Introduction to Clinical Medicine and Pathology (PDF)

MMI 3013/HON 3253/MMI 6613 Intro to Clinical Medicine Lecture 1 Introduction to Clinical Medicine and Pathology (and a little history) Thomas G. Forsthuber, M.D. Dr. Med. Professor of Immunology Office: BSE 3.250B Office hours: Monday, 4:30 – 5:...

MMI 3013/HON 3253/MMI 6613 Intro to Clinical Medicine Lecture 1 Introduction to Clinical Medicine and Pathology (and a little history) Thomas G. Forsthuber, M.D. Dr. Med. Professor of Immunology Office: BSE 3.250B Office hours: Monday, 4:30 – 5:30 PM per Zoom or in-person E-mail: [email protected] How the class works: This course will be more fun if you participate This course is an introductory course to human diseases and underlying disease concepts Ask if you have questions First, we will discuss basic medical/pathological principles. Then we will discuss specific diseases During each lecture we will present a “case of the day” Illness does not look pretty. Be prepared for some graphic images. We will do Kahoots for review and fun This is the nature of medicine. You have been warned. There will be 4 multiple choice exams. Best 3 out of 4 count for The syllabus for the class explains the most important questions grade. Attendance at in-person lectures is required. Grading scheme and other information is in the syllabus Follow University Health and Safety guidelines (e.g. Covid, Flu) Recording of class content including live lectures is not Handouts will be posted on Canvas (before class if possible) allowed except under conditions outlined in syllabus. Exams are based on handouts. Please don’t take pictures. We will use parscore forms for exams Distribution of lecture content, including live lectures, is Grades will be posted ASAP after the exam strictly prohibited. No extra credit or make-up exams Second course will be offered during Spring semester with additional medical concepts in a group-based case presentation format (BIO 4473, Advanced Clinical Medicine). Pre-req is the present course. Handouts for the lectures will be posted before (if possible) each class Suggested Books for additional reading: Kumar, Abbas, Aster: Robbins Basic Pathology (Elsevier-Sounders, 10th edition or higher, ISBN 9780323353175; suggested) (~$91.99) Kumar, Abbas, Fausto, Aster: Pathologic Basis of disease (Elsevier- Sounders, 8th edition or higher, ISBN 978-1-4160-3121-5) MedScape for further readings: https://www.medscape.com/for-you StatPearls: https://www.ncbi.nlm.nih.gov/books/NBK430685/ Fun facts: The beginnings of “medicine” Today we will: Chinese traditional medicine over 5000 years old The Sumerians (Mesopotamia/today Syria/Iraq) and Egyptians knew about disease states and Briefly talk about the history of medicine had healers and specialists (3000 BC) Introduce some important and useful general medical Diseases were caused by bad spirits, worms, principles intestinal decay, punishment from the gods Today Introduce common clinical lab and diagnostic tests Greece is generally considered the cradle of modern Western medicine Greek medicine moved away from “supernatural” to natural causes, observation and logical thinking Greek Medicine revolved around the four “humors”: blood, phlegm, yellow bile, black bile. Not “science” but a step to form theories Greeks did not test their theories (no human anatomical studies or autopsies).  Imhotep Edwin Smith Papyrus © Jeff Dahl - Fragment from the Edwin-Smith Papyrus Two noteworthy ancient doctors Imhotep – “the one who comes in peace” (probably 2650 BC): pyramid builder and physician to the pharaoh Professional title: “Shepherd of the anus” Hippocrates (460-377 BC) founded a school of physicians whose writing have been preserved. He is credited with the Hippocratic Oath. He was instrumental in developing the four-humor theory. Earliest known writing on medicine Purchased in 1862 by Edwin Smith, American Egyptologist, from Mustafa Agha Imhotep speculated to be original author Includes information on trauma surgery, anatomy, diagnosis and treatment of 48 medical conditions including heart failure! Imhotep rejected “magic” in favor of science for healing Romans advanced Greek medicine Hippocrates (460 BC) Celsus (Aulus Celsus, roman writer/physician: 30 BC – 38 AD) identified the cardinal signs of inflammation. – He translated the work cancer from “crab” like growth described by the Greeks (Hippocrates). – He wrote “De Medicina”, a book on surgery, diet, pharmacy, etc. which