Chapter 9 Stress and Adaptation General Adaptation Syndrome (GAS) Hans Selye Stress as a term to mean an orchestrated set of bodily responses to any form of noxious stimuli Selye injected rats with ovarian extract and saw: Enlarged adrenal cortex Thymic atrophy Bleeding ulcers in stomach and duodenum Stages of the General Adaptation Syndrome (GAS) Alarm stage: arousal of body defenses CNS aroused fight-or-flight concept Generalized stimulation of the sympathetic nervous system and the HPA (Hypothalamus-pituitary-adrenocortical axis) resulting in release of catecholamines and cortisol Resistance or adaptation stage: Body selects the most effective and economical channels of defense Remove it or adapt to it If body does not adapt, it goes into the exhaustion stage Adaptation implies that an individual has successfully created a new balance between the stressor and the ability to deal with stress Exhaustion stage: compensatory mechanisms breakdown Resources are depleted and signs of wear and tear appear, stress overwhelms the bodys defenses/disease or death Increased cortisol levels = GI ulcers, etc. Homeostasis: the purposeful maintenance of a stable internal environment Does not occur by chance is the result of organized self-government Physiologic processes opposing change each stress response involves: Operates by negative feedback mechanisms constancy of the internal environment When monitored function or value decreases below the set point of the system, the feedback mechanism causes the function or value to increase (ideally back to within set point) When the function or value is increased above the set point, the feedback mechanism causes it to decrease A sensor detects a change An integrator/comparator sums and compares incoming data with set point (normal) Effector system returns the sensed function to within the range of the set point (normal) Functions of the bodys control systems Regulate cellular function Control life processes Integrate functions of the different organ systems Stress A state manifested by symptoms that arise from the coordinated activation of the neuroendocrine and immune systems (GAS) Neuroendocrine responsesHormones associated with the stress responseSource of the hormonePhysiologic effects

Catecholamines (NE, epinephrine)Locus Caeruleus (LC, adrenal medullaIncrease in insulin release and increase in glucagon release resulting in increased glycogenolysis, gluconeogenesis, lipolysis, proteolysis, and decreased glucose uptake by peripheral tissues.Increase in HR, cardiac contractility, and vascular smooth muscle contractions.Relaxation of bronchial smooth muscle.

Corticotropin-releasing factor (CRF)HypothalamusStimulates ACTH release from anterior pituitary and increased activity of the LC neurons.

Adrenocorticotropic hormone (ACTH)Anterior pituitaryStimulates the synthesis and release of cortisol.

Glucocorticoid hormones (e.g., cortisol)Adrenal cortexPotentiates the actions of epinephrine and glucagon.Inhibits the release and/or actions of the reproductive hormones and thyroid-stimulating hormone.Produces a decrease in immune cells and inflammatory mediators

Mineralocorticoid hormones (e.g., aldosterone)Adrenal cortexIncreases sodium absorption by the kidneys.

Antidiuretic hormone (ADH vasopressin)Hypothalamus, posterior pituitaryIncreases water absorption by the kidneys.Produces vasoconstriction of the blood vessels.Stimulates the release of ACTH.

