- and cardiac muscles can increase their strength P are among the signals responsible for this only by hypertrophy. Thus, skeletal muscles hy- 1 growth regulation. pertrophy through training (body-building) or The regeneration of labile and stable cells atrophy from disuse ( e.g., leg muscle in a plas- does not necessarily mean that the original tis- ter cast after fracture or due to loss of innerva- sue structure is reconstituted. For this to hap- tion). Cardiac hypertrophy develops normally pen, the extracellular matrix must be intact, as in athletes requiring a high cardiac output (cy- it serves as the guiding system for the shape, cling, cross-country skiing), or abnormally, for growth, migration, and differentiation of the example, in hypertensive people (-> p. 222 ff.). cell (-> C). The extracellular matrix consists of Atrophied cells are not dead; they can be reacti- fibrous structural proteins (collagen 1, 11 and V; vated — with the exception of permanent cells elastin) and an intercellular matrix of glycopro- ( brain atrophy). However, similar signal path- teins ( e.g., fibronectin and laminin) that are ways lead to atrophy and to “programmed cell embedded in a gel of proteoglycans and glyco- death” or apoptosis (-> p. 14), so that an in- saminoglycans. The extracellular matrix bor - creased number of cells may die in an atrophic ders on epithelial, endothelial, and smooth tissue ( -> D ). muscle cells in the form of basal lamina ( -> E). Metaplasia is a reversible transformation of Integrins are proteins of the cell membrane one mature cell type into another (-> E). This, that connect the extracellular matrix with the too, is usually an adaptive course of events. intracellular cytoskeleton and transmit signals The transitional epithelium of the urinary for the growth, migration, and differentiation bladder, for example, undergoes metaplasia to of the cell to the cell interior (-> C). If, as hap- squamous epithelium on being traumatized by pens in severe tissue damage, the matrix is ex- kidney stones, and so does esophageal epi- tensively destroyed (e.g., in a deep gastric ulcer thelium in reflux esophagitis ( -> p. 150 ff.), or.. [ -> p 156 ff ] or large skin wound), the original ciliated epithelium of the respiratory tract in tissue is replaced by scar tissue. In this case oth- heavy smokers. The replacement epithelium erwise resting cells of the connective tissue may better withstand unphysiological de- and mesenchyme also proliferate ( see above ). mands, but the stimuli that sustain lasting When so-called permanent cells have died metaplasia can also promote the development they can hardly be replaced, because they are of tumor cells ( -> p. 16). 4 r— C. Regulation of Cell Proliferation, Motility and Differentiation Growth- Ions Extracellular promoting matrix hormones Y Cell membrane i\ II Growth factors A Messenger W substances and Ions \ X\\ ^Cytoskeleton: Integrins * I ' Adapt ion other signals \ Cell Steroid Receptors 'YT and Growth hormones > Genome Cell nucleus v v Cell Synthesis of growth factors Differentiation Biosynthesis Form Adhesion Migration Proliferation 1.2. D Changes in Cell Population Plate Stimulated Proliferation Inhibited II Larger Inhibited Apoptosis Cell population - Stimulated ASmaller Stem cell population \ I Differentiation f Stem cell population larger smaller — E. Cell Adaptation Epithelial cells Basal lamina Reflux esophagitis Normal (esophageal epithelium) Pregnancy (uterus) Chronic gastritis Smoking (gastric epithelium) (respiratory Hypertension Sport epithelium) (heart) (heart, skeletal P aster cast Pregnancy (uterus) muscles) (skeletal muscles) \f \t \ - Metaplasia Hypertrophy — I Hyperplasia Atrophy - * ¥ * 5  Abnormalities of Intracellular Signal Transmission Most hormones bind to receptors of the cell Some peptide hormones and neurotrans- membrane (-> A 1-3). Usually through media- mitters, for example, somatostatin , adenosine tion of guanine nucleotide-binding proteins ( C , ( A receptor ), dopamine ( D2 receptor ), seroto- proteins ), the hormone-receptor interaction nin ( Sla ), angiotensin II, and acetylcholine ( M 2 causes the