Pathophysiology - 01 Basic Mechanisms

PATHOPHYSIOLOGY DISEASE CATEGORIES LECTURE 1 - BASIC MECHANISMS OF PATHOPHYSIOLOGY DEFINITION OF TERMS • • • • Pathology - result of disease and changes in homeostasis Homeostasis - process of maintaining normal balance within the body. Disease - when homeostasis isn’t maintained, disease ensues Pathophysiology - the study of abnormal functions in the body and how disease processes work. PATHOGENESIS • • • • The development of a disease is referred to as (-genesis = origin or development). The sequence of events that leads from cause of disease to structural and functional abnormalities, to how the disease manifests itself and finally to the resolution or recovery of the disease. Example: common cold o Cause = exposure and inoculation of cold virus o Incubation time = virus multiplies o Manifestation = host begins to have signs and symptoms (sore throat, itchy eyes, runny nose, etc.) o Recovery = return to previous state of health Pathogenesis of a diseases may be explained in terms of time: o acute disease – disease of sudden onset which runs a severe but short course o chronic – long-term (sometimes reoccurring) illness PREDISPOSING FACTORS (RISK FACTORS) • • • • • • • • Age o Newborn babies ▪ immature immune system ▪ liver enzymes necessary for detoxification o Elderly ▪ decrease in immune function ▪ decline in homeostatic mechanisms Sex - some diseases are more prone to one gender than the other Genetic makeup (familial tendencies for: diabetes, asthma, migraines, etc.) Stress - increases body’s production of corticosteroids, which decreases immune system function. Lifestyle - personal habits in regard to diet, exercise, weight control, smoking, alcohol consumption, sexual practice Occupation - exposure to loud noises, pollutants, repetitive movements, heavy equipment, high places, etc. Preexisting illness o illnesses can lower body’s resistance and make individuals more susceptible to other diseases o chronic illness interferes with proper function of some body systems, therefore complicating disease Environmental exposure o prolonged exposure to cold or heat can lower the body’s resistance o exposure to allergens o long-term exposure to sunlight o long-term exposure to occupational chemicals • Disease processes can be categorized into one of two groups: structural or functional • Structural Disease (Organic Disease) o involve physical & biochemical changes w/in the cells o structural changes in cells are initiated by two types of agents: ▪ Exogenous - those that are external, i.e. trauma, chemical injury, and microbial infections. ▪ Endogenous - those that are internal, i.e. vascular insufficiency, immunological/ autoimmune reactions, and diseases that are a result of abnormal metabolism. • The hallmark characteristic of structural disease is the lesion. o The word lesion comes from Latin language and means “to hurt.” o Lesion is a widely used term to describe many types of cellular changes that result in tissue abnormalities. (cuts, fractures, masses, etc.) o Lesions are primarily detected by observation with the naked eye or with a microscope. • Examples of Varying Effects Of Structural And Functional Diseases Disease Type of Disease Nature of Manifestation Common cold Structural (viral Structural (runny infection) nose, sneezing) Tension Functional Functional (pain) headaches (muscle spasm) Benign tumor that Structural (tumor) Structural (mass) produces mass Exogenous Functional Structural obesity caused by (hunger) (obesity) craving food Cancer of Structural Functional esophagus (cancer) (inability to eat) CAUSES OF DISEASE • • • • To better understand and identify different structural diseases and their cause, they are commonly subclassified: Infectious Diseases o those diseases that are caused by invasion and colonization of pathogenic microorganisms o examples: fungal infection, bacterial infection, and viral infection Immunologic Diseases o Three immunologic categories: o overreaction by immune system (hypersensitivity) o under-reaction by immune system (immune deficiency disease such as AIDS). o autoimmune disease – destruction of one’s own tissues by antibodies produced by one’s own immune system Nutritional Diseaseso diseases created by insufficient resources for body o protein deficiency – difficulty in healing or formation of new body tissue; decrease in antibody production o vitamin or mineral deficiencies – may lead to interference in biochemical reactions of metabolism o Obesity • • • • • • • Neoplasms (“new growth”) o the uncontrolled growth of abnormal cells o growth may be benign or malignant(cancerous) Metabolic Diseases o an upset in the biochemical reactions that govern body processes or metabolism o Sub-classified as nutritional because the upset is often connected to carbohydrate, fat, or protein metabolism Genetic Diseases o inherited or hereditary diseases due to transmission of defective genes or chromosomes from one or both parents o examples: diabetes, Down Syndrome, hemophilia, cleft lip Congenital Disease (also referred to an anomaly/defect) o a defect in fetal development that may create a functional (physiologic) or structural (physical) abnormality which presents itself at birth o these defects may be genetic; they may be exposure to chemicals, drugs, or viruses during the pregnancy; they may be a spontaneous event Trauma o physical force that mechanically disrupts the structure of the body (therefore, disrupts body function) o result of trauma is generally referred to as an injury o results of trauma include bruises, abrasions, cuts, fractures, burns, etc. Physical Agents - diseases that result from physical agents such as temperature extremes, electrical shock, radiation, and poisons Inflammatory Diseases - diseases that are usually secondary to primary disease such as infection or autoimmune disease. • • THE DISEASE PROCESS • Manifestations of Disease o To treat a patient, a physician must first know the manifestations of a disease. o Manifestation refers to how a disease “presents or shows itself”. o Manifestation is also called clinical presentation and includes both signs and symptoms. o Signs ▪ objective physical observations as noted by the person who examines the patient ▪ this examination is called a physical or the physical examination ▪ during the physical, the health professional may use techniques such as: • ausculation - use of stethoscope to listen to body cavities • palpation - feeling lightly or pressing firmly on internal organs or structures • percussion - tapping over various body areas to produce vibrating sound that is indicative of air, fluid, size of organ ▪ examples of signs are: temperature, blood pressure, respiratory rate, abnormal heart sounds, mass, enlarged organs, edema o Symptoms - refer to the patient’s awareness of abnormalities/discomfort. Symptoms aren’t measurable and based on the patient’s subjective • • perception, i.e. pain, nausea, weakness, fatigue, dizziness ▪ The written description of symptoms in the patient’s record is referred to as patient history. Care of the Patient ▪ Caring for the patient involves three major steps: 1. obtaining a history to ascertain the patient’s symptoms and to review any past or present medical problems that might relate 2. performing a physical examination on the patient 3. laboratory tests, radiologic, and clinical procedures to detect chemical and physiologic abnormalities to aid in establishing the diagnosis Etiology and Related Terms o The etiology of disease is its cause (term literally means the study of causes). o If the cause of a disease has never been discovered (disease is unknown), the cause is referred to as idiopathic. o One may also refer to an idiopathic disease as “unknown etiology”. o Iatrogenic disease (-iatro = medicine, physician) means that the disease arose as a result of a prescribed treatment ▪ Examples: ▪ Cushing-like Syndrome as result of steroid therapy ▪ immunosupression and/or anemia as a result of chemotherapy o A nosocomial disease is one that was acquired from a clinical setting (hospital; physician’s office; clinic). ▪ postoperative patient develops staph infection from surgical instrument that wasn’t properly sterilized ▪ child develops cold after being exposed to other sick children at the pediatrician’s office Diagnosis o Process of assigning a name to a patient’s condition. o When clusters of findings with more than one disease are found, they are called syndromes. o Diagnosis is needed to determine the treatment and potential outcome of a disease. Treatment (therapy) o Treatment of a disease should be as precise as possible in order to attempt a cure. o Treatment interventions may include: exercise, nutritional modifications, physical therapy, medications, surgery, and education o Three common therapies are: o Supportive therapy – includes rest, optimal nutrition, fluids, possible antibiotics to prevent a secondary infection while the immune system is recovering o Palliative therapy – not a curative therapy; provides relief from signs and symptoms of their disease ▪ Examples of this therapy might include: steroids, pain relievers, possible surgery (removal of tumor, etc.) ▪ This treatment used for terminal illnesses and other serious chronic conditions for which there is no cure o Preventive therapy – care given to prevent disease ▪ Examples: mammograms, blood pressure screenings, routine dental care, colon cancer tests • Prognosis o The prognosis is the predicted or expected outcome of the disease o Prognosis is often listed as: ▪ Good (full recovery) ▪ Guarded (full recovery may or may not occur) ▪ Poor (not expected to recover) • Direct Contact o Some animal and plant cells can communicate directly through junctions through which signals can travel between adjacent cells. • Reception, Transduction, Response o In order for the signal to cause a response in a cell, that cell must have the proper signaling system. Cells without, ignore the signal. o Reception: the signal binds to a specific cellular protein called a receptor, usually on the cell’s surface o Signal Transduction: the binding causes a change in conformation, which then converts the signal into a cell response o Cellular Response: the transduction system causes a specific cell response, ie. Altered gene expression, enzyme activation Signal Reception and the Initiation of Transduction o A chemical signal binds to a receptor protein causing the protein to change shape o The signal is complementary to the receptor protein (like an active site) o The signal behaves as a Ligand: A small molecule that binds to a larger one. This binding can lead to: o Change in protein conformation, allowing it to interact w/ other cell molecules o Aggregation of receptor complexes Overview of Cell Signaling: REVIEW OF NORMAL CELL STRUCTURE AND FUNCTION • CELL TO CELL COMMUNICATION • • Cell Signaling o Autocrine - cell respond to substances which they themselves release and thus changes takes place in the cell itself (ex. Tumor cells) o Paracrine Signaling - a cell secretes the signal into extracellular fluid, acts on nearby cell o Endocrine - signal to cells which are some distance apart (Hormones) ▪ Examples: Ethylene in plants, insulin in animals o Synaptic Signaling - a nerve cell releases a signal (ie. neurotransmitter) into a synapse. The target cells are other nerve cells or muscle cells Local and Distant Cell Communication • • Most Signal Receptors are Plasma-membrane proteins o 3 Types: o G-Protein-Linked Receptors ▪ Weaves in and out of the membrane 7 times (has 7 transmembrane domains) ▪ Example: Epinephrine receptor ▪ The receptor causes a response by interacting with proteins on the cytoplasmic side called Gproteins, cause they bind Guanine nucleotides, GDP, GTP • G proteins bound to GDP: Inactive • G proteins bound to GTP: Active ▪ o o G (protein) • When a ligand binds to a G-ProteinReceptor, the conformation changes and reacts w/ a G-protein, which causes the GDP to be displaced by GTP, thus activating it. • The activated G protein binds to another protein, usually an enzyme, resulting in the activation of a target enzyme. • This is temporary, as the G-protein has GTPase, which breaks it back down to GDP Tyrosine-Kinase Receptors ▪ 2 Parts: ▪ Extracellular ligand-binding domain, ▪ Cytosolic domain posessing tyrosine-kinase enzyme activity ▪ Examples: Growth Factors like PDGFs ( a family of factors which modulate the cell cycle) 1. Ligand binding causes aggregation of 2 receptor units, forming receptor dimers 2. Aggregation activates the tyrosine-kinase activity in cytoplasm 3. These catalyze transfer of phosphate groups from ATP to tyrosine (an amino acid) in a protein. If this protein is part of the cytoplasmic T-K receptor, it’s called autophosphorylation 4. The phosphorylated domain of the receptor reacts w/other proteins, resulting in the activation of another, RELAY protein or proteins. This can jump start MANY transduction systems simultaneously 5. One of the relay proteins may be Protein Phosphatase, which hydrolyzes a Phosphate off of proteins, possibly the tyrosines in the T-K receptors, thus inactivating them. -Negative feedback ▪ Tyrosine-Kinase Reception: • • Ion-channel receptors ▪ Some signals bind to ligand-gated ion channels. ▪ These are protein pores which open/close due to ligand binding, allowing/blocking the flow of specific ions (Na+, Ca2+) • ie.: Neurotransmitters ▪ These can be on the plasma membrane or in the cytoplasm or in the nucleus. The latter are called intracellular receptors, and must be able to pass through the plasma membrane. • ie: Steroids, Thyroid hormones, N.O. ▪ Structure of an ion-gated channel: Signal Transduction Pathways o Pathways relay signals from receptors→Cell responses: The ligand signal is not passed directly, but the signal INFORMATION is. At every step the signal is converted or transduced Protein Phosphorylation as signal transduction o Caused by protein kinases o Very common o Commonly found in cytoplasm o Don’t act upon themselves (like T-K), but on other proteins, and attach phosphates to serine or threonine residues o Some activate, some deactivate target proteins o Protein Phosphatases reverse these o Phosphorylation cascade: • Ions o Second Messengers: signal transduction components which are not proteins, but are small water soluble molecules or ions. o Two second messenger systems: o Cyclic AMP (cAMP) ▪ Ligand binds to receptor(1st message) ▪ Receptor conformation changes -> G-Protein complex is activated ▪ Active G-Protein activates adenyl cyclase (on cytoplasmic side of mem.) ▪ Adenyl cyclase converts ATP to cAMP ▪ cAMP binds to/activates protein kinase A ▪ Protein kinase A phosphorylates various other proteins, leading to a cell response ▪ Signal Transduction Pathways • Pathways relay signals from receptors→Cell responses: The ligand signal is not passed directly, but the signal INFORMATION is. At every step signal is converted or transduced ▪ Maintenance of Ca2+ in Animal cells: ▪ Ca2+ and IP3 in signaling pathways cAMP as 2nd Messenger: • o ▪ CA2+-Inositol Triphosphate (IP3) System ▪ Many cells induce a specific response by increasing their cytoplasm’s Ca+ concentration. ▪ Ca2+ can be increased by: • Ligand binding to Ca2+-gated ion channel • Activation of IP3 signaling pathway ▪ ACTIVATION: 1. Ligand→Conformational Change in receptor 2. Receptor→activates enzyme phospholipase→These hydrolyze membrane phospholipids→give rise to 2nd messengers: IP3 and diacylglycerol 3. Diacylglycerol→Protein kinase 4. IP3 binds to Ca2+-gated channels on ER, where CA2+ is stored 5. CA2+→signal transduction by affecting target proteins directly or indirectly by binding indirectly to calmodulin→modulates Protein kinases and phosphatases Cellular Response - can involve regulation of cytoplasmic activities or transcription in nucleus o In Cytoplasm: ▪ Can affect function/activity of proteins which can: ▪ Rearrange cytoskeleton ▪ Open/close ion channels ▪ Serve at key points in matabolic pathways o In Nucleus: ▪ Signaling system affects synthesis of new proteins/enzymes by modulating gene expression ▪ Can regulate transcription (DNA→mRNA) factors ▪ Dysfunction in these can lead to cancer, etc o Cytoplasmic Response: o Nuclear Response: • • Amplification/Specification of Cell Response o Amplification: Production of 2nd messengers (cAMP) intrinsically amplify signal. When this is linked to a phosphorylation cascade, the result is almost exponential o Signal Specificity: Only target cells have the appropriate machinery to respond to a given signal (ligand). o Different cells can have different signal transduction pathways inside, so 1 signal molecule can affect different cells differently o Specificity of Cell Signaling: • • CELLULAR ADAPTATION • • • • Permits survival and maintenance of cell function May alter differentiation of genes enabling a cell to change size or form. Is a normal adaptive response to an appropriate stimulus Atrophy o environmental conditions ▪ Is adaptive and reversible ▪ results in a decrease in cell size (cells shrink) o Types ▪ Disuse atrophy (paralysis) ▪ Degeneration atrophy (MS) ▪ Ischemic atrophy (kidney, heart) ▪ Malnutrition atrophy (starvation) ▪ Loss of endocrine stimulation (uterine, breast) Hyperthrophy o Causes an increase in cell size & cell function o Results in an increase in tissue mass o Seen in cardiac, skeletal, and muscle tissue o These cells are not capable of mitosis (so, no  number or hyperplasia) o May be a normal physiologic response (as seen in an increase in muscle size with exercise) o May be a pathological response as in myocardial hypertrophy from hypertension or valve disease o Example: Left ventricular hypertrophy (LVH) ▪ A pathological hypertrophy resulting in  size of heart due to  workload caused by hypertension. ▪ There is an increase in size but function is compromised ▪ However, there is a LIMIT to the amount the tissue can enlarge Hyperplasia o Occurs due to a response from appropriate stimulus and ceases when stimulus is removed o An increase in number of cells o Restricted to cells capable of mitosis ▪ epidermis, intestinal epithelium, glandular tissue. o Physiological hyperplasia: uterus and breast enlarge in pregnancy o May be a physiological response and occur with hypertrophy ( in both cell size & number) ▪ wound healing o May also be a non-physiologic hyperplasia ▪ Seen in prostatic hypertrophy (BPH), endometrial hyperplasia due to increased hormone stimulation, or thyroid enlargement o Goiter – thyroid hyperplasia Metaplasia o One cell type is replaced by another o May predispose to cancer o Involves reprogramming of undifferentiated stem cells o Allows cells to better survive in a hostile environment o Is reversible o Is a response to chronic irritation and inflammation o Cells that are normally columnar or stratified may change to squamous. ▪ Examples: ▪ With continued smoke exposure, ciliated columnar cells are changed to stratified squamous cells ▪ Cervical cells change when exposed to STD/HPV o • • Think metamorphosis/change from one form to another ▪ Continued exposure may predispose to cancerous transformations. Dysplasia (atypical Hyperplasia) o Deranged cell growth resulting in cells of varying size, shape, and appearance ▪ May be associated with chronic irritation or inflammation ▪ May be reversible if offending agent is removed o Dysplasia is considered a strong precursor of cancer!!! ▪ Example: Cervical dysplasia o However, dysplasia is an adaptive process – may or may not lead to cancer o Decrease risk if irritation is removed or inflammation treated. Anaplasia o Cells differentiate to a more immature or embryonic form. o Malignant tumors are characterized by anaplastic cell growth. CAUSES OF CELL INJURY • • • • • • • Chemical Agents Hypoxia Infectious agents (bacteria, viruses, fungi) Physical and mechanical agents Genetic factors Nutritional imbalances Individuals have different abilities to adapt to these stressors