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Slide 1-

Cell Injury, Death, Inflammation, and Repair J. Matthew Velkey matt.velkey@duke.edu 454A Davison, Duke South (green zone)
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Cellular Adaptation to Injury or Stress Injury or Stress Increased demand Decreased stimulation or lack of nutrients Chronic irritation Adaptation Hyperplasia or hypertrophy Atrophy Metaplasia
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Adapted - Normal - Injured Cells
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Adaptations Hypertrophy Hyperplasia Atrophy Metaplasia
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Hypertrophy Increase in the size of cells results in increased size of the organ May be Physiologic or Pathologic
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Examples of Physiologic Hypertrophy Increased workload - skeletal muscle cardiac muscle Hormone induced –pregnant uterus
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Physiologic hypertrophy Gravid uterus and Normal uterus
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Hyperplasia Increase in the number of cells results in increase in size of the organ. May be Physiologic or Pathologic.
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Physiologic Hyperplasia Hormonal hyperplasia Female breast; puberty and pregnancy Compensatory hyperplasia Prometheus Unilateral nephrectomy Erythroid hyperplasia of bone marrow in chronic hypoxia (mountain climbers).
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Pathologic Hyperplasia Excessive hormone stimulation Endometrial hyperplasia Prostatic hyperplasia Viral infections Papilloma virus (warts)
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Atrophy Reduced size of an organ due to a decrease in cell size and number. Physiologic atrophy – notochord, post partum uterus Pathologic atrophy – local or generalized
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Causes and Examples of Atrophy Decreased workload (disuse atrophy) Loss of innervation (denervation atrophy) Diminished blood supply (ischemia) Inadequate nutrition (marasmus, cachexia) Loss of endocrine stimulation (menopause) Aging (senile atrophy) Pressure (enlarging benign tumor)
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Normal Atrophy
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Metaplasia Reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type. Usually occurs in response to stress or chronic irritation.
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Causes and Examples of Metaplasia Tobacco smoke - Squamous metaplasia in the respiratory tract, most common. Gastric acid reflux - Gastric metaplasia of distal esophagus; Barrett esophagus. Repeated skeletal muscle injury with hemorrhage- muscle replaced by bone; myositis ossificans.
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Bronchus with Columnar to Squamous Metaplasia
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Esophagus with Squamous to Columnar metaplasia
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Mechanisms of Metaplasia Re-programing of stem cells that exist in normal tissue. Induced by cytokines, growth factors and other environmental signals Retinoic acid may play a role. Exact mechanism is unknown.
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Cell Injury and Death Reversible – reduced ATP, cellular swelling Irreversible – two types of cell death Necrosis – always pathologic Apoptosis – may be physiologic or pathologic
Slide 21-

Necrosis vs. Apoptosis
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Causes of Cell Injury Oxygen deprivation (hypoxia or ischemia) Physical Agents (trauma) Chemical agents and Drugs Infectious Agents Immunologic Reactions Genetic Derangements Nutritional Imbalances
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Reversible and Irreversible Cell Injury
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Reversible and Irreversible Cell Injury normal kidney tubules reversibly injured kidney tubules irreversibly injured kidney tubules Chromatin clumping Membrane blebbing Swelling of ER and mitochondria (slight eosinophilia) Nuclear fragmentation and loss Membrane disintegration Swelling and rupture of ER, mitochondria, & lysosomes (marked eosinophilia)
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Morphologic Alterations in Irreversible Injury (Necrosis) Cytoplasmic Eosinophilia – denatured proteins and whorls of cytoplasm (myelin figures) stain strongly with eosin. Also, loss of ribosomes decreases overall basophilia. Nuclear (3 patterns) Karyolysis - nucleus becomes pale and eventually disappears Pyknosis - nucleus shrinks, chromatin condenses, becomes deeply basophilic Karyorrhexis – nucleus undergoes fragmentation These nuclear patterns may occur together or separately and not necessarily in any particular order. Regardless of the pattern(s) observed, the net result is that nuclei in dead cells completely disappear after 1-2 days.