release of an intracellular second receptor ), act by inhibiting AC and thus re - messenger which transmits the hormonal sig- ducing the intracellular cAMP concentration , nal within the cell. A given hormone stimulates via an inhibiting G protein ( G; ) (-> A 2 ). Some the formation of different intracellular second hormones can , by binding to different recep- messengers. Abnormalities can occur if, for ex- tors, either increase the cAMP concentration ample, the number of receptors is reduced ( e.g., (epinephrine: p-receptor; dopamine: Dt recep- downregulation at persistently high hormone tor ), or reduce it ( epinephrine: a2- receptor; concentrations ), the receptor’s affinity for the dopamine: D2 receptor ). hormone is reduced , or coupling to the intra- The cAMP signaling cascade can be influ- cellular signaling cascade is impaired ( -> A; re- enced by toxins and drugs, namely cholera toxin ceptor defects ). from Vibrio cholerae, the causative organism of Fundametls The heterotrimeric C proteins consist of cholera, and other toxins prevent the deactiva- three subunits, namely a, J3, and y. When the tion of the as subunit. The result is the uncon- hormone binds to the receptor, guanosine 5'- trolled activation of AC and subsequently of triphosphate ( GTP) is bound to the a subunit in cAMP-dependent Cl- channels, so that unre- exchange for guanosine 5'-diphosphate ( GDP ), strained secretion of sodium chloride into the 1 and the a subunit is then released from the p gut lumen causes massive diarrhea (-» p.162 ). subunit. The a subunit that has been activated Pertussis toxin from Hemophilus pertussis, the in this way is then inactivated by dephosphory- bacillus that causes whooping-cough ( pertus- lation of GTP to GDP (intrinsic GTPase ) and can sis ), blocks the Gs protein and thus raises the thus be re-associated with the p-y subunits. cAMP concentration (disinhibition of AC). Numerous peptide hormones activate via a Forskolin directly stimulates AC, while xanthine stimulating G protein ( Gs ) an adenylyl cyclase derivatives , for example, theophylline or caf- (AC), which forms cyclic adenosine monophos- feine, inhibit phosphodiesterase and thus the phate ( cAMP) (-> A1 ). cAMP activates protein breakdown of cAMP (-> A 4 ). The xanthine de- kinase A ( PKA), which phosphorylates and rivatives are, however, mainly effective by acti- thus influences enzymes, transport molecules, vating purinergic receptors. and a variety of other proteins. cAMP can also In addition to cAMP, cyclic guanosine mono- be involved in gene expression via PKA and phosphate ( cGMP ) serves as an intracellular phosphorylation of a cAMP-responsive ele- messenger (-> A 5 ). cGMP is formed by guanylyl ment-binding protein ( CREB ). cAMP is convert-. cyclase cGMP achieves its effect primarily via ed to noncyclic AMP by intracellular phospho- activation of a protein kinase G ( PKG ). Atrial na- diesterases and the signal thus turned off. The triuretic factor (ANF ) and nitric oxide ( NO ) are following hormones act via an increase in intra - among the substances that act via cGMP. cellular cAMP concentration: corticotropin Other intracellular transmitters are 1,4,5- (ACTH ), lutotropin ( luteinizing hormone [ LH ]), inositol triphosphate ( IP3 ), 1,3,4,5-inositol tet- thyrotropin (TSH ), prolactin, somatotropin, rakisphosphate ( IP4 ), and diacylglycerol ( DAG ). some of the liberines ( releasing hormones A membrane- bound phospholipase C ( PLC ) [ RH ] ) and statins ( release-inhibiting hormones splits phosphatidylinositol diphosphate ( PIP2 ) [ RIH ] ), glucagon, parathyroid hormone ( PTH ), into IP3 and DAG after being activated by a G0 calcitonin, vasopressin ( antidiuretic hormone protein. This reaction is triggered by epineph- [ ADH ]; V2 receptors ), gastrin, secretin, vasoac- rine ( oq ), acetylcholine ( M, receptor ), histamine tive intestinal peptide ( VIP ), oxytocin, adeno- ( H, receptor ), ADH receptor ), pancreozymin sine (A2 receptor ), serotonin ( S2 receptor ), dop- ( CCK ), angiotensin II, thyrotropin-releasing 6 , amine ( D receptor ), histamine ( H2 receptor ) hormone (TRH ), substance P, and