Locus Caeruleus Central to the neural component of the neuroendocrine response to stress Densely populated with neurons that produce NE and is thought to be the central integrating site for the ANS response to stressful stimuli LC-NE system has afferent pathways to the hypothalamus, the limbic system, the hippocampus, and the cerebral cortex Corticotropin-releasing factor (CRF) A small peptide hormone found in both the hypothalamus and in extrahypothalamic structures (limbic system and brain stem) Growth hormones: decrease during stress Thyroid hormones: decrease during stress Reproductive hormones: may decrease during stress ADH (from posterior pituitary): increased = water retention and vasoconstriction Cortisol (from adrenal cortex): suppresses immune function, increases glucose levels = decreased healing, suppressed inflammatory process, reduces WBCs to fight infections, stimulates gastric acid secretion NE and epinephrine Everyday wear and tear on the body Adaptation The ability to respond to challenges of physical or psychological homeostasis and to return to a balanced state Stressors Events or environmental agents responsible for initiating the stress response Can be endogenous (age, gender, genes) or exogenous (diet, environment) or a mix of both NOT ALL STRESS IS DETRIMENTAL Types of stress Eustress: mild, brief, controllable stress Distress: severe, long uncontrolled stress Allostasis Physiologic changes in the neuroendocrine, autonomic and immune system in response to altered homeostasis Factors affecting ability to adapt Physiological reserve and previous learning Time: acute or chronic Genetics Age: very old and very young less adaptable Health status: other illnesses present may interfere with adaptation Nutrition: deficiency or excess Sleep-wake cycles: immunity affected Hardiness Psychosocial factors Physiologic reserve The ability of the body systems to increase their function given the need to adapt RBCs and oxygen your body can carry more than you actually use Anatomic reserve Paired organs that are nor needed to ensure the continued existence and maintenance of the internal environment Lungs, kindeys, and adrenals you have 2 of each so you can survive!! PTSD Intrusion (flashbacks) The occurrence of flashbacks during waking hours or nightmares in which the event is relived, often in vivid and frightening detail Avoidance (emotional numbing) The emotional numbing that accompanies this disorder and disrupts important personal relationships-depression- may have survivor guilt Hyperarousal (irritability, vigilance, exaggerated startles reflex, over concern with safety) The presence of increased irritability, difficulty concentrating, an exaggerated startle reflex, and increased vigilance and concern over safety Must have these symptoms for at least a month for a diagnosis of PTSD Nonpharmacologic tx for stress Relaxation techniques Guided imagery Music therapy Massage Biofeedback Cellular Adaptation, Injury, and Death All disease processes and most injuries are a result of cellular injury or death Cellular adaptation A cell responds to it environment by adjusting structure and function to meet demands In response to physiologic stresses or pathologic stimuli, cells adapt to achieve a steady state (homeostasis) The adaptive responses are: Atrophy (decrease in size) Cell shrinks in an attempt to reduce its workload Hypertrophy (increase in size) 2 types Physiologic A uterus enlarges in response to estrogen signals Pathologic The enlargement of the heart in response to hypertension Hyperplasia (increase in number) Cells that are capable of mitotic division will accelerate mitosis in order to increase their number and functional ability Metaplasia (change in form) When exposed to persistent injury, cells will replace themselves with a different type that is better able to deal with that injury Example: Barretts Esophagus after long exposure to reflux Dysplasia A dysfunctional effort to adapt Usually considered pre-neoplastic Cellular injury In early stages, mild forms of cell injury us reversible in the injurious agent is removed Continual cell damage and injury causes an irreversible state that the cell cannot recover from and the cell dies Causes of cell injury Oxygen deprivation Hypoxia most common cause of cell injury Cell swells Anaerobic glycolysis tries to compensate Lactate is produced Cellular pH, impairing other cell functions This process can be reversed until plasma membrane and mitochondrial membranes are critically damaged Interferes with cellular metabolism and generation of ATP NO O2 = NO ATP! Decrease in ATP slows cell processes The energy dependent Na+K+ pump Na+ accumulates in the cell drawing water in Highly reactive oxygen species (ROS) Highly volatile free radicals will react with any chemical with which they come in contact with Can damage proteins, fats, DNA Chemical agents Some toxic chemicals are inherently reactive Heavy metals (lead, mercury) Toxic gases (carbon monoxide) Corrosives (acids, alkalis) Antimetabolites (cyclophosphamide, vincristine) Physical agents Mechanical forces Direct trauma to cell membranes Blunt force trauma Direct penetrating