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Patterns of Tissue Necrosis Coagulative Necrosis Liquefactive Necrosis Fat Necrosis Caseous Necrosis Fibrinoid Necrosis
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Coagulative Necrosis Pattern of cell death characterized by progressive loss of cell structure, with coagulation of cellular constituents and persistence of cellular outlines for a period of time, often until inflammatory cells arrive and degrade the remnants.
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Myocardial infarction: another example of coagulative necrosis
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Liquefactive Necrosis Pattern of cell death characterized by dissolution of necrotic cells. Typically seen in an abscess where there are large numbers of neutrophils present, which release hydrolytic enzymes that break down the dead cells so rapidly that pus forms. Pus is the liquefied remnants of dead cells, including dead neutrophils.
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Coagulative Necrosis Liquefactive Necrosis KIDNEY
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Caseous Necrosis The pattern of cell injury that occurs with granulomatous inflammation in response to certain microorganisms (tuberculosis). The host response to the organisms is a chronic inflammatory response and in the center of the caseating granuloma there is an area of cellular debris with the appearance and consistency of cottage cheese.
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Fat Necrosis When lipases are released into adipose tissue, triglycerides are cleaved into fatty acids, which bind and precipitate calcium ions, forming insoluble salts. These salts look chalky white on gross examination and are basophilic in histological sections stained with H&E.
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FAT NECROSIS
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Fibrinoid Necrosis The pattern of cell injury that occurs in the wall of arteries in cases of vasculitis. There is necrosis of smooth muscle cells of the tunica media and endothelial damage which allows plasma proteins, (primarily fibrin) to be deposited in the area of medial necrosis.
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FIBRINOID NECROSIS Fibrinoid necrosis
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Mechanisms of Cell Injury Cellular response to injury depends on nature, duration and severity of injury. Consequences of injury depend on type, state and adaptability of the injured cell. Cell injury results from different biochemical mechanisms acting on essential cellular components.
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Mechanisms of Cell Injury Depletion of ATP Mitochondrial Damage Entry of Calcium into the cell Increase reactive oxygen species (ROS) Membrane Damage DNA damage, Protein misfolding
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Depletion of ATP ATP depletion and decreased ATP synthesis are common with both hypoxic and toxic (or chemical) injury, causing: Reduction in Na+, K+- ATPase pump activity Increase in anaerobic glycolysis (if possible) Failure of Ca++ export pump Reduced protein synthesis
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Consequences of Mitochondrial Damage NECROSIS Loss of membrane potential via membrane permeability transition. Results in failed oxidative phosphorylation and loss of ATP. OR APOPTOSIS Membrane damage leads to leakage of Cytochrome c and other pro-apoptotic proteins.
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Calcium Influx Intracellular Ca++ is normally low and is sequestered in mitochondria and endoplasmic reticulum Extracellular Ca++ is high Gradients are normally maintained by Ca++ Mg++ ATPase pumps Increased cytosolic Ca++ activates enzymes such as ATPases, phopholipases, proteases, endonucleases that can lead to cell injury and death. Increased Ca++ is also pro-apoptotic
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Reactive Oxygen Species Free radical is unpaired electron which makes the atom or molecule extremely reactive. React with and modify cellular constituents. Initiate self perpetuating processes when they react with atoms and molecules. Electrons are frequently added to O2 to create biologically important ROS.
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Biologically Important ROS Superoxide anion radical O2 + e- --> O2- Produced by phagocyte oxidase, damages lipids, proteins and DNA. Hydrogen peroxide H2O2 Generated by SOD and by oxidases, destroys microbes, may act at distant sites (not a radical, per se, but very reactive). Hydroxyl radical .OH Generated from H2O by hydrolysis, most reactive, damages lipids, proteins and DNA.