still exists. Galen (Claudius Galenus, 129-201 AD, Greek physician. Considered one of the greatest physicians of all times. He worked as a physician to the Roman gladiators. His writings guided medicine for 1,500 years into the Middle Ages. Worked for roman emperor Claudius Aurelius and his son. Was the first to describe that: Arteries are filled with blood instead of “pneuma” (air). Urine is produced by kidneys Hippocratic Oath Spinal cord and spinal nerves control muscle function Hippocratic school taught careful observation, careful The heart is the origin of blood vessels, brain origin of nerves reporting of symptoms, use of observation for Sensory nerves are different from motor nerves prognostication Since he couldn’t do autopsies on humans so he got some facts Instrumental in developing the theory of the four humors wrong (he studied monkeys).  Edward Jenner (1749-1823) Medicine transforms into a science: Introduced first systematic vaccination Medicine did not advance beyond the teachings of Galen until the He discovered that cowpox could protect against smallpox Renaissance (13th – 14th century) – no substantial advancements) Leonardo da Vinci (1452-1519) learned from human dissection about the functions of muscles, bones, and tendons. William Harvey (1578-1657) Discovered that the blood is moved through the body by the heart (famous book ‘De Motu Cordis et Sanguinis’) Rudolf Virchow (1821-1905) introduced the concept of cellular pathology – diseases arise from alterations within cells and tissues using microscopic observation Ignaz Semmelweis (1818-1865) Robert Koch (1843-1910) Founder of modern bacteriology Established that sanitary conditions in surgery and the healthcare setting saves countless lives He compared childbed fever in maternity wards staffed by midwife vs doctors and medical students He became known as the “savior of mothers” Discovered causes of tuberculosis, cholera, anthrax  Louis Pasteur (1822-1895) The first “cellular pathologist”: Rudolf Virchow Ilustrierte Zeitung Berlin, 1902 Virchow is frequently called the “Father of modern Pathology” Credited with first recognizing leukemia Virchow’s node: enlarged left supra-clavicular lymph node as early sign of gastric cancer Discovered principles of vaccination, fermentation, and pasteurization Discovered pulmonary thromboembolism (he coined the term embolism) Discovered first vaccines for rabies and anthrax Founded cellular pathology and encouraged his students to think “cellular” and use microscopes “The only source for a living cell is another living cell” Sir Joseph Lister (1827-1912) Sigmund Freud (1856-1939) Father of psychoanalysis Father of antiseptic surgery Used phenol to sterilize instruments, wounds, dressings  George Papanicolaou (1883-1962) Sir Alexander Fleming (1881-1955) He discovered that vaginal smear could detect uterine cancer (1943) Discovery of penicillin and research on lysozyme He was a pioneer in early cancer detection He noticed in 1928 that mold (Penicillium notatum) inhibited the growth of Staphylococcus aureus on a culture plate Basic Principles of Human Disease The four pillars to understanding disease: Human diseases in the broadest sense are undesired deviations from the Disease etiology: the cause(s) of a disease. norm (the “generally accepted standard”) – Infection, injury, genetic defects, – Example: Streptococcus pneumonia infection of the lungs Diseases are usually detected if they cause signs or symptoms Pathogenesis: the disease process – Signs: Fever, high blood pressure, bleeding = can be seen by doctor, – Example: Streptococcus infection of the lung leads to lung detected by clinical tests (for example X-ray) damage, inflammation, fluid accumulation – Symptoms: pain, drowsiness, vertigo = reported by the patient, cannot Lesion = Morphologic changes/ultrastructural : structural changes in the affected tissues be measured. – Example: Bacterial pneumonia leads to lobar consolidation, inflammatory infiltrates, lung edema Some diseases are predetermined: example - genetic defects Functional changes = impaired function of an organ system = Some diseases are acquired: example - infection, trauma, degenerative clinical manifestation – Example: Lobar bronchopneumonia, fever, pain, malaise, possibly death! Some diseases can be seen by eye: example - jaundice Pathogenesis Functional Some diseases may be visible only with medical tests, imaging: example – Etiology Lesion changes pigment or inclusions visible in cells by microscope, urine protein.  