trauma Hypothermic injury Severe vasoconstriction and increased blood viscosity causes ischemia With continued exposure, vasodilation may occur Cytosol freezes and intracellular ice crystals form Hyperthermic injury Microvascular coagulation Increased metabolic processes Direct tissue destruction Electrical injury Cells of the body act as conductors of electricity Neural and cardiac impulses are interrupted Hyperthermic destruction occurs Current flows through the path of least resistance Electromagnetic radiation Direct-hit: breakage of chemical bonds holding DNA together Ionizing radiation: orbital electrons are knocked off Activated oxygen molecules act like free radicals and steal other electrons Genetic damage Radiation induced cell death Infectious agents Immunological reactions Genetic defects Nutritional imbalances Most vitamins, minerals, and some amino acids must come from diet Cell injury can come from a deficiency or excess of nutrients Aging Reversible cell injury and cell death Cell destruction and removal can involve 2 mechanisms Apoptosis Programmed cell death Highly selective process that eliminates injured and aged cells thereby controlling tissue regeneration Cell death/necrosis Refers to cell death in an organ or in tissues that are still part of a living person Cellular autodigestion Also initiates an inflammatory process In contrast to apoptosis which functions in removing cells so new ones can replace them, necrosis often interferes with cell replacement and tissue regeneration Gangrene occurs with a considerable mass of tissue undergoes necrosis Types of necrosis Liquefaction neuron and glial cells of the brain Turn to softened center of abscess with discharge of contents Cells dies but catalytic enzymes are not destroyed Coagulation Dead cells convert to gray, firm mass Opaque state Seen in heart, kidney, and adrenal glands Caseous exclusive to TB Body walls this off and middle becomes white, soft, and fragile Dead cells persist as a cheese-like debris in lungs Immune mechanism Gangrene (wet/dry/gas) When a considerable amount of tissue undergoes necrosis Dry SLOW Affected tissues becomes dry and shrinks, skin wrinkles Color changes to dark brown or black Causes an inflammatory reaction Line of demarcation between dead and healthy tissue Typically and arterial problem Mainly confined to the extremities (clot) Wet RAPID It is a form of liquefaction necrosis Due to interference of venous blood return Affect area is cold, swollen, and pulseless Skin is moist, black, and under tension Blebs form on the surface Liquefaction occurs Foul odor caused by bacterial action Can become systemic = death if not stopped Can affect internal organs/extremities Dry can convert to wet if bacteria invade Gas RAPIDLY FATAL Gangrene that results from clostridium bacteria, usually clostridium perfringes Anaerobic spore-forming organisms Produce toxins that cause cell membrane to dissolve = edema, death to muscle cells, renal failure Prone to occur in trauma and compound fractures in which dirt and debris are embedded in wounds Produces hydrogen sulfide gas This is why it is so serious and rapidly fatal Antibiotics are used and may need surgical intervention and amputation to stop the spread Phases of wound healing Inflammatory Begins at time of injury Prepares wound environment for healing Hemostasis first (to promote blood clotting) Next come the vascular and cellular phases of inflammation Cleans debris (phagocytosis) WBCs Promotes growth of blood vessels Attracts fibroblasts Proliferative Begins 2-3 days after injury, may last 3 weeks Fibroblasts synthesize collagen (peaks in 5-7 days) Proliferation of fibroblasts and vascular endothelial cell form granulation tissue serve as foundation of scar tissue Tissue is fragile, bleeds easily due to newly developing capillary beds Remodeling (Maturation) Begins 3 weeks after injury; lasts for months to 2 years Continuous remodeling: collagen synthesis and lysis of scar tissue cell Increases tensile strength of the wound over time Really only ever gets to 70-80% of normal strength

Neoplasia Characteristics of cancer Disorder of altered cell differentiation and growth results in neoplasia (new growth) Growth is uncoordinated and relatively autonomous Lacks normal regulatory controls over cell growth and division Tends to increase in size and grow after stimulus eases or needs of the organism are met Components of tissue renewal and repair Cell proliferation Process of cell division Inherent adaptive mechanism for replacing body cells Cell differentiation Process of specialization New cells acquire the structure and function of cells they replace Apoptosis A form of programmed cell death to eliminate unwanted cells Cell division G1 (gap 1): the postmitotic phase DNA synthesis ceases, while ribonucleic acid (RNA) and protein synthesis and cell growth take place S phase: DNA synthesis occurs Gives rise to 2 separate set of chromosomes, one for each daughter cell G2 (gap 2): the premitotic phase DNA synthesis ceases RNA and protein synthesis continues M phase: the phase of cellular division or mitosis Stem cells Reserve cells that remain