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“NORMAL” ROS FUNCTIONS: Normal metabolism and respiration Absorption of radiant energy Inflammation Enzymatic metabolism of chemicals or drugs Nitric oxide synthesis Reactive Oxygen Species
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Membrane Damage EFFECTS: Mitochondrial membrane damage causes increased cytosolic Ca++, oxidative stress, lipid peroxidation, phospholipase activity, loss of membrane potential, leakage of Cytochrome c Plasma membrane damage causes loss of osmotic balance, loss of proteins, enzymes and nucleic acids. Injury to lysosome membranes causes leakage of enzymes with destruction of cellular components. ROS  lipid peroxidation ↓ phospholipid synthesis ↑ phospholipid degradation (Ca influx activates phospholipases) Cytoskeletal damage (Ca influx also activates proteases)
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DNA damage Protein misfolding If DNA damage to cell is too severe, apoptosis is initiated. Improperly folded proteins can also initiate apoptosis (to be discussed shortly...)
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Several mechanisms of injury may be at play in any given situation Types of cell injury: Ischemic and Hypoxic Injury (shutting off blood flow or deprivation of oxygen) Ischemia-Reperfusion Injury Chemical Injury Radiation injury Mechanisms of cell injury: Depletion of ATP Mitochondrial Damage Entry of Calcium into the cell Increase reactive oxygen species (ROS) Membrane Damage DNA damage, Protein misfolding
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Regardless of the type or mechanism, extensive cell injury results in death either by necrosis or apoptosis Necrosis Loss of functional tissue Impaired organ function, transient or permanent Apoptosis Removal of damaged or unnecessary cells
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General Characteristics NECROSIS “Accidental” Usually affects large areas of contiguous cells Cells and organelles swell Control of intracellular environment is lost, cells rupture and spill contents INDUCES INFLAMMATION APOPTOSIS “Programmed” Usually affects scattered individual cells Cells contract Control of intracellular environment maintained, cytoplasm packaged as “apoptotic bodies” DOES NOT INDUCE INFLAMMATION
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Apoptosis
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Apoptosis Mitochondrial (intrinsic) induction –activation of pro-apoptotic proteins and/or downregulation of anti-apoptotic proteins leads to loss of mitochondrial membrane integrity and release of CytC and other pro-apoptotic factors Death receptor (extrinsic) induction –cell receptors respond to signals (either secreted or by direct contact with other cells) to directly induce apoptosis Convergent “execution” phase –caspases (cysteine-aspartic-acid-proteases) activate DNAses, cytoskeletal proteases, and phosphatidylserine “flippase” Removal of dead cells –ligands expressed on surface membrane (e.g. phosphatidylserine and/or glycoproteins) signal phagocytosis by macrophages
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Causes of Apoptosis may be Physiologic or Pathologic Physiologic Embryogenesis and fetal development. Hormone dependent involution. Prostate glandular epithelium after castration Regression of lactating breast after weaning Cell loss in proliferating cell populations. Immature lymphocytes Epithelial cells in the GI tract Elimination of self-reactive lymphocytes. Death of cells that have served their function. Neutrophils, Lymphocytes Pathologic DNA damage due to radiation, chemotherapy. Accumulation of misfolded proteins leads to ER stress which ends with apoptosis. Cell death in viral infections that induce apoptosis such as HIV and Adenovirus or by the host immune response such as hepatitis. Organ atrophy after duct obstruction.
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Intracellular accumulations Lipids Steatosis Cholesterol and Cholesterol Esters Proteins Glycogen Pigments
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Abnormal metabolism – Steatosis (Fatty change) Abnormal protein folding – Alpha 1 antitrypsin deficiency Lack of enzyme – Lysosomal storage disease Indigestible material – Carbon or heme
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Causes of Steatosis (Fatty Liver ) Alcohol is a hepatotoxin that leads to increased synthesis and reduced breakdown of lipids. Nonalcoholic fatty liver disease is associated with diabetes and obesity. CCl4 and protein malnutrition cause reduced synthesis of apoproteins. Hypoxia inhibits fatty acid oxidation. Starvation increases mobilization of fatty acids from peripheral stores.