serotonin (S , and prostaglandins. receptor ). IP3 releases Ca 2+ from intracellular stores. Emptying of the stores opens Ca2+ chan- Transcription factors (-> A 9) regulate the nels of the cell membrane (-> A 6 ). Ca2+ can also synthesis of new proteins. They travel into the enter the cell through ligand -gated Ca2+ chan- nucleus and bind to the appropriate DNA se- nels. Ca2+, in part bound to calmodulin and quences, thus controlling gene expression. II through subsequent activation of a calmodu- Transcription factors may be regulated by + lin-dependent kinase ( CaM kinase ), influences phosphorylation ( see above ). I Transmio numerous cellular functions, such as epithelial The degradation of proteins is similarly un- transport, release of hormones, and cell prolif- der tight regulation. Ubiquitin ligases attach eration. DAG and Ca 2+ stimulate protein kinase the signal peptide ubiquitin at the respective C ( PKC ), which in turn regulates other kinases, proteins. Ubiquitinylated proteins are degraded transcription factors (see below ) and the cyto- through the proteasome pathway. Regulation skeleton. PKC also activates the Na +/ H+ ex- changer leading to cytosolic alkalization and an increase in cell volume. Numerous cell func- of ubiquitin ligases includes phosphorylation. Arachidonic acid, a polyunsaturated fatty acid , can be split from membrane lipids, in- Signal tions are influenced in this way, among them metabolism, I A 8). Ca2+ activates an endothelial NO synthase, which releases NO from arginine. NO stimu- lates, e.g., in smooth muscle cells, a protein ki- cluding DAG, by phospholipase A (-> A 10 ). Arachidonic acid itself has some cellular effects ( e.g., on ion channels ), but through the action of cyclo-oxygenase can also be converted to prostaglandins and thromboxane, which exert their effects partly by activating adenylyl cy- Intracelu of nase G, which fosters the Ca2+ extrusion, de- creases cytosolic Ca2+ concentration and thus leads to vasodilation. NO also acts through ni- trosylation of proteins. Insulin and growth factors activate tyrosine clase and guanylyl cyclase. Arachidonic acid can also be converted to leukotrienes by lipoxy genase. Prostaglandins and leukotrienes are especially important during inflammation (-> p. 52 ff.) and not only serve as intracellular - Disorde kinases (-> A 8), which can themselves be part messengers, but also as extracellular mediators of the receptor or associate with the receptor (-> p. 322 ). Lipoxygenase inhibitors and cyclo - upon stimulation. Kinases are frequently effec- oxygenase inhibitors, frequently used thera- tive through phosphorylation of further ki- peutically ( e.g., as inhibitors of inflammation nases, triggering a kinase cascade. Tyrosine ki- and platelet aggregation ), inhibit the formation nases, for instance, activate-with the involve- of leukotrienes and prostaglandins. — ment of the small G-protein Ras the protein kinase Raf, which triggers via a MAP-kinase-ki- Some mediators ( e.g., the tumor necrosis factor [TNF] and CD95 [ Fas/Apol ] ligand ) acti- nase the MAP ( mitogen activated ) kinase. This vate acid sphingomyelinase , which forms cer- “ snowball effect” results in an avalanche-like in- amide from sphingomyelin (-> A 11 ). Ceramide crease of the cellular signal. The p-38 kinase and triggers a series of cellular effects, such as acti- the Jun kinase that regulate gene expression via vation of small G proteins ( e.g., Ras ), of kinases, transcription factors are also activated via such phosphatases, and caspases, i.e. proteases cascades. Janus kinases (JAK ) activate the tran- which cleave proteins at cysteine-aspartate scription factor STAT via tyrosine phosphoryla- sites. The effects of ceramide are especially im- tion, thereby mediating the effects of interfer- portant in signal transduction of apoptotic cell ons, growth hormones, and prolactin. Activin, death (-> p. 14 ). anti-mullerian hormone, and the transforming Steroid hormones (glucocorticoids, aldoste- growth factor TGF- p regulate the Smad tran- rone, sex hormones ), thyroid hormones (TR), scription factors via a serine/threonine kinase. calcitriol ( VDR ), retinoids ( RAR), and lipids Phosphorylated proteins are dephosphory- ( PPAR) bind to intracellular ( cytosolic or nucle- lated by phosphatases, which thus terminate ar ) receptor proteins (-> A12 ). The hormone- re- the action of the kinases. The Ca2+-activated ceptor complex attaches itself to the DNA of the phosphatase calcineurin activates the transcrip- cell nucleus and in this way regulates protein tion factor NFAT, which, among other actions, synthesis. Hormones can also block transcrip- promotes hypertrophy of vascular smooth mus- tion. For instance, calcitriol inhibits transcrip- 7 cle cells and activation of T-lymphocytes. tion factor NFKB ( p. 10 ) through the vitamin D receptor ( VDR).  i— A. Intracellular Signal Transmission and Possible Disorders Inhibitory hormones Stimulating hormones Receptor o Growth factors, o defects 1 2 insulin, etc. , i sv Mutations: RB Oncogenes \ Activated G | protein 8 N Steroid \ Activated Gs protein a: GTP hormones \ \\ \ Fundametls 1 \\ \ XP \ \ \ \ GDP ^ GTP Cholera toxin Forskolin Adenylyl Pertussis toxin Phospho- diesterase GDP cyclase Xanthine ATP derivatives cAMP AY7 Kinase cascade AMP 12 * Intracellular receptor L Protein kinase A Cell nucleus DNA Receptor defects Signal Intracelu o R0 fU fO 3 O zr ZJ Zl Activated of / Disorde G0 protein 6 P a0 / II GTP + I > Phospholipase inhibitor 1.4 Transmio Phospho- # lipase C + Ca 2+ > Y\ Phospho- 10 1.3 lipase A stored in organelles Plate DAG Arachidonic IP3 Lip- acid oxygenase LO inhibitor S / Cyclo- Phorbol ester oxygenase Leukotriene Protein kinase C CO inhibitor Calcineurin Prostaglandins I < > NO NOS Calmodulin Guanylyl cyclase Guanylyl anylyl cyclase *** 5 GTP GTP Protein TNF cGMP / CaM kinase G kinase Ceramide ^ Sphingomyelinase " ?Sphingomyelin enzymes, transport proteins » 9 Cell interior Cell membrane  - - PI3 Kinase Dependent Signal Transduction The phosphatidylinositol -3-kinase ( PI3-kinase ) hamartin ( tuberin sclerosis complex, TSC ). TSC is bound to phosphorylated tyrosine residues inactivates the small G - protein Rheb (-> A 9 ). and associated IRS 1 ( insulin receptor substrate Activated Rheb stimulates the kinase mTOR 1 ) of activated growth factor and insulin re - ( mammalian target of rapamycin ), a protein ceptors (-> A1 ). The PI 3-kinase generates that stimulates cellular substrate uptake, pro - PI3 4 5 P3 ( phosphatidylinositol-3,4, 5-triphos - tein synthesis , and cell proliferation. The inhi- phate ), which is anchored in the cell mem- bition of tuberin by PKB /Akt therefore stimu- brane. PI3 4 5 P3 binds to PDK1 ( phosphoinosi - lates mTOR. Conversely, TSC is stimulated and tide - dependent kinase 1 ) and protein kinase B thus mTOR is inhibited by the AMP-activated ( PKB /Akt ). PDK1 then phosphorylates and thus kinase (AMPK ). Energy depletion increases the activates PKB/Akt ( -> A 2 ). It is inhibited by cal - cellular AMP concentration and thus activates citriol ( p. 7 ). AMPK, which in turn inhibits mTOR. PKB /Akt stimulates several transport pro - PKB /Akt phosphorylates, and thereby inacti- cesses , such as the glucose carrier GLUT4 ( -> A 3). vates, glycogen synthase kinase 3 ( GSK3a and It phosphorylates and thus inactivates the anti- GSK3|3 ) ( -> A10 ). The GSK3 is further inhibited Fundametls proliferative and proapoptotic forkhead tran- by the growth factor Wnt , an effect involving scription factor FKHRL 1 ( FoxOl ) and thus fosters the frizzled receptor and the dishevelled pro - cell proliferation and counteracts apoptosis tein. GSK3 binds to a protein complex consist- (-> A 4). PKB /Akt further phosphorylates and ing of axin, von Hippel-Lindau protein ( vHL), thereby activates MDM 2, which inhibits the and adenomatous polyposis coli (APC ). The 1 proapoptotic transcription factor p53 (-> A 5). complex binds the multifunctional protein p- PDK1 and PKB /Akt regulate gene expression catenin. GSK3 phosphorylates (3-catenin, thus further via the transcription factor NFKB triggering its degradation. p-Catenin may bind (-> A 6 ). NFKB is bound to the inhibitory protein to E-cadherin, which establishes a contact to IKB and is thereby retained