inactive until there is a need for cel replacement Self-renewal Potency Totipotent: produced by fertilization of an egg Can differentiate into embryonic and extraembryonic cells Pluripotent: can differentiate into the three germ layers of the embryo (echoderm, mesoderm, endoderm: all organs) Multipotent: give rise to only a few cell types Unipotent: give rise to one type of differentiated cell, but retain the property of self-renewal Muscle satellite cell Epidermal stem cell Spermatogonium Basal cell of the olfactory epithelium Tumors Adding the suffix oma to the parenchymal tissue type from which the growth originated Neoplasms Benign Slow, progressive rate of growth that may come to a standstill or regress An expansive manner of growth Inability to metastasize to distant sites Composed of well-differentiated cells that resemble the cells of the tissue of origin Malignant Grow rapidly and spread widely Have the potential to kill regardless of their original location Compress blood vessels and outgrow their blood supply, causing ischemia and tissue necrosis Rob normal tissues of essential nutrients Liberate enzymes and toxins that destroy tumor tissue AND normal tissue Factors that differentiate benign and malignant tumors Cell characteristics Benign = well-differentiated cells Malignant = loss of differentiation in cells Manner of growth Benign = expansive manner of growth, but typically remain in one place Malignant = use seeding, direct invasion, and blood/lymph to grow Rate of growth Benign = slow and progressive Malignant = rapid and spread widely Potential for metastasizing or spreading Benign = little chance of metastasizing Malignant = great chance of metastasizing Tendency to cause tissue damage Benign = tissue damage minimal Malignant = compresses blood vessels causing ischemia and tissue necrosis Liberates enzymes that may kill both tumor tissue but healthy tissue as well Capacity to cause death Benign = may press on vital organs, but overall lower potential of death Malignant = may rapidly invade or seed into organs and other sites which give high chance of death Anaplasia = term used to describe the loss of differentiation in cancerous tissue cells Genes that control cell growth and replication Proto-oncogenes normal genes that become cancer causing oncogenes if mutated They are heavily involved in growth factors and promoted cancer when turned on They get erroneously activated Tumor suppressor genes They actually inhibit cellular proliferation, but when switched off they can create an environment in which cancer is promotes TP53 gene mutation in this gene is implicated in the development of breast, lung, and colon cancer Genes that control programmed cell death or apoptosis Genes that regulate repair of damaged DNA Steps involving the transformation of normal cells into cancer cells Initiation irreversible event Cell exposed to doses of carcinogenic agents making them susceptible to malignant transformation Proliferation is required (cell must be able to divide) Promotion Unregulated accelerated growth in already initiated cells caused by various chemical and growth factors Progression Tumor cells acquire malignant phenotypic changes that promote invasiveness, metastatic competence, autonomous growth tendencies, and increased karyotypic instability DNA damage (mutation) Initiation Proliferation (growth promoters) promotion Development of cancerous phenotype progression Detectable tumor size is 1 cm by then it already has 1 billion cells in it Tumors cannot grow more than about 2mm unless they grow blood vessels into the tumor (angiogenesis) Treatments Chemotherapy Radiation Contraindicated in childhood cancer treatment as it has been shown to have long-lasting and even delayed effectsInnate and Adaptive Immunity Immune response Immune response = the collective, coordinated response of the cells and molecules of the immune system to protect against infectious disease Purpose of the immune system To neutralize, eliminate, or destroy microorganisms that invade the body To recognize and eliminate aberrant cell like cancer Immune Defenses Innate/NON-specific immunity The natural resistance a person is born with Adaptive/Specific immunity 2nd line of defense Response is less rapid than innate, but more effective Can also produce undesirable effects: Allergies: an excessive immune response Autoimmune disease: immune system recognizes self-tissue as foreign Components of the immune system Skin, mucous membranes, phagocyte system, lymphoid system (spleen, thymus gland, and lymph nodes), bone marrow Principle cells in the immune system Lymphocytes: recognize and respond to foreign antigens Accessory cells: Macrophages and dendritic cells (monocytes) Function as antigen-presenting cells by the processing of a complex antigen into epitopes required for the activation of lymphocytes Mediators of immune system Cytokines Soluble proteins secreted by cells of both the innate and adaptive immunity Chemokines Cytokines that stimulate the migration and activation of immune and inflammatory cells Colony-stimulating factors Stimulate the growth and differentiation of bone marrow progenitors