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85.1.pg.fattyliver 85-Fatty Liver (Gross)
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Intracellular lipid accumulation: atherosclerotic plaque
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Intracellular lipid accumulation: xanthoma
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Indigestible material: Pigments Exogenous Pigment – Carbon in lung = anthracosis Endogenous Pigments Hemosiderin- multiple transfusions Lipofuscin- aging pigment Melanin- skin and neurotransmission Bilirubin-hepatocytes
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Exogenous pigment Anthracotic pigment in Lung
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Endogenous pigments Hemosiderin Brown pigment Breakdown product of hemoglobin Contains ferrous iron (so turns blue when stained with K-ferrocyanide, aka Prussian blue stain) Lipofuscin Brown pigment “wear and tear” pigment from peroxidation of membrane lipids Does NOT contain ferrous iron (so does not react with Prussian blue stain) Present in long-lived cells
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Pathologic Calcification Dystrophic Calcification – occurs in areas of necrosis and atherosclerosis. Metastatic Calcification – occurs in normal tissues when there is hypercalcemia.
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Metastatic Calcification Excess Parathyroid hormone Destruction of bone Vitamin D disorders Renal failure
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Conclusions Cell injury may occur by a variety of mechanisms and sources - endogenous (ischemia/inflammation) or exogenous (drugs/toxins) Cell injury can be reversible or irreversible. Reversible cell injury can result in changes which may recover when the cause is removed, or which may persist. Irreversible (lethal) cell injury may cause only transient functional impairment if the dead cells can be replaced. Alternatively, lethal cell injury may lead to permanent functional impairment if the dead cells can not be replaced. Cell death (apoptosis) is a normal mechanism to remove damaged cells which can be activated in pathologic conditions. Substances may be deposited within cells in response to cell injury.
Slide 72-

Inflammation and Wound Healing
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What is Inflammation? Response to injury (including infection) Reaction of blood vessels leads to: Accumulation of fluid and leukocytes in extravascular tissues Destroys, dilutes, or walls off the injurious agent Initiates the repair process Fundamentally a protective response May be potentially harmful Hypersensitivity reactions to insect bites, drugs, contrast media in radiology Chronic diseases: arthritis, atherosclerosis Disfiguring scars, visceral adhesions Consists of two general components Vascular reaction Cellular reaction Controlled by a variety of chemical mediators Derived from plasma proteins Derived from cells inside and outside of blood vessels
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Historical Highlights Celsus, a first century A.D. Roman, listed four cardinal signs of acute inflammation: Rubor (erythema [redness]): vasodilatation, increased blood flow Tumor (swelling): extravascular accumulation of fluid Calor (heat): vasodilatation, increased blood flow Dolor (pain)
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Types of Inflammation Acute inflammation Short duration Edema Mainly neutrophils Granulomatous inflammation Distinctive pattern of chronic inflammation Activated macrophages (epithelioid cells) predominate +/- Multinucleated giant cells Chronic inflammation Longer duration Lymphocytes & macrophages predominate Fibrosis New blood vessels (angiogenesis)
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Acute Inflammation Three major components: Increase in blood flow (redness & warmth) Edema results from increased hydrostatic pressure (vasodilation) and lowered intravascular osmotic pressure (protein leakage) Leukocytes emigrate from microcirculation and accumulate in the focus of injury Stimuli: infections, trauma, physical or chemical agents, foreign bodies, immune reactions
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Edema in inflammation Edema is a general term for swelling (usu. due to fluid) Plasma proteins in blood maintain a “colloid osmotic pressure” to help draw fluid that leaks out into tissue bed via hydrostatic pressure Dysregulation of hydrostatic pressure (e.g. heart failure) and/or colloid pressure (decresased protein synthesis/retention) pushes out more fluid (transudate) into tissue bed Inflammation causes endothelial cells to separate, thus allowing fluid + protein (exudate) to enter tissue bed.
