Week 2 bio sem 2 Inflammation and Nsailds PDF

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INFLAMMATION AND NSAIDs

Week 2 BIO 05/08/2019

Inflammation - Local response of vascularised living tissue injury it is protective response serves to bring defense and initiate healing mechanisms to the site - Inflammation is helpful in preparing body area for new tissue growth after infection or injury and to start the healing process The process - destroys, dilutes or neutralises injurious agent - Stimulates the immune response - Cleans up dead tissue debris and starts healing ❖ But excessive inflammatory response can injure normal tissue too - Causes include infection, physical agents, chemicals, tissues necrosis ischaemia (lack of blood supply) forign bodies, immune reactions Inflammatory Response ❖ Local nonspecific response of living tissues to injury Response - Localised the infection damage - Destroy or remove pathogens irritants - Promotes repair and wound healing Step 1 - Increase (blood) flow to the site and increase permeability ( capillary and lined with epithelial cells which react to histamine) Step 2 - WBCs leak from blood vessels into tissues than phagocytes engulf and destroy bacteria Vessel dilation ❖ Mast cells and basophils release histamine and causes local vessels dilation resulting in - Increase blood flow and redness and warmth - Increased capillary permeability - Phagocyte move out of vessels into intracellular fluid (ICF) - Oedema (swelling) due to fluids seeping from capillaries Cell damage - Cell damage leads to release of arachidonic acid from the cell membrane than arachidonic acid is metabolized by lipoxygenase and cyclooxygenase pathway to form - Leukotrienes (a powerful chemotaxin) (They show the direction they should go towards the invader) - Prostaglandins (increase permeability oedema pain) Acute Vs Chronic inflammation Acute inflammation - Relatively short duration (hours to days) - Primarily characterized by exudation of fluid and plasma proteins and neutrophilic infiltration Chronic inflammation - Longer duration (days to years) - Characterised by monuclears inflation macro[[hages and lymphocytes - Vascular proliferation scarring ❖ Different cells between the both types of inflammation (chronic contains mostly round cells) Signs of inflammation . (common exam questions ) - Rubor : redness (hyperaemia) Calor : warm hypermias - Dolor : pain nerve chemical med Tumor : exudation  Loss of function

Microscopic changes Vascular phases - changes in vascular calibre and flow - Fluid leaks into the interstitium a transudate has a low protein content usually caused by an alteration in a hydrostatic pressure and exudate has a high protein content caused by increased vascular permeability - Histamine causes vasodilation which increase permeability of blood vessels - More fluid is escaping through the capillaries Cellular phases - Cells move into intersection ( they are moving ) - white blood cells margination and emigration directional movement towards the injured area chemotaxis ( blood cells sense bacteria are move towards they and eat engulf and kill them) phagocytosis killing Complement system this is a common question in exams - Complement is a group of proteins circulate in the blood which undergoes a series of activation process results in the formation of chemical mediators (happens in traumas with a goal of following ) - The complement system is a addition supporting system mechanism of inflammation there is 9 inactive protein and they produce the following C3a - increase vascular permeability C5a- chemotaxis and increase vascular permeability C5-9- membrane attack complex (MAC) lysis of target cell (attack bacteria) Chemicals mediator and their roles Histamine - vasodilation increased permeability stimulates PG synthesis and chemotaxis Prostaglandins (PGs) vasodilation fever altered platelet function Thromboxane - platelet aggregation vasoconstriction Completions systems - capillary permeability chemotaxis cell lysis Bradykinin - vasodilation capillary permeability mammoth uscile construction Cytokines - communication between inflation cells Leukotrienes - bronchoconstriction chemotaxins increased capillary permeability Cellular response - Nonspecific the same response against all pathogens cells involved are Neutrophils, monocytes/ macrophages (phagocytic), mast cells, basophils