of immune cells Cells in innate immunity Macrophages Dendritic cells bridge between innate and adaptive immunity Mast cells NK cells Can be divided into 2 main subsets based on their ability to excrete proinflammatory cytokines Ability to spontaneously kill target organisms which relies on the recognition of specific PAMPs with the microorganism type Complement proteins Basophils Eosinophils Neutrophils Granulocytes Cells in adaptive immunity B cells antibodies T cells CD4+ T cells CD8+ T cells Components for Innate immunity Epithelial barriers Phagocytic cells (neutrophils and macrophages) NK cells Plasma proteins Opsonins facilitates phagocytosis Cytokines chemical signaling TNF (tumor necrosis factor) Interleukins (IL) Interferons (IFN) Chemokines Acute-phase proteins/reactants Two types Mannose-binding ligand binds specifically to mannose residues C-reactive protein binds to both phospholipids and sugars that are found on the surface of the microbes Both act as costimulatory opsonins and enhance the binding of phagocytic cells to invading microorganisms Complement system a process that involves plasma proteins found in the blood which are essential for the activity of antibodies When foreign bodies invade, this system activates Primary function: promotion of inflammation and destruction of the microbes Three phases of complement system reactions Initiation or activation Activation by one of the three pathways listed below Amplification of inflammation All pathways lead to the activation of complement protein C3 and its enzymatic cleavage into C3b (larger) and C3a (smaller) segments C3a = chemoattractant for neutrophils C3b = becomes attached to the microbe and acts as an opsonin for phagocytosis and acts as an enzyme to cleave C5 into 2 components C5a = produces vasodilation and increases vascular permeability C5b leads to late-step membrane attack responses Membrane attack response C3b bind to other complement proteins to form an enzyme that cleaves C5 C5a = stimulates the influx on neutrophils in the vascular phase of acute inflammation C5b = remains attached to the microbe initiates the formation of a complex of complement proteins C6, C7, C8, and C9 into a membrane attack complex protein, or pore that allows fluids and ions to enter and cause cell lysis Multiple pathways that result in recognizing microbes and complement system activation Classic pathway Activated by certain types of antibodies bound to antigen and is part of humoral immunity Lectin pathway Activated by plasma lectin that binds to mannose on microbes and activates the classical pathway in the absence of antibody Alternative pathway Activated on microbial cell surfaces in the absence of antibody Is a component of innate immunity Cytolysis Opsonization Chemotaxis Anaphylaxis Adaptive immunity Types of adaptive immune response Humoral immunity/antibody mediated Mediated by molecules in the blood The principal defense against extracellular microbes and toxins Cellular immunity/cell mediated Mediated by specific T lymphocytes Defends against intracellular microbes such as viruses Lymphocytes B cells Humoral immunity that have memory Produce antibodies Matures in the bone marrow and differentiate into memory cells or immunoglobulins IgA found in mucous, saliva, tears, and breast milk. Protects against pathogens IgD part of the B cell receptor. Activates basophils and masts cells IgE protects against parasitic worms. Responsible for allergic reactions IgG Secreted by plasma cells in the blood. Able to cross the placenta into the fetus IgM may be attached to the surface of a B cell or secreted into the blood. Responsible for early stages of immunity Antigens are substances foreign to the host that can stimulate an immune response Production begins about 72 hours after exposure Antibodies recognize antigens Receptors on immune cells Secreted proteins

T cells Cell mediated immunity that have memory Destroys antigens Matures in the thymus Regulatory cells (helper and suppressor cells) Assist in orchestrating and controlling the immune response Helper T cells activate other lymphocytes and phagocytes Regulatory T cells keep these cells in check so that an exaggerated immune response does not occur Cytotoxic T cells effector cells Effector cells (killer cells) Accomplish the final stages of the immune response with the elimination of the antigen Activated T lymphocytes, mononuclear phagocytes, and other leukocytes function as effector cells in different immune responses An antigen presenting cell (APC) eats a virus the APC breaks down that virus molecule but take a piece of it and presents it on the cell surface via a major histocompatibility complex type 2 (MHC II) A helper-T cell with a T cell receptor attaches to the epitope of the virus piece (antigen) which activates the helper-T cell helper-T cell sends out cytokines to cytotoxic T cells so that they can bind to the viral epitope of the target cell via the T cell receptor (TCR) and releases toxic materials into the target cell resulting in target cell death the helper-T cell sends out cytokines which activates the B cell with membrane bound Ig molecules that make