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Leukocyte Extravasation Extravasation: delivery of leukocytes from the vessel lumen to the interstitium In the lumen: margination, rolling, and adhesion Migration across the endothelium (diapedesis) Migration in the interstitial tissue (chemotaxis) Leukocytes ingest offending agents (phagocytosis), kill microbes, and degrade necrotic tissue and foreign antigens There is a balance between the helpful and harmful effects of extravasated leukocytes
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Neutrophil Morphology Neutrophils Eosinophil
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Leukocyte Margination Photomicrograph courtesy of Dr. James G. Lewis
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Leukocyte Diapedesis Photomicrograph courtesy of Dr. James G. Lewis
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Sequence of Leukocyte Emigration Neutrophils predominate during the first 6 to 24 hours Monocytes in 24 to 48 hours Induction/activation of different adhesion molecule pairs and specific chemotactic factors in different phases of inflammation
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Sequence of Events - Injury
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Sequence of Events - Infection
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Outcomes of Acute Inflammation Complete resolution Abscess formation Fibrosis After substantial tissue destruction In tissues that do not regenerate After abundant fibrin exudation, especially in serous cavities (pleura, peritoneum) Progression to chronic inflammation
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Types of Inflammation: acute vs. chronic Types of repair: resolution vs. organization (fibrosis)
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Morphologic Patterns of Acute Inflammation Serous inflammation: Outpouring of thin fluid (serous effusion, blisters) Fibrinous inflammation: Body cavities; leakage of fibrin; may lead to scar tissue (adhesions) Suppurative (purulent) inflammation: Pus or purulent exudate (neutrophils, debris, edema fluid); abscess: localized collections of pus Ulcers: Local defect of the surface of an organ or tissue produced by the sloughing (shedding) of inflammatory necrotic tissue
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Fibrinous Pericarditis
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Fibrinous Pericarditis
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Fibrinous Pleuritis
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Suppurative (purulent) inflammation: Abscess
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Gastric Ulcer
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Gastric Ulcer
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Systemic Manifestations Endocrine and metabolic Secretion of acute phase proteins by the liver Increased production of glucocorticoids (stress response) Decreased secretion of vasopressin leads to reduced volume of body fluid to be warmed Fever Improves efficiency of leukocyte killing Impairs replication of many offending organisms
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Systemic Manifestations Autonomic Redirection of blood flow from skin to deep vascular beds minimizes heat loss Increased pulse and blood pressure Behavioral Shivering (rigors), chills (search for warmth), anorexia (loss of appetite), somnolence, and malaise
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Systemic Manifestations Leukocytosis: increased leukocyte count in the blood Neutrophilia: bacterial infections Lymphocytosis: infectious mononucleosis, mumps, measles Eosinophilia: Parasites, asthma, hay fever Leukopenia: reduced leukocyte count Typhoid fever, some viruses, rickettsiae, protozoa
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Chronic Inflammation Inflammation of prolonged duration (weeks or months) Active inflammation, tissue destruction, and attempts at repair are proceeding simultaneously May follow acute inflammation or begin insidiously and often asymptomatically Persistent infections, exposure to toxic agents such as silica (silicosis), or by autoimmunity
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Chronic Inflammation Persistent infections Treponema pallidum [syphilis], viruses, fungi, parasites Exposure to toxic agents Exogenous: silica (silicosis) Endogenous: toxic plasma lipid components (atherosclerosis) Autoimmunity Rheumatoid arthritis, systemic lupus erythematosus
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Chronic Inflammation Histological features Infiltration with mononuclear cells (macrophages, lymphocytes, and plasma cells) Tissue destruction (induced by the inflammatory cells) Healing by replacement of damaged tissue by connective tissue (fibrosis) and new blood vessels (angiogenesis)