How to recognize diseases (pathologic The diagnosis begins with observation alterations): A) The right arm is affected Reported by the patient (e.g. pain, nausea) B) The left arm is affected Gross examination: The alteration (lesion) is visible by naked eye (physical examination, autopsy) Histologic examination: Alterations are visible by microscope Laboratory examination: e.g. blood tests, urine sample, DNA test Specialized examinations: X-ray, ultrasound, endoscopy, magnetic resonance imaging, The scientific foundation for the cardinal signs of inflammation: The “old” physicians recognized “disease”: The four phases of acute inflammation: Celsus (30 BC – 38 AD) I. 0 – 4 hours: preformed factors: The four cardinal signs of acute inflammation: Antibodies, complement, serum Calor (heat) factors, vasoactive factors, Dolor (pain) CS: RUBOR, CALOR, Rubor (redness) II. 4 - 48 hours: influx of Tumor (swelling) neutrophils CS: RUBOR, CALOR, DOLOR, Galen (129-201 AD) TUMOR Fifth sign: functio laesa = Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 14 August 2006 10:46 PM) III. 24-96 hours: influx of Impaired function macrophages CS: RUBOR, CALOR, DOLOR, TUMOR, FUNCTIO LAESA WebPath IV. > 96 hours: adaptive immunity: T lymphocytes are activated and migrate to inflammatory site CS: DOLOR, TUMOR, FUNCTIO LAESA  Intro to Clinical Medicine Before we test: How do we arrive at a clinical diagnosis? Diagnostic Tests Information about the current illness/problem of the patient – Most important: is it an emergency/life threatening The patient history Thomas G. Forsthuber, M.D. Dr. Med. The physical examination Professor of Immunology, Adjunct Professor of Molecular Microbiology, and Immunology Office: BSE 3.250B Diagnostic tests E-mail: [email protected] Office Hours: Monday 4:30 – 5:30 pm Current illness: The patient history When did the symptoms/signs start? Circumstances? – Current and past medical history Is this the first time the patient had these symptoms? – Are there other concurrent medical problems? Are the symptoms getting worse, better, or remain stable? – Other patient issues that could be relevant: Smoking? What steps did the patient take? Did anything help or change? Alcohol, Drugs Social issues, employment, job loss If the patient had this in the past, was there a significant change? – Family history – Any other information that might help with the case  The physical examination Diagnostic tests and procedures – Cultivate the art of observation Non-invasive procedures: – Be systematic in your examination – Eye/ear/throat inspection, neurological test of reflexes, – Develop a routine that you follow – Urine test, throat swab – Know your tools (i.e. the stethoscope!) – X-ray, ultrasound, MRI, CT, ECG, – The future: mobile ultrasound devices – Note: If it does not break the skin it is considered non-invasive (fancy!) Invasive procedures: – Blood draw, spinal tap, biopsy, endoscopy, – Note: If it breaks the skin it is considered invasive! Note: There is no generally accepted definition for “invasive procedure” I. Common Lab tests: Common blood tests: - CBC – Complete blood count (+ Diff) Other important lab tests: - CMP - Comprehensive metabolic panel - Urine: protein, microorganisms, pH, blood, Electrolytes (Na, K, Cl, Ca), glucose, - Stool – blood, parasites, fat blood urea nitrogen (BUN), creatinine - Cerebrospinal fluid, cells, proteins, microorganisms (Crea), liver enzymes (AST, ALT), etc. - Plasma proteins (albumin, enzymes, immunoglobulins - Antibodies (serologic tests) - Hormones (e.g. thyroid hormones) - Disease biomarkers (e.g. for myocardial infarct, pancreatitis, liver disease, renal Pictures courtesy WebPath (Utah) disease) Dr. Edward Klatt, MD - Erythrocyte sedimentation rate = ESR (today only useful for myeloma, temporal arteritis, polymyalgia rheumatica) - Drugs  Blood is routinely analyzed in medicine White Blood Cells (WBC) Sysmex analyzer for CBC (complete blood count): Blood: CBC (complete blood count): RBC: 5 x 10e6/ul Hb: g/100 ml (normal 14 – 16 g/ dL = dL = 100 ml (1/10 of a liter) Pictures courtesy WebPath (Utah) Dr. Edward Klatt, MD Common terms for abnormal CBC CBC in medical charts (Fishbone) Type of Cell Increase Decrease erythrocytosis or anemia or Red Blood Cells (RBC) polycythemia erythroblastopenia White Blood Cells Hgb leukocytosis leukopenia (WBC): 16 -- lymphocytes -- lymphocytosis -- lymphocytopenia WBC Plt -- granulocytes: -- granulocytosis -- granulocytopenia or 8.9 275 agranulocytosis -- --neutrophils -- --neutrophilia -- --neutropenia -- --eosinophils -- --eosinophilia -- --eosinopenia Platelets thrombocytosis thrombocytopenia All cell lines --- pancytopenia www.wikipedia.com  II. Measuring electrical activity for diagnostic purposes Electrocardiogram (ECG, EKG): Measures electrical activity of the heart Electroencephalogram (EEG): electrical activity of the brain Electromyogram (EMG): electrical activity of muscle lused in Neurology to diagnose Als , Ms , mysthenia gravis) ECG (also EKG) Electric conduction of the heart Typical ECG strip Sinus node QRS (+) (SA node) ECG T AV node P P wave: atrial depolarization -controlledbea QRS complex: ventricular depolarization T wave: repolarization of the ventricle SA node = sinoatrial node AV node = atrioventricular node Mnemonic: Dog and the cookie  II. Measuring electrical activity ST-elevation in MI Not good: Bad: Ventricular flutter 250-300 beats/min Sinusoidal waves V-FIB Worse: Ventricular Fibrillation: no clear electrical activity  Intro to Clinical Medicine Diagnostic Tests Part 2 Thomas G. Forsthuber, M.D. Dr. Med. Professor of Immunology, Adjunct Professor of Molecular Microbiology, and Immunology Office: BSE 3.250B E‐mail: [email protected] Office Hours: Monday 4:30 – 5:30 pm X‐Ray examination ‐ X‐rays were discovered by Wilhelm Roentgen in 1895. ‐ He worked with electron beams (a cathode‐ray tube) in his lab and discovered that a fluorescent screen nearby started glowing. ‐ He found that X‐rays could go through tissue, but not bones and metal, and could expose photographic film. ‐ X‐rays (and gamma rays) are electromagnetic radiation (photons) similar to light but of much shorter wavelength (much higher energy level). ‐ Light has wavelength of 6000 angstroms, X‐rays are 1 angstrom (0.1 nm), and gamma rays are 0.0001 angstrom. ‐ X‐rays and ionizing radiation is measured in Sievert (Sv). ‐ It used to be measure in rem (Roentgen equivalent in man). ‐ Sievert is used to measure the radiation dose to the human body ‐ 1 Sv = 100 rem ‐ 1 rem = 0.01 Sv  How much radiation is dangerous? Chernobyl control 1Sv = 100 rem room: 300 Sv/hr (30,000 rem) Death in 1 minute! Equal to 1,000 chest x‐rays Chernobyl control room tourism: Equal to 20 chest 1.13 mSv/5 x‐rays minutes ~10 X‐ rays per 5 minutes X‐ray continued X-ray photons  Digitizing of X‐ray images with photostimulable phosphor plates Excited electrons trapped in phosphor “color centers” ‐> Luminescence ‐> Source: Wiki Computed tomographic Scan (CT) https://www.youtube.com/watch?v=l9swbAtRRbg CT uses motorized scanner that circles around patient CT obtains many serial x‐ray images that are then compiled to a 3‐D image Intermountain Medical Imaging, Boise, Idaho CT can reveal much more details than X‐ray Individual scans of CT (serial images) use lower intensity x‐rays But – overall X‐ray exposure is significantly higher with CT than X‐ray Enhanced X‐ray studies with contrast material Brain Aneurysm After treatment Nuclear Medicine Patients are injected with radioactive material (e.g. I-131) that is then enriched in areas of highest activity. Thyroid adenoma Metastatic cancer of thyroid Magnetic resonance imaging (MRI) https://www.youtube.com/watch?v=1CGzk‐nV06g  Note: MRI uses strong magnets – no magnetic material in the room MRI machines are very noisy – patients get earplugs or headphones MRI is superior for viewing soft tissues MRI images can be “weighted” based on the structures that they should enhance by timing of the RF pulse. T1 – One tissue is bright – fat T2 – Two tissues are bright – fat and water T1 is better for anatomy, T2 is better for pathology MRI can be used with contrast materials – Gadolinium Enhances visibility of structures such as blood vessels Courtesy GeekyMedics T1 – ONE tissue is bright: fat T2 – TWO tissues are bright: fat and water (WW2 – Water is White in T2)  Same tissue, different methods CT MRI PET Computed Magnetic resonance Positron Emission Tomography Imaging Tomography Noninvasive Noninvasive Injection of Uses: X-rays Magnetic and radiowave radioactive material fields gamma-rays CAT scan = Computer Axial Tomography  Ultrasound Ultrasound uses a transducer to generate high‐frequency sound waves (>20,000 Hz) to detect tissues in the body Humans cannot hear these sound waves These soundwaves generate echo's that are reflected back differently to the transducer because tissues in the body have different densities Ultrasound (sonography) can be used for many human conditions (heart conditions, blood vessels, internal organs, etc.) Ultrasound is painless and works through the skin https://www.youtube.com/watch?v=I1Bdp2tMFsY  Biopsy, Histology, Cytology Biopsies are performed to obtain tissue for histologic examination. Example: Breast biopsy, bone marrow biopsy Histology: examination of tissue with the microscope. Tissue is intact and morphology preserved Cytology: Cells are recovered by various means. Single cells are usually recovered and tissue structure is not preserved. Example: pap smear, bronchoalveolar lavage (BAL), urine cytology Histology: Skin www.brooksidepress.org Cytology: Pap smear  Tissue processing Clinicians (or Pathologists) remove tissue by needle or surgery and preserve it in a fixative or frozen for examination by the pathologist. Upon receiving of the tissue, the pathologist inspects the tissue, describes the tissue, marks the tissue, and dissects the tissue. Pictures courtesy WebPath (Utah) Dr. Edward Klatt, MD Tissue processing Tissues must be processed before sections can be obtained for histologic examination. Tissues are frequently embedded in paraffin Another way to process tissue is called “frozen section”. Frozen section is frequently done during surgery to give the surgeon fast information needed for his work. Frozen section: Quick freezing of the tissue in butanol/liquid nitrogen. Pictures courtesy WebPath (Utah) Dr. Edward Klatt, MD  Sections must be stained for examination Sections must be stained with dyes before they can be examined by the pathologist Most common stain is H&E (Hematoxylin and Eosin). Hematoxylin is a basic dye and stains nucleic acid in the cell nucleus blue. Eosin (acidic) stains the cytoplasm reddish/pink. Pictures courtesy WebPath (Utah) Dr. Edward Klatt, MD Special stains H&E Some tissue structures are difficult to see with standard H&E “Special stains” help PAS discriminate particular tissues PAS (periodic acid Schiff) staining: Detection of glycogen in liver or muscle. Fungi also stain PAS positive. Masson’sTrichrome staining: collagen (for example liver Trichrome cirrhosis)  Immunofluorescence staining IF staining can specifically identify particular cell types, tissues, molecules Example: Immunoglobulins and complement in post‐ infectious glomerulonephritis  Intro to Clinical Medicine Lecture (3) Mechanisms of tissue injury Thomas G. Forsthuber, M.D. Dr. Med. Professor of Immunology Office: BSE 3.250B E-mail: [email protected] Office Hours: Monday 4:30 – 5:30 – ZOOM link Canvas Pathological Diagnosis based on macroscopic/microscopic changes Living cells and tissues adapt to a changing environment or stress Failure of adaptive mechanisms leads to cell injury or cell death. Cellular changes/injury can be visible at the organ or at the cellular level Tissues can also show changes related to aging Macroscopic or microscopic changes to tissues are important for pathological diagnosis Macroscopic changes (Organ level): – Hypertrophy, atrophy, dysplasia – Pigmentation, calcification – Fatty change Microscopic changes (Cellular level) – Pigmentation, inclusions (e.g. iron, fat, Lipofuscin) – Multi-nucleation – Apoptosis, necrosis  Macroscopic changes in liver disease Which one is the “fatty” Liver? A B Microscopic changes in liver disease Normal liver Fatty liver Portal vein Hyaline inclusions in the liver = Mallory bodies Alcohol! Hemosiderin H&E Prussian blue (Iron)  Tissue responses to stress Increased demand or Hypertrophy, hyperplasia chronic stimulation Decreased demand, lack of Atrophy stimulation Chronic injury Metaplasia Hypertrophy: Cells increase in size, organs may increase in size Hyperplasia: Increase in the number of cells Atrophy: Shrinkage in cell size (or organ) Metaplasia: Cells change from one cell type to another Hypertrophy: In dividing and non-dividing cells Hyperplasia: Only with dividing cells Physiologic hypertrophy Uterus Uterus histology Pregnant Normal Normal Pregnant  Pathologic Hypertrophy Hyperplasia Prostate Hyperplasia (Nodular hyperplasia, BPH= benign prostatic hyperplasia) Prostate hyperplasia (proliferation of glands) Testosterone converted in prostate stromal cells to dihydrotestosterone (x10 more potent)  Atrophy Physiologic atrophy: Shrinkage of the uterus after pregnancy, – Mechanism: loss of hormonal stimulation, developmental gene regulation, Pathologic atrophy: muscle atrophy after fracture, brain with Alzheimer's – Inactivity, loss of innervation, loss of perfusion/blood supply, lack of nutrition, loss of hormonal stimulation, aging, pressure Atrophy A B  Quick histology primer epithelial cells Most body surfaces are lined by Epithelial cells Agnes Lacombe, University of British Columbia Three types of epithelium: “Simple epithelium” SQUAMOUS Epithelium: Lining of body cavities, Vessels, alveoli (lung) CUBOIDAL Epithelium: Lining nephrons, Thyroid glands, surface of ovaries COLUMNAR Epithelium: Gut including stomach & large intestine, gallbladder, Lining of uterus Upper respiratory tract  Epithelial cells form ONE layer (simple epithelium) or SHEETS (stratified epithelium) Single layer Arranged in sheets or layers Metaplasia Squamous metaplasia: Upper airways = smokers Stress Columnar Squamous Epithelium Epithelium Intestinal metaplasia: Intestinal metaplasisia Gastro-esphageal junction= Barrett’s esophagus GERD Squamous Columnar Epithelium Epithelium (glandular type)  Metaplasia Curtesy Medbullets “Fatal” stress – cells die! Causes of cell death: Oxygen deprivation Physical insult (heat, cold, electric) Chemical Infectious Immune Genetic Nutrition Death by Necrosis Apoptosis necrosis or Inflammation! Silent! apoptosis  Classical apoptosis sign: DNA laddering Apoptosis Necrosis Normal - Caspase = Cysteine- Aspartate protease -Laddering is due to caspase-activated Dnase (CAD) - CAD cuts DNA into small fragments - Fragments are multiples of 280 bp (length of DNA wrapped around histones) Apoptosis pathways Extrinsic (death receptor-mediated) apoptosis pathway Intrinsic (mitochondria-mediated) apoptosis pathway Third pathway: Endoplasmic reticulum stress pathway (mediated by too much or to little Ca++) Extrinsic apoptosis pathway Intrinsic apoptosis pathway  Necrosis Violent tissue death: necrosis Normal tissue Necrotic tissue Myocardial infarct: ischemic necrosis of myocardium  Necrosis Coagulative Necrosis: Liquefactive Necrosis: “Dry necrosis”. Basic “Liquid necrosis”. Tissue cell outline maintained. dissolves. Every structure lost. Nuclei lost, cytoplasm No cells visible. eosinophil. Hypoxic cell Brain shows liquefactive death necrosis! Seen in Infarcts Seen in severe Infections “Clinical” types of necrosis Gangrene (gangrenous necrosis): – Dry or wet gangrene – Often after loss of blood supply -> coagulative necrosis – Example: diabetic foot, peripheral arterial disease, frost bite Caseous necrosis: Tuberculosis, lung cavity filled with “cheesy” white-yellow material. -> liquefactive necrosis Fat necrosis: Fat destruction of the mesentery (tissue-fat- sheet in the belly). Frequently after pancreatitis.  Important: The brain usually shows liquefactive necrosis Intro to Clinical Medicine Wound healing Thomas G. Forsthuber, M.D. Dr. Med. Professor of Immunology Office: BSE 3.250B E-mail: [email protected] Office Hours: Monday 4:30 – 5:30 – ZOOM link in Canvas Tissue repair Inflammation is usually associated with damage/dead tissue Dead tissue is a potential source of infection and impairs tissue repair. Dead tissue must be removed and/or repaired. Damaged tissue may be completely replaced (“like new”) or replaced by a scar (“cheap” replacement) Tissue repair must be well controlled If repair is excessive new medical issues may arise (e.g. excess scar formation = keloid or liver cirrhosis) If tissue inflammatory stimulus continues fibrosis may be result.  Note: Tissue regeneration: lost tissue re-grows. –Occurs in tissues with high turnover – skin, gut, bone marrow –Rarely occurs in organs, except for the liver (and kidney) –Depends on intact tissue scaffold –Requires that “tissue stem cells” survive Healing: –Healing is a combination of regeneration and scar formation –Scar formation is the replacement of original tissue with fibrous tissue Regeneration Some tissues, like the liver, can regenerate. GI and skin epithelium can regenerate completely Liver donor before Liver donor after transplant: transplant Liver has regenerated = compensatory growth  Regeneration and healing requires tissue stem cells Liver stem cells Growth factors and cytokines in wound healing Macrophages are architects of wound healing/tissue repair via cytokines and growth factors Cytokines and growth factors orchestrate would healing Growth factors affect: – cell proliferation – cell migration – angiogenesis (growth of blood vessels) – Tissue matrix formation – Deposit of collagen = fibrosis (Some) important growth factors: – Transforming growth factor beta (TGF-, fibrosis); – Vascular endothelial growth factor (VEGF, vessels);  Wound healing Wound healing is a multistep process First phase: Inflammatory phase – removal of damaged/dead tissue Second Phase: Proliferative phase – Angiogenesis (new blood vessel formation) – Granulation tissue formation – Wound contraction (myofibroblasts) Third phase: Maturation phase – Tissue remodeling (collagen) – Removal of unneeded cells (apoptosis) – Reconstitution of the extracellular matrix Wound healing Inflammatory phase Proliferative phase Maturation phase  “Uncomplicated” wound healing Healing by First intention Uncomplicated wound: Edges are close, not infected Proper epithelialization of wound surface Angiogenesis Fibroblast proliferation and collagen deposition Remodeling As good as new – maybe not even scar “Complicated” wound healing “Healing by second intention” Wound has larger gaps – Infected wound, more tissue damage, foreign body More inflammation More granulation tissue Wound contraction becomes important = mediated by myofibroblasts that contract at the edges. Healing is usually less perfect and leaves scar = fibrous tissue, thinner epithelial cover  What impairs wound healing? Locally – Impaired perfusion, infection, foreign body, hematomas, denervation, necrotic tissue, mechanical stress, type of tissue, surgical technique, Systemic – Age, pre-existing conditions (diabetes, malnutrition, atherosclerosis, drugs (steroids, chemotherapy), genetic disorders, trauma, vitamin deficiency, Complications of wound healing (skin) Healing is incomplete (deficient scar) – Wound dehiscence = edges of the wound separate – Ulcer formation = wound does not heal (not epithelialized) Excessive scar formation – Hypertrophic scar = raised scar tissue that remains within boundaries of the original wound – Keloid = Overgrowth of scare tissue beyond original wound – Aggressive scars = desmoid tumors (aggressive fibromatosis) Benign tumors but can grow aggressively and even invade surrounding tissues. NOT cancer and does not metastasize! Wound contraction – Contractures = after burns  Keloid Ongoing inflammatory stimulus leads to fibrosis! Example: Liver cirrhosis Intro to Clinical Medicine Inflammation and repair Thomas G. Forsthuber, M.D. Dr. Med. Professor of Immunology Office: BSE 3.250B E-mail: [email protected] Office Hours: Monday 4:30 – 5:30 – ZOOM link in Canvas Inflammation Inflammation is a mechanism to protect an organism from danger Typically, this danger comes from invading pathogens (infection) or tissue damage through other means (necrotic tissue death) Inflammation is meant to eliminate the source of danger, restrict its extent (wall off), and help repair the damage Inflammation has two main components: – Vascular component – Cellular component Based on the timing and the involved cells one can distinguish between acute and chronic inflammation The inflammatory response varies to a certain degree between tissues and organs  Inflammation: Without preexisting immunity: preformed mechanisms and innate immunity are the first line of defense With preexisting immunity: adaptive immunity (e.g. antibodies) facilitates activation of defense mechanisms Key events: ALERT – WALL OFF – DESTROY - REPAIR First: alarm the body that something is going on! Second: wall off and prevent the spread of the pathogens from the entrance site to the blood and other tissues Third: bring “troops” to the site of action to destroy danger Fourth: Set stage for repair by growing blood vessels and proliferate fibroblasts Inflammation cannot (should) not go on indefinitely The inflammatory process is supposed to stop when the offender is eliminated There are specific mechanisms that terminate/restrict an inflammatory process In the end, the goal is not to eliminate the offender at the cost of destroying the host Therefore: different tissues, different inflammatory responses  Events that trigger inflammation: Infections Trauma (injury) – Mechanical injury – Physical injury (heat, frostbite) – Chemicals – Foreign bodies Tissue necrosis Immune reactions (for example in hypersensitivity disorders) The big players: Blood vessels Inflammatory cells Vasoactive factors (e.g. Histamine, Bradykinins) Complement system Blood clotting system  Sequence of inflammatory events Inflammatory events after infection: Example: Microbes enter tissue through breach in skin Microbes are coated with