up receptor sites that can bind with specific epitopes of antigens that the B cells then divide several times to form populations (clones) of cells that continue to differentiate into several types of effector and memory cells (helper-T cell differentiates into the cytotoxic [as stated before] and memory T cells; B cells differentiate into plasma cells [to make more antibodies for that specific antigen] and memory B cell) B cells may even recognize and antibody before the T cell and interact with a helper-T cell by presenting part of the antigen on its surface via an MHC II and connecting with the TCR on the helper-T cell MHC helps immune system recognize foreign substances Class I: all nucleated cells Present processed antigen to cytotoxic CD8+ T cells Restrict cytolysis to virus-infected cells, tumor cells, and transplanted cells Class II: are immune cells, APC, B cells, and macrophages Present processed antigenic fragments to CD4+ T cells Necessary for effective interaction among immune cellsInflammation, Tissue Repair, and Wound Healing Immunity First line of defense: innate immunity Second line of defense: Inflammation Third line of defense: Adaptive immunity Inflammation Goals: Limit and control the inflammatory process Prevent and limit infection and further damage Initiate adaptive immune response Initiate healing Inflammatory response is a protective mechanism that is stimulated when tissue is injured 3 purposes: Neutralize invading agents Limit spread to other tissues Prepare damages tissue for repair Inflammatory response involves: Vascular response Vasoconstriction from seconds to 10 minutes Produces tissue hypoxia and acidosis Vasodilation follows vasoconstriction Produces redness, pain, heat, edema, and impaired function Platelets move to site and adhere to vascular collagen Platelets release fibronectin (fibrin) to form meshwork and stimulate clotting Venous capillaries become permeable Fluid (protein-rich) leaks into the surrounding tissue to wall off the site Also is the exudate As fluid moves out of the vessels, stagnation of blood occurs allowing for next phase Cellular response Margination and adhesion Leukocytes (mainly) neutrophils (that were recruited to the site on injury via cytokines) line the endothelium of blood vessels Transmigration Leukocytes (mainly) neutrophils slide through pores of the vessels into the inflamed tissue Chemotaxis Migration of leukocytes (mainly) neutrophils to site of tissue injury via a chemical gradient (like chemokines) Activation of leukocytes (mainly) neutrophils Enclose the foreign substances Intracellular killing Chemical response Activated granulocytes, lymphocytes, and macrophages release chemical mediators Histamine (released by mast cells and basophils Among first to be released during acute inflammation Increases vasodilation and vascular permeability Primary activator of endothelial cell retraction H1 receptor: smooth muscle cells in bronchi H2: parietal cell of the stomach mucosa Bradykinins (activated kinin system results in its release) Increases vascular permeability Vasodilates Contracts smooth muscle cells Platelet activating factor Generated from a complex lipid stored in cell membrane Induces platelet aggregation Activates neutrophils Potent eosinophil chemoattractant Cytokines IFN Primarily protect host against viral infections Primarily play role in modulation of inflammatory response IFN and IFN produces primarily by macrophages IFN produced primarily by T lymphocytes TNF Endogenous pyrogen Induces synthesis of proinflammatory substances in liver Prolonged exposure can cause intravascular coagulation with subsequent thrombosis production IL Produced by macrophages and lymphocytes Produced in response to presence of invading microorganism or activation of inflammatory process Primary function is to enhance acquired immune response though: Molecular expression Induction of leukocyte maturation Enhance leukocyte chemotaxis General enhancement or suppression of inflammatory process Arachidonic acid Released by phospholipases Initiates series of complex reactions which Leads to production of eicosanoid family inflammatory mediators Lipooxygenase (LOX) Leukotrienes Induces smooth muscle contraction Constricts pulmonary airways Increases microvasculature permeability Cyclooxygenase (COX) Prostaglandins Induces vasodilation and bronchoconstriction Stimulate platelet aggregation Act as chemotactic factor Responsible for increased sensation of pain Thromboxane Vasoconstricts Increases bronchoconstriction Promotes platelet function Aspirin and other NSAIDs work as COX inhibitors Acute and chronic inflammation Acute Of relatively short duration Nonspecific early response to injury Infiltration of neutrophils Aimed primarily at removing the injurious agent and limiting tissue damage Heat, swelling, redness, pain, exudative fluids Exudate Serous watery exudate: indicates early inflammation Fibrinous Thick, clotted exudate: indicated more advanced inflammation Purulent pus: indicated a bacterial infection Sanguineous/hemorrhagic contains blood: indicated bleeding Systemic manifestations Fever Sepsis Leukocytosis Increased