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Chronic Inflammatory Cells Macrophages Lymphocytes
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Chronic Inflammation
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Chronic Inflammation
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Macrophages Monocytes begin to emigrate into tissues early in inflammation where they transform into the larger phagocytic cell known as the macrophage Macrophages predominate by 48 hours Recruitment (circulating monocytes); division; immobilization Activation results in secretion of biologically active products
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Macrophages
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Other Cells in Chronic Inflammation Lymphocytes Produce inflammatory mediators Participate in cell-mediated immune reactions Plasma cells produce antibody Lymphocytes and macrophages interact in a bi-directional fashion
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Chronic Inflammatory Cells Plasma cells Russell bodies
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Other Cells in Chronic Inflammation Eosinophils Immune reactions mediated by IgE Parasitic infections Eosinophil granules contain a protein that is toxic to parasites Mast cells Release mediators (histamine) and cytokines
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Eosinophil Morphology
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Chronic Cellulitis
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Granulomatous Inflammation Distinctive pattern of chronic inflammation Predominant cell type is an activated macrophage with a modified epithelial-like (epithelioid) appearance Giant cells may or may not be present Granuloma: Focal area of granulomatous inflammation
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Granulomatous Inflammation Foreign body granulomas: Form when foreign material is too large to be engulfed by a single macrophage Immune granulomas: Insoluble or poorly soluble particles elicit a cell-mediated immune response
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Granulomatous Response to Suture
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Chemical Mediators of Inflammation General principles of chemical mediators May be derived from plasma or cells Most bind to specific receptors on target cells Can stimulate release of mediators by target cells, which may amplify or ameliorate the inflammatory response May act on one or a few target cells, have widespread targets, and may have differing effects depending on cell and tissue types Usually short-lived Most have the potential to cause harmful effects
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Chemical Mediators of Inflammation Vasoactive mediators Histamine Bradykinin Complement (C3a, C5a) Prostaglandins/leukotrienes Platelet activating factor Nitric oxide Chemotactic factors Complement (C5a) Leukotriene (B4) Platelet activating factor Cytokines (IL-1, TNF) Chemokines Nitric oxide
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Histamine Mast cells (also basophils and platelets) Release mechanisms Binding of antigen (allergen) to IgE on mast cells releases histamine-containing granules Release by nonimmune mechanisms such as cold, trauma, or other chemical mediators Release by other mediators Dilates arterioles and increases permeability of venules (wheal and flare reaction)
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Complement Proteins found in greatest concentration in the plasma Require activation Increase vascular permeability and cause vasodilation Mainly by releasing histamine from mast cells Increase leukocyte adhesion, chemotaxis, and activation C3b attaches to bacterial wall and enhances phagocytosis by neutrophils & macrophages
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Bradykinin Small peptide released from plasma precursors Increases vascular permeability Dilates blood vessels Causes pain Rapid inactivation
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Arachidonic Acid Metabolites Prostaglandins Vasodilators: prostacyclin (PGI2), PGE1, PGE2, PGD2 Vasoconstrictors: thromboxane A2 Pain (PGE2 makes tissue hypersensitive to bradykinin) Fever (PGE2) Production blocked by steroids and nonsteroidal anti-inflammatory agents (NSAIDs) Leukotrienes Increase vascular permeability: leukotrienes C4, D4, E4 Vasoconstriction: leukotrienes C4, D4, E4 Leukocyte adhesion & chemotaxis: leukotriene B4, HETE, lipoxins Production blocked by steroids but not conventional NSAIDs
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Figure 2-16 Robbins and Cotran Pathologic Basis of Disease, 7th Ed.