antibodies and/or complement (see later) Antibodies bind complement, complement factors are cleaved and complement cascade is activated Complement factors C3a and C5a activate other cells, such as tissue mast cells Tissue mast cells release vasoactive factors: – Histamine = short acting vasodilator, released early – Bradykinin = released later, long acting vasodilator Vasodilators increase blood flow into tissues, but speed of blood flow slows down in affected areas Immune cells become recruited and activated. First cells: Neutrophils Next: macrophages/DC. They release factors that induce additional defensive mechanisms, such as fever (CNS) and acute phase proteins (liver) Blood vessels are central players in inflammation: Vascular dilation and permeability! Increased blood flow = Lesion turns red and warm! (Rubor & Calor)  How to achieve vascular changes: Inflammatory and noninflammatory cells can produce vasoactive mediators: Mediators inducing vascular dilation: – Histamine, nitric oxide, Bradykinin, prostaglandins, Serotonin – Primarily act on arterioles (very small arteries) -> more in, less out! Mediators that increase vascular permeability: – Histamine, Bradykinin, Serotonin, complement factors (C3a, C5a) Physiology of vascular changes Normal state: No fluid excess in tissues Lymphatic vessels drain excess fluid from tissues During inflammation More blood flow and fluid leaks into tissues  Vascular dilation triggers key tissue events in acute inflammation Vascular dilation: – Altered blood flow creates “turbulence” of blood cells (marginalization) = inflammatory cells leave the blood stream and migrate into tissues – Increased oxygen demand by cells lowers tissue oxygen levels – Decreased oxygen in tissues results in lower (acidic) pH in inflamed region = inflammatory enzymes work better – Altered blood flow promotes blood clot formation to stop bleeding and wall off injury Enhanced vascular permeability: – Inflammatory proteins can get into injured tissue – Inflammatory cells can easier migrate through vessel walls Fluid in tissues/cavities is clinically/diagnostically relevant: Transudate vs. Exudate Transudate: - low in protein, 30g/L; specific gravity > 1.020; cloudy, - Infections, pneumonia, Tb, malignancy, pulmonary embolism Light’s Criteria: Used to differentiate between transudate and exudate “Fluid” protein to serum protein ratio > 0.5 = exudate Edema: Transudate or exudate in tissue or body cavities Pus: Fluid contains many leukocytes (neutrophils, macrophages)  Antibodies and complement are important to alert immune defenses and destroy microbes Complement system consists of over 30 proteins The are usually activated in sequential order: C1 -> C2a/C4b -> C3 -> C5, C6, C7, C8, C9 C3 is the central molecule C3a and C5a serve as soluble signals for other cells Inflammatory cells migrate to sites of inflammation in a defined sequence of steps  Inflammatory mediators produced by phagocytes and liver have systemic effects Acute phase reactants trigger acute phase response: Acute phase reactants: “positive” = proinflammatory C-reactive protein (CRP) Serum amyloid A (SAA) Complement (C3, C4) Fibrinogen Mostly made by liver “negative” = anti-inflammatory Transferrin Albumin Systemic effects of inflammation Systemic changes during acute inflammation are called “acute phase response” FEVER is induced by endogenous pyrogens (IL-1, TNF) that induce PGE2 via enhancement of cyclooxygenase-2. Acute phase proteins (e.g. CRP, SAA) help in defense against infection LEUKOCYTOSIS ( > 10,000 leukocytes/ul blood) – Neutrophilia, lymphocytosis, eosinophilia, INCREASED PULSE/enhanced blood pressure (BP) CHILLS, MALAISE, Very severe change: – Septic shock syndrome – Disseminated intravascular coagulation (DIC)  Fever = Pyrexia A person is considered to have fever when: Rectal temperature (anal) is 38oC or higher (100.4oF) Oral temperature (mouth) 37.5oC or higher (99.5oF) Axillary temperature (armpits) 37.2oC or higher (99oF) Often fever is graded as follows: low-grade: 38 - 39 °C (99.5 - 102.2 °F) moderate: 39 - 40 °C (102.2 - 104 °F) high-grade: > 40 °C (> 104 °F) Hyperpyrexia: > 42 °C (> 107.6 °F) Forsthuber’s conversion trick: 40°C = 104°F -> -2°F = -1°C Acute versus chronic inflammation Acute inflammation: Neutrophils, necrosis, edema, Chronic inflammation: lymphocytes, fibrosis, Acute inflammation Chronic inflammation Neutrophils Lyphocytes Dilated vessels Fibrosis Edema Changes in tissue architecture