number of circulating leukocytes Increased plasma protein synthesis Acute phase reactants C-reactive protein Fibrinogen Haptoglobin Chronic Self-perpetuating and may last from weeks to years Infiltration by mononuclear cell (macrophages) and lymphocytes Proliferation of fibroblasts Unsuccessful acute inflammatory response Characteristics Dense infiltration of lymphocytes and macrophages Granuloma formation Epithelioid cell formation Giant cell formation Wound healing Primary intention Wounds that heal under conditions of minimal tissue loss and wound edges are approximated Secondary intention Great loss of tissue with contamination Phases of wound healing Inflammatory Begins at time of injury Prepares wound environment for healing Hemostasis first (to promote blood clotting) Next come the vascular and cellular phases of inflammation Cleans debris (phagocytosis) WBCs Promotes growth of blood vessels Attracts fibroblasts Proliferative Begins 2-3 days after injury, may last 3 weeks Fibroblasts synthesize collagen (peaks in 5-7 days) Proliferation of fibroblasts and vascular endothelial cell form granulation tissue serve as foundation of scar tissue Tissue is fragile, bleeds easily due to newly developing capillary beds Granulation, epithelialization, collagen formation Remodeling (Maturation) Begins 3 weeks after injury; lasts for months to 2 years Continuous remodeling: collagen synthesis and lysis of scar tissue cell Continuation of cellular differentiation Scar tissue formation Scar remodeling Increases tensile strength of the wound over time Really only ever gets to 70-80% of normal strengthDisorders of the Immune Response Alterations of the immune system Hypersensitivity or allergic reactions Inappropriate or excessive activation of the immune system 4 types Type I IgE mediated (immediate hypersensitivity) Begins rapidly following antigen challenge Allergic reaction Anaphylaxis Begins with mast cell of basophil sensitization Mast cells are normally in connective tissue beneath skin and mucous membranes of respiratory, GI, and Gu tracts Primary or initial phase response 5-30 minutes after exposure Vasodilation Vascular leakage Smooth muscle constriction Histamine mediated Secondary or late phase response 2-8 hours after exposure and may last several days Intense infiltration of tissues with inflammatory cells Tissue destruction and epithelial damage Arachidonic acid and cytokine mediated Type II antibody mediated Reaction is mediated by IgG or IgM 3 mechanisms reactions can affect cell Cell destruction by activation of complement cascade Antibody dependent cell mediated cytotoxicity NK cells release toxins Antibodies cause cell destruction through phagocytosis Hemolytic disease of newborns Rh factor Mismatched blood transfusions Cell inflammation caused by neutrophil by-products (reactive oxygen intermediates and enzymes) Cell dysfunction which prevents normal interactions by inappropriately stimulating or destroying the receptor Graves disease Myesthenia Gravis Type III complex mediated Insoluble Antigen-Antibody (immune) complexes formed in circulation and deposited in vessel walls or tissues. Binds to soluble antigen released into blood or body fluids and subsequently deposited in tissues (large area) Once deposited, immune response elicits an inflammatory response and lysosomal enzymes are released into the inflammatory site instead of into the phagolysosomes causing tissue damage Systemic Immune Complex Serum sickness (antibiotics, food, venom), autoimmune vasculitis, glomerulonephritis Local Immune Complex Arthus Reaction Type IV cell mediated Cell-mediated: sensitized T cells attack antigen Direct cell-mediated cytotoxicity Cytotoxic T cells Viral reactions Hepatisis Delayed-type hypersensitivity Macrophages, T helper cells Tuberculin test, allergic contact dermatitis, hypersensitivity pneumonitis Transplant rejection Categories of transplant tissue: ALLOGENIC: may or may not be related but have similar HLA types SYNGENEIC: identical twins AUTOLOGOUS: same person Organ graft rejection Hyper-acute Circulating antibodies react with the graft Type III Arthus-type reaction Immediate post transplant Acute Generation of T cells, antibodies against graft Within first few months post transfer Chronic Blood vessels in the graft gradually damaged Manifests in the dense intimal fibrous tissue of blood vessels in the transplanted organ Mechanism is NOT well understood Prolonged period of time GRAFT vs Host Disease (GVHD) Transplant needs a functional immune component. Host tissues has antigens foreign to donor tissue. Host immunity compromised. Autoimmune disorders Normally, self-reactive immune cells are destroyed or suppressed. In autoimmunity, self-tolerance breaks down and the immune system attacks self-antigens destroys body tissues Autoimmune disorders Systemic Lupus Erythematosus (SLE) Autoimmune Hemolytic Anemia (AIHA) Hashimoto Thyroiditis Immunodeficiency states Primarygenetic Humoral (B-cell) deficiencies Cellular (T-cell) deficiencies Severe combined immunodeficiencies (SCID) Wiskott-Aldrich syndrome Acquiredconsequence of another event Malnutrition Immunosuppressant drugs AIDS