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Platelet Activating Factor Subclass of phospholipids Synthesized by stimulated platelets, leukocytes, endothelium Inflammatory effects Stimulates platelet aggregation Vasoconstriction and bronchoconstriction Vasodilation and increased venular permeability Increased leukocyte adhesion to endothelium, chemotaxis, degranulation, and oxidative burst Increases synthesis of arachidonic acid metabolites by leukocytes and other cells
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Cytokines Proteins produced by many cell types (principally activated lymphocytes & macrophages) Modulate the function of other cell types Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are the major cytokines that mediate inflammation
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Figure 2-18 Robbins and Cotran Pathologic Basis of Disease, 7th Ed.
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Chemokines Small proteins that act primarily as chemoattractants for specific types of leukocytes (approximately 40 known) Stimulate leukocyte recruitment in inflammation Control the normal migration of cells through tissues (organogenesis and maintenance of tissue organization) Examples: IL-8, eotaxin, lymphotactin
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Nitric Oxide Figure 2-19 Robbins and Cotran Pathologic Basis of Disease, 7th Ed.
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Other Mediators Neutrophil granules: Cationic proteins increase vascular permeability, immobilize neutrophils, chemotactic for mononuclear phagocytes Neutral proteases generate other mediators and degrade tissue Oxygen-Derived Free Radicals: Produced during phagocytosis by neutrophils (“respiratory burst”) Tissue damage including endothelium
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Summary of Inflammatory Mediators Vasodilation Prostaglandins Nitric oxide Histamine Increased vascular permeability Histamine, serotonin Complement (C3a, C5a) Bradykinin Leukotrienes (C4, D4, E4) Platelet Activating Factor Substance P
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Summary of Inflammatory Mediators Chemotaxis, leukocyte activation Complement (C5a) Leukotriene B4 Chemokines IL-1, TNF Bacterial products Fever Interleukin-1 Tumor necrosis factor Prostaglandins
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Summary of Inflammatory Mediators Pain Prostaglandins Bradykinin Tissue Damage Neutrophil and macrophage lysosomal enzymes Oxygen metabolites Nitric oxide
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Wound Healing A complex but orderly process involving many of the chemical mediators previously discussed, along with many other growth factors and cell-matrix interactions. Occurs in the following steps: Injury induces acute inflammation Parenchymal cells regenerate Both parenchymal and connective tissue cells migrate and proliferate Extracellular matrix is produced Parenchyma and connective tissue matrix remodel Increase in wound strength due to collagen deposition
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Wound Healing Time Course
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Granulation Tissue Hallmark of healing Term comes from soft, pink, granular appearance when viewed from the surface of a wound Histology: Proliferation of small blood vessels and fibroblasts; tissue often edematous
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Granulation Tissue
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Granulation Tissue
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Healing by 1st intention vs. 2nd intention By 1st intention: “clean” incision limited scarring or wound contraction By 2nd intention: ulcers or lacerations often scarring and wound contraction
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Ulcers: an example of healing by 2nd intention
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Resolution of Inflammation: “Regeneration” vs. “Healing”
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An example of healing by fibrosis: Myocardial Infarction Edge of acute infarct
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Myocardial Infarct: healing (aka “remote”) Healing (remote) infarct
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Myocardial Infarct: healing (trichrome stain) Masson trichrome stain for collagen
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Variables affecting repair Infection –prolongs inflammation, increases degree of tissue injury Nutrition –protein or vitamin deficiency can impair synthesis of new proteins Anti-inflammatory drugs –can impede fibrosis necessary for repair Mechanical variables –tension, pressure, or the presence of foreign bodies can affect repair Vascular disease –limits nutrient and oxygen supply required for repairing tissues Tissue type –only tissues capable of renewing will regenerate, otherwise healing is by fibrosis Degree of exudate removal –adequate removal of exudate allows RESOLUTION of the injury (general restoration of the normal tissue architecture); inadequate removal results in ORGANIZATION (abnormal, dysfunctional tissue architecture) Regulation of cell proliferation –abnormal proliferation of connective tissue may inhibit re-epithelialization and/or raised scars (keloids)