in the cytosol. IKB is neighboring cells. Free (3-catenin travels into phosphorylated by IKB kinase ( IKK ) leading to its the nucleus, interacts with the TCF/ Lef tran- ubiquitinylation and degradation. In the ab- scription complex and thus stimulates the ex- sence of IKB, NFKB travels into the nucleus and pression of several genes important for cell stimulates gene expression. Functions stimulat- proliferation. Wnt and activated PKB /Akt foster ed by NFKB include the synthesis of extracellular cell proliferation in part through inhibition of matrix proteins favoring the development of fi- GSK3 and subsequent stimulation of (3 - cate- brosis. PKB /Akt phosphorylates and thereby ac- nin-dependent gene expression. tivates IKK leading to activation of NFKB. The IKK PDK1 phosphorylates and thereby activates is further activated by TNF-a and interleukin 1. serum- and glucocorticoid-inducible kinase PKB /Akt phosphorylates Bad (-> A 7 ), a pro- ( SGK 1 ). The expression of SGK 1 is stimulated tein stimulating the release of cytochrome c by glucocorticoids, mineralocorticoids, TGF- p , from mitochondria and thereby triggering hyperglycemia, ischemia, and hyperosmolarity. apoptosis (^ p. 14 ). Phosphorylated Bad is SGK1 stimulates a variety of carriers, channels, bound to protein 14-3-3 and is thus prevented and the Na+/ K+ ATPase. The kinase shares sever- from interacting with mitochondria. PKB /Akt al target proteins with PKB /Akt. Following stim- phosphorylates and thereby inactivates cas - ulation of its expression , it may play a leading pase 9, a protease similarly involved in the sig- part in PI3K-dependent signaling. SGK1 pro - naling cascade leading to apoptosis ( -> p. 14 ). motes hypertension, obesity, development of Accordingly, PKB /Akt inhibits apoptosis. diabetes , platelet activation, and tumor growth. PKB /Akt phosphorylates and thereby acti- The phosphatase PTEN dephosphorylates vates NO synthase. NO may similarly inhibit PI3 4 5 P3 and thereby terminates PI3 4 -de - apoptosis. PKB /Akt activates p47phox and thus ^ pendent signal transduction (-> A11 ). Accord- stimulates the formation of reactive oxygen ingly, PTEN inhibits cell proliferation. Oxidative 10 species ( ROS ) (-> A 8). stress ( -> p. 92 ) inactivates PTEN and thus in- PKB /Akt phosphorylates and thereby inac- creases the activity of Akt/ PKB and SGK. tivates tuberin, which forms a complex with  A. PI3 Kinase- Dependent Signal Transduction Growth factors Transductio ROS BAD Apoptosis Receptor |Rg1 P P ^ p47Phox 1 0 CO Signal Nr PlPo I 1_ Q 8 P BAD Depndet 14- 3- 3 PDK 1 > IKK PIP3 6 Inhibitor protein -. Kina-se 2 ,r P >r IKB P NFKB Nr 3 P PI PKB/ Akt > NOS V Degradation 1.5 NO Plate 8\ 11 PTEN 3 8 GLUT4 Nr 10 V. MDM2 Glucose TSC : r. GSK3 Wnt FRZ ^ Axin APC ) 9 4 5 P -catenin // ^ Rheb. 2I p-catenin P p53 Cadherin P i N/ FKHRL1 Degradation Nr £ — mTOR Substrate ^ J Protein expression Cell Cell proliferation membrane Cell nucleus 11  Necrotic Cell Death The survival of the cell is dependent on the occur when Na+ entry exceeds the maximal maintenance of cell volume and the intracellu- transport capacity of the Na+/ K+-ATPase. Nu- lar milieu (-> A). As the cell membrane is highly merous endogenous substances ( e.g., the neu- permeable to water, and water follows the os - rotransmitter glutamate) and exogenous poi- motic gradient ( -> A 1), the cell depends on sons (e.g., oxidants) increase the entry of Na + osmotic equilibrium to maintain its volume. In and/ or Ca2+ via the activation of the respective order to counterbalance the high intracellular channels (-> B). concentration of proteins, amino acids, and The increase in cytosolic Na+ concentration other organic substrates, the cell lowers the cy- not only leads to cell swelling, but also, via im- tosolic ionic concentration. This is accom- pairment of the 3Na+/Ca2+ exchanger, to an in- plished by the Na+/K+- ATPase, which pumps crease in cytosolic Ca2+ concentration. Ca2+ Na+ out of the cell in exchange for K+ ( -> A 2)... produces a series of cellular effects (-> p 6 ff ), Normally the cell membrane is only slightly including penetration into the mitochondria