Unit 1- General Principles & Terminology Sept 2023 PDF

Lecture 1 General Principles & Terminology Tuesday 4th September 2023 Unit 1 – General Principles & Terminology Topics – Definitions – Capillary membrane dynamics – Body fluids – Lymphatic system – Functions of white blood cells including the role of polymorphs, monocytes, macrophages and lympho...

Lecture 1 General Principles & Terminology Tuesday 4th September 2023 Unit 1 – General Principles & Terminology Topics – Definitions – Capillary membrane dynamics – Body fluids – Lymphatic system – Functions of white blood cells including the role of polymorphs, monocytes, macrophages and lymphocytes in cellular/tissue injury. Definitions – Disease = literally means lack of ‘ease’ is the pattern of the body’s response to some form of injury that causes a deviation from or variation of normal conditions – Pathology = the study of disease and how it impacts the body Disease Causes/aetiology: – Hereditary - Vascular – Congenital - Metabolic - Iatrogenic* – Trauma - Idiopathic* – Infection - nosocomial* - community-acquired* Communicable vs non-communicable* – Signs: are objective or measurable manifestations of a disease eg. Facial droop – Symptoms: subjective; not measurable or observable. It is the experiences the patient feels and describes eg. Headache – Give examples – Symptomatic = showing evidence of disease – Asymptomatic = showing no evidence of disease – Syndrome = linked combination of signs & symptoms that characterizes a specific disease – Diagnosis = precise disease process affecting the patient i.e identification – Prognosis = expected patient course & outcome* Pathogenesis = sequence of events producing cellular changes that ultimately lead to observable changes known as manifestations – This process includes - the pathogen that gets you sick eg. bacteria, viruses, parasites, fungi - the method of how you got it eg. food, contact, air - the changes in the cells once it gets in the body eg. The pathogen replicates in the cells lining the respiratory tract - the observable changes (manifiestations) Example, Barrett’s esophagus, COVID 19 Disease duration – Acute = quick onset; last for short period eg. pneumonia – Chronic = slow onset; last for a long time eg SLE – Sequelae = an acute illness may be followed by lasting effects eg. CVA  Morphology – The structure of cells or tissue – Pathologic conditions may cause morphologic changes that alter normal body tissues – Disease process may be destructive, decreasing the normal tissue density - Radiographically – subtractive, lytic, destructive * example - Require decrease in exposure technique – Disease processes may cause increases in normal tissue density - Additive, sclerotic * example - require increase in exposure technique Multiple myeloma - lytic Bone metastases from prostate cancer - sclerotic Altered Cellular Biology – To protect themselves and avoid injury, cells adapt by altering the genes responsible for their function and differentiation in response to their environment – When a cell is injured and unable to maintain homeostasis, it can respond in several ways. It may - adapt and recover from the injury, or - it may die as a result of the injury – Many cells adapt by altering their pattern of growth – Atrophy eg. Muscle – loss of innervation – Hypertrophy eg. Exercise; heart - if the aortic valve is diseased, then the left ventricle enlarges because of the increased muscle mass needed to pump blood into aorta ‘size’ – Hyperplasia - as a result of excessive proliferation “number” - eg. Liver is resected – ‘Greek mythology’; hormonal - endometrium – Metaplasia - conversion of one cell type into another cell type that is not normal for that tissue “cell type” - eg. Barrett’s oesophagus: normal stratified squamous à simple columnar epithelium - eg. Smokers respiratory tract: columnar ciliated epithelium of bronchial airways à stratified squamous epithelium (no mucus, no cilia) – Dysplasia - not a true adaptive change - abnormal changes of mature cells. Individual cells within a tissue vary in size, shape, and colour, and they are often non- functional. - considered precancerous - aka atypical hyperplasia - eg. Cervix, respiratory tract – ‘low grade’, ‘high grade’ – https://www.youtube.com/watch?v=OZaS16IpStE Disease Classifications – Congenital and hereditary – Inflammatory – Degenerative – Metabolic – Traumatic – Neoplastic Congenital and Hereditary – Congenital = diseases that are present at birth and resulting from genetic or environmental factors; sporadic. e.g. Down Syndrome – Hereditary diseases are caused by developmental disorders genetically transmitted from either parent to a child through abnormalities of individual genes in chromosomes and are derived from ancestors. eg. Hemophilia – A congenital defect is not necessarily hereditary because it may have been acquired in utero eg. Zika virus. – Give Examples acquired in utero* Fetal Alcohol Syndrome Pregnant women for morning sickness Limb anomalies Inflammatory – Results from the body’s reaction to a localized injurious agent. – Types of inflammatory diseases include infective, toxic and allergic diseases. - infective: viruses, bacteria, fungi – Some diseases in this classification are considered autoimmune disorders. Under normal conditions, antibodies are formed in response to foreign antigens. In certain diseases, however, they form against and injure the patient’s own tissues. These are known as autoantibodies, and diseases associated with them are termed autoimmune disorders eg Rheumatoid arthritis, SLE, MS Infection – Refers to an inflammatory process caused by a disease-causing organism – The invading pathogenic agent multiplies and causes injurious effects. Degenerative – caused by deterioration of the body; usually associated with the aging process – Some degenerative conditions may exist in younger patients. - eg. Following traumatic injury (athletes) – The process of ageing results from the gradual maturation of physiologic processes that reach a peak and then gradually fade (i.e., degenerate) to a point at which the body can no longer survive. – E.g. atherosclerosis, osteoporosis, osteoarthritis Metabolic – Definition: diseases caused by a disturbance of the normal physiologic function of the body. – Endocrine disorders eg. diabetes mellitus, hyperparathyroidism, disturbances of fluid and electrolyte balance. – Dehydration is the most common disturbance of fluid balance – Give examples of electrolytes eg. Na+ – Discuss how electrolytes may become depleted eg. Diuretic use – Endocrine glands secrete hormones into the bloodstream to regulate metabolic functions - thyroid, parathyroid, pancreas, pituitary gland, ovaries, testes – Hypersecretion or hyposecretion Traumatic – May result from mechanical forces such as crushing or twisting of a body part, from the effects of ionizing radiation on the human body, extreme effects from hot (burns) or cold (frostbite). Neoplastic – Neoplastic disease results in new, abnormal tissue growth. – Normally, growing and maturing cells are subject to mechanisms that direct cell proliferation (=cell division) and cell differentiation (=process of cellular specialization), controlling their growth rate - When this control mechanism goes awry because of mutations within the chromosomes of the cell an overgrowth of cells develop resulting in a neoplasm – In neoplastic disease: parenchymal cell proliferation and differentiation are altered – Benign vs malignant neoplasm: differentiated vs undifferentiated/invasion – Metastatic spread into - circulatory system: hematogeneous spread - lymphatic system: lymphatic spread Cancer (malignant neoplasm) types: - lymphoma - sarcoma - leukemia Recap 2) An increase in the number of cells is said to be: – A) atrophy – B) hypertrophy – C) hyperplasia – D) metaplasia Which one of the following disease classifications is present at birth? – A) degenerative – B) metabolic – C) congenital – D) inflammatory Capillary membrane dynamics Capillaries – Smallest of the body’s blood vessels – Endothelial lining , one cell layer thick – 5-10 micrometer diameter – Connect arterioles to venules – Help in the exchange of water, oxygen, carbon dioxide, nutrients and waste chemicals between the blood and the tissues Types of capillaries Types of capillaries Continuous: – the endothelial cells provide an uninterrupted lining, and they only allow smaller molecules, such as water and ions to diffuse through – Most common; least permeable – Found in skeletal muscles, gonads, skin Fenestrated – have pores in the endothelial cells – allow small molecules and limited amounts of protein to diffuse – Found in endocrine glands, intestines, pancreas and glomeruli of kidneys Sinusoidal – have larger openings (30-40 μm ) – allow red and white blood cells and various serum proteins to pass – Found in bone marrow, lymph nodes, adrenal gland, also subtypes within liver and spleen Diffusion – Net movement of a substance from a region of high concentration to a region of low concentration Filtration – Mechanical or physical operation which is used for the separation of solids from fluids by interposing a medium through which only the fluid can pass Diffusion – bidirectional along the whole length of the capillary - Diffusion of any one material is independent of diffusion of any other substances – net movement is governed by concentration gradient – hydrostatic & oncotic pressures (Starling forces) are not involved in diffusion – This is the process responsible for net movement of gases*, nutrients and wastes (as these substances move down their concentration gradients) – There is no net movement of water across the capillary wall due to diffusion - this is remarkable considering the huge volume of water involved. Filtration – really ultrafiltration as proteins cannot easily cross most capillary membranes – volumes involved are much smaller then the diffusional flux – fluid movement can be either inwards (absorption) or outwards, but not both at any particular position along the capillary – net movement is governed by the balance of the hydrostatic and oncotic pressure gradients (the Starling forces) – This process is not important for net movement of gases, nutrients & wastes; the net movement of water is important. Definitions related to Starling’s forces: – Hydrostatic pressure = the pressure exerted