permeable for Na+ (-> A 3 ), but highly perme- and, via inhibition of mitochondrial res- able for K+, so that K+ diffuses out again piration, ATP deficiency (-> B ). Fundametls (-» A 4). This K+-efflux creates an inside nega- If there is a lack of 02, energy metabolism tive potential (-> A 5 ) which drives Cl- out of switches to anaerobic glycolysis. The formation the cell (-> A 6 ). The low cytosolic Cl- concen- of lactic acid, which dissociates into lactate and tration osmotically counterbalances the high H+, causes cytosolic acidosis that interferes cytosolic concentration of organic solutes. The with the functions of the intracellular enzymes, 1 Na+/K+-ATPase uses up adenosine 5'-triphos- thus resulting in the inhibition of glycolysis so phate (ATP) and maintenance of a constant cell that this last source of ATP dries up ( -> B ). The volume thus requires energy. generation of lactate further leads to extracel- Reduction in cytosolic Na+ concentration by lular acidosis, which influences cell function the Na+/K+-ATPase is necessary not only to through H+-sensing receptors and channels. avoid cell swelling, but also because the steep During energy deficiency, the cell is more electrochemical gradient for Na+ is utilized for likely to be exposed to oxidative damage, be- a series of transport processes. The Na+/ H+ ex- cause the cellular protective mechanisms changer (-> A 9 ) eliminates one H+ for one Na+, against oxidants ( 02 radicals) are ATP-depen- while the 3 Na+/Ca2+ exchanger (-» A 8 ) elimi- dent ( -> B). Oxidative stress may destroy the nates one Ca2+ for 3 Na+. Na+-bound transport cell membrane (lipid peroxidation) and intra- processes also allow the ( secondarily) active cellular macromolecules may be released in uptake of amino acids, glucose, phosphate, etc. the intracellular space. As the immune system into the cell (-> A 7 ). Lastly, depolarization is not normally exposed to intracellular macro- achieved by opening the Na+ channels molecules, there is no immune tolerance to ( -> A 10) serves to regulate the function of ex- them. The immune system is activated and in- citable cells, e.g., signal processing and trans- flammation occurs, resulting in further cell mission in the nervous system and the trigger- damage. ing of muscle contractions. The time-span before necrotic cell death oc- As the activity of Na+-transporting carriers curs due to interruption of energy supply de- and channels continuously brings Na+ into the pends on the extent of Na+ and Ca2+ entry, and cell, survival of the cell requires the continuous thus, for example, on the activity of excitable activity of the Na+/ K+-ATPase. This intracellular cells or the transport rate of epithelial cells. As Na+ homeostasis may be disrupted if the activ- the voltage-gated Na+ channels of excitable ity of the Na+/ K+-ATPase is impaired by ATP de- cells are activated by depolarization of the cell ficiency (ischemia, hypoxia, hypoglycemia). The membrane, depolarization can accelerate cell intracellular I Na+ channels Osmotic equilibrium t 6 7 1Ca2+ 8 H+ 9H Na+ y/ Death Cell Amino acids, glucose , etc. Na+ 3 Na+ Na+. 4- ^— V — r— V — K+ Necroti 1.6 Cellular K+ transport processes or Cl 0 ® Plate r- B. Necrosis Poisoning Endogenous substances (e. g. oxidants) (e. g. glutamate) Hypoglycemia Hypoxia, ischemia Cell activity (excitation, transport) c. deficiency Phospho- O Glucose deficiency ° 2 |ipase Lactate A Mitochondrial Ca w respiration * Na 7^ 7- - V- Anaerobic glycolysis % ATP| p. 2 ff.). Apoptosis, as op- tion of the CD95 ( Fas/ Apol ) receptor or the posed to necrosis (-> p.12 ), is programmed withdrawal of growth factors ( GFs ). DNA dam- cell death and , like cell division (-> p. 2 ff., 16 ), age encourages apoptosis via a p53 protein. In is a finely regulated physiological mechanism. ischemia, for example, the affected cells some- Apoptosis serves to adapt the tissue to chang- times express the CD95 receptor and thus enter ing demands, to eliminate superfluous cells apoptosis. In this way they “ anticipate necrotic during embryonic development and to remove cell death” and so prevent the release of intra- harmful cells such as tumor cells, virus-infected cellular macromolecules that would cause in- cells, or immune-competent cells that react flammation (-> p. 12 ). against the body’s own antigens. Pathologically increased apoptosis ( H> B ) Apoptosis is mediated by a signaling cascade may be triggered by ischemia, toxins, massive (-» A): the stimulation of distinct receptors ( see osmotic cell shrinkage, radiation , or inflamma - below ), excessive activation of Ca 2+ channels, tion (infections, autoimmune disease ). The Fundametls oxidative stress, or cell injury by other mecha- apoptosis may result in the inappropriate nisms leads to activation of protein-cleaving death of functionally essential cells, leading to caspases and of a sphingomyelinase that re- organ insufficiency (-> B ). In this way apoptosis leases ceramide from sphingomyelin. Incorpo- will, for example , bring about transplant rejec- ration of the proteins Bak or Bax into the mito- tion, neuronal degeneration ( e.g., Parkinson’s or 1 chondrial membrane leads to depolarization of Alzheimer’s disease, amyotrophic lateral scle- the mitochondria and cytochrome c release, ef- rosis, quadriplegia, multiple sclerosis ) as well fects inhibited by the similar proteins Bcl-2 and as toxic, ischemic, and /or inflammatory death Bcl-xL. The effect of Bcl-xL is in turn abrogated of liver cells ( liver failure ), of B cells of the by the related protein Bad. After binding to the pancreatic islets ( type 1 diabetes mellitus ), of APAF-1 protein , cytochrome c released from erythropoietic cells (aplastic anemia ), or of the mitochondria activates caspase 9. The cas- lymphocytes (immunodeficiency, e.g., in HIV cade eventually results in the activation of cas- infection ). pase 3, which stimulates an endonuclease lead- Pathologically reduced apoptosis leads to an. ing to DNA fragmentation The protease cal- excess of affected cells (-» C). Among the causes pain is activated , which degrades the cyto- are disorders of endocrine or paracrine regula - skeleton. The cell loses electrolytes and organic tion, genetic defects , or viral infections ( e.g., osmolytes, proteins are broken down, and the with the Epstein-Barr virus ). Absent apoptosis cell finally shrinks and disintegrates into small of virus-infected cells can result in persistent particles. Scrambling of the cell membrane infections. Cells that escape apoptosis can de- leads to phosphatidylserine exposure at the velop into tumor cells. Insufficient apoptosis of cell surface, which fosters the binding and sub- immunocompetent cells, directed against the sequent engulfment of cellular particles by body’s own cells, is a cause of autoimmune dis- macrophages. In this way the cell disappears ease (-> p. 60 ). In addition, an excess of cells can without intracellular macromolecules being cause functional abnormalities, for example, released and, therefore , without causing in- persistent progesterone formation in the ab- flammation. PKB /Akt inhibits apoptosis by sence of apoptosis of the corpus luteum cells. phosphorylation and thus inactivation of Bad , Lack of apoptosis can also result in abnormal caspase 9, and proapoptotic forkhead tran- embryonic development ( e.g., syndactyly ). scription factors (-> p. 10 ). 14  A. Triggering and Development of Apoptosis CD95 JO -L L 1 TNF -a K+, or, HCO3 " Organic osmolytes X t -> > *Zi XJ Ischemia Energy 1 Phagocytosis deficiency / Ceramide Oxidative 2 Ca * // * -.11 Apotic stress Osmotic B ). In stage I ( > 32 °C), warming is done pas- 2 latory range) and infants (especially newborns ), sively and externally ( warm room, blankets, who have a relatively high ratio of body surface foil). In stage II, active warming must be under- area to mass, low resting heat production, and taken ( electric blankets, warm infusions, possi- a thin subcutaneous fat layer, are particularly at bly hemodialysis with heat exchanger) under risk. While unclad young adults can maintain a. careful monitoring In stage III hypothermia constant core temperature, even when the am- with circulatory arrest, active warming by bient temperature drops to ca. 27 °C because of