by a fluid at equilibrium – Oncotic pressure = a form of osmotic pressure exerted by proteins in blood vessels plasma that usually tends to pull water into the circulatory system – Starling’s forces = describes the net movement of fluid Capillary process Net filtration occurs near the arterial end of the capillary since capillary hydrostatic pressure (CHP) is greater than blood colloidal osmotic pressure (BCOP). There is no net movement of fluid near the midpoint since CHP = BCOP. Net reabsorption occurs near the venous end since BCOP is greater than CHP. https://courses.lumenlearning.com/suny-ap2/chapter/capillary-exchange/ NFP changes at different points in a capillary bed. Close to the arterial end of the capillary, it is approximately 10 mm Hg, because the CHP of 35 mm Hg minus the BCOP of 25 mm Hg equals 10 mm Hg. Recall that the hydrostatic and osmotic pressures of the interstitial fluid are essentially negligible. Thus, the NFP of 10 mm Hg drives a net movement of fluid out of the capillary at the arterial end. At approximately the middle of the capillary, the CHP is about the same as the BCOP of 25 mm Hg, so the NFP drops to zero. At this point, there is no net change of volume: Fluid moves out of the capillary at the same rate as it moves into the capillary. Near the venous end of the capillary, the CHP has dwindled to about 18 mm Hg due to loss of fluid. Because the BCOP remains steady at 25 mm Hg, water is drawn into the capillary, that is, reabsorption occurs. Starling forces in Pathology – Most cases result in excessive water filtration out of capillaries – Derangements of vascular permeability – Architecture of the capillaries is damaged – Can occur due to immune mediated processes or thermal damage – Derangements of hydrostatic pressure gradient Pathologically increased hydrostatic pressure on venous side of circulation i.e. congestion Eg. venous thrombosis, right heart failure – Derangements of oncotic pressure Usually due to reductions in plasma oncotic pressure, from poor synthesis or excessive loss of plasma proteins from capillaries, especially albumin Body fluids  Body fluids Definition = liquids originating inside the body of living people Includes fluids that are Excreted Secreted Total Body water - Intracellular - Extracellular - Intravascular (blood plasma) - Extravascular - Interstitial - Lymphatic fluid (sometimes included in interstitial fluid) - Transcellular  Body fluids Definition = liquids originating inside the body of living people Includes fluids that are Excreted Secreted Total Body water 60% - Intracellular 2/3 - Extracellular 1/3 - Intravascular (blood plasma) 1/4 - Extravascular 3/4 - Interstitial - Lymphatic fluid (sometimes included in interstitial fluid) - Transcellular: Often not calculated as a fraction of the extracellular fluid, but it is 5% of extracellular fluid (~ 2.5% of TBW). Source: DOI https://doi.org/10.1007/978-1-4939-1737-2_7 Body fluids examples: – Breast milk – Ear wax – Urine – Amniotic fluid – ….. Abnormal Body Fluid: – Caused by injury and/or inflammation seen with conditions such as heart failure, cirrhosis – Caused by an imbalance between the pressure within blood vessels Seen with conditions such as infections, malignancies or autoimmune diseases – Transcellular = ocular, Cerebrospinal fluid, joint fluid. - is thought of as separate from interstitial and intravascular compartments and not in dynamic equilibrium with them. - It is the smallest component of extracellular fluid. - It is often not calculated as a fraction of the extracellular fluid, but it is 5% of extracellular fluid (2.5% of total body water). Lymphatic system Role – Parallels the cardiovascular system – It is a one way system Returns lymph fluid via vessels to the cardiovascular system for eventual elimination of toxic by-products by end organs - End organs include kidney, liver, colon, skin and lungs Role (cont’d) – Restoration of excess interstitial fluid and proteins to the blood – Absorption of fats and fat-soluble vitamins from the digestive system and transport of these elements to the venous circulation – Defence against invading organisms Lymphatic system constitutes Lymph Contains nutrients, oxygen, hormones, and fatty acids, as well as toxins and cellular waste products, that are transported to and from cellular tissues Lymphatic vessels Transport lymph from peripheral tissues to the veins of the cardiovascular system Lymph nodes Monitors the composition of lymph, the location of pathogen engulfment and eradication, the immunologic response, and the regulation site Spleen Monitors the composition of blood components, the location of pathogen engulfment and eradication, the immunologic response, and the regulation site Thymus Serves as the site of T-lymphocyte maturation, development, and control Diseases of Lymphatic System – Lymphedema Inadequate drainage - Primary, impaired or missing vessels - Secondary, acquired, consequence of trauma, infection or surgical procedure – Lymphoma Group of cancers that originate in the lymphatic system – Lymphadenopathy Nodes become swollen or enlarged as a consequence of infection – Lymphadenitis Inflammation of lymph nodes, causing swelling reddening and tenderness of skin overlying the lymph node – Splenomegaly – Tonsillitis ‘Kissing’ tonsils White Blood Cells (WBC) Blood is made up of : – Red blood cells (aka erythrocytes) – White blood cells (aka leukocytes) – Platelets (aka thrombocytes) – and Plasma https://www.horiba.com/en_en/technology/measured-and-controlled-objects/liquid/blood-plasma/  WBCs – Aka leukocytes – Cells of the immune system – Involved in defending the body against infections diseases and foreign invaders – All are produced from a pleuripotent cell in the marrow, the hematopoetic stem cell – Found throughout the body, including the blood and lymphatic system – Number in the blood is often an indicator of disease - Increase in number is called leukocytosis - Decrease in number is called leukopenia Types of WBC 1. Granulocyte leukocytes – Aka Polymorphonuclear (PMN) leukocytes – because of varying shapes of the nucleus – Make up between 50 to 70 % of WBCs – Presence of differently staining granules in their cytoplasm - granules: are membrane bound enzymes that digest endocytosed particles 2. Agranulocyte leukocytes - aka Mononuclear leukocytes - Absence of granules Types of Granulocyte leukocytes - Neutrophil – MC; 60% of WBCs - Basophil - Eosinophil - Mast cell Types of Agranulocyte leukocytes - Lymphocytes - Monocytes - Macrophages Granulocytes (Neutrophils) – Defend against bacterial or fungal infection – Usually first responders to microbial infection – Their activity and death in large numbers forms pus. – Active in phagocytizing bacteria – Not able to renew their lysosomes and die after having phagocytized a few pathogens. – Make up 60-70% of total leukocyte count in human blood – Lifespan, 5.4 days Neutrophils - 2 -5 nucleus segments Granulocytes (Eosinophils) – Primarily deal with parasitic infections – Predominant inflammatory cells in allergic reactions. – Nucleus is bi-lobed. Granulocytes (Basophils) – Chiefly responsible for allergic and antigen response – Release the chemical histamine causing vasodilation – Nucleus is bi- or tri-lobed – Characterized by their large blue granules. Granulocytes (mast cells) – they mediate host defence against pathogens (e.g., parasites) and allergic reactions, particularly anaphylaxis. Agranulocytes – Aka mononuclear leukocytes – Lack granules – Types - lymphocytes - monocytes - macrophage Agranulocytes Lymphocyte – More common in the lymphatic system than in blood – Have a deeply staining nucleus that may be eccentric in location, with a relatively small amount of cytoplasm – Types - B cells - T cells - Natural killer cells Agranulocytes (Lymphocytes) B cells – Make antibodies that bind to pathogens – Block pathogen invasion – Activate the complement system T cells – CD4+ helper cells - Bind antigenic peptides MHCII - Make cytokines - Help coordintae the immune system – CD8+ cytotoxic T cells - Bind antigens on MHC1 complex of virus infected or tumour cells and kills them – NK cells - Able to kill cells that do not display MHC class 1 molecules Agranulocytes Monocytes – Share the function of phagocytosis with neutrophils – Present pieces of pathogens to T cells for recognition leading to an antibody response – When they leave the bloodstream they become tissue macrophages – Can replace their lysosomes – Kidney shaped nucleus, abundant cytoplasm Agranulocytes Macrophages – Phagocytose or engulf and digest cellular debris, and pathogens – Stimulate lymphocytes and other immune cells to respond to pathogens – Monocyte ----------- Bone Marrow; Blood. When monocytes leave the bloodstream they become macrophages – Adipose Tissue Macrophages ---------- Adipose Tissue. – Kupffer Cell ------------ Liver. – Sinus Histiocytes ------------- Lymph Node. – Alveolar Macrophage (dust cell) ------------- Pulmonary alveolus of Lungs. – Langerhans Cell ------------- Skin & Mucosa. – Microglia ------------ Central Nervous System. – Osteoclasts ------------- Bone Function of WBCs in tissue injury (Revisit in Unit 2B in detail) – Tissue injury –>initial response is acute inflammation – Tissue injury can be caused by: trauma, infection, chemical substances – Inflammatory response consists of 4 events: - alterations in blood flow & vascular permeability - migration of circulating WBCs to the interstitium of the injured tissue - phagocytosis & enzymatic digestion of dead cells and tissue elements - repair of injury by regeneration of normal parenchymal cells or proliferation of granulation tissue and eventual scar formation – Local injury à dilation of arterioles, capillaries, venules à increase in blood flow in & around injury site ‘hyperemia àheat & redness; WBCs migrate to area of injuryà venules & capillaries become abnormally permeable à passage of protein-rich plasma across vessel walls into the interstitium “ exudate’; WBCs cross capillary walls into the injured tissues where they engulf & enzymatically digest infecting organisms & cellular debris by ‘phagocytosis’ à swelling associated with inflammation à pain à removal of necrotic debris leads à repair Signs of inflammation – Redness , rubor – Swelling ,tumor – Tenderness, dolor – Increased temperature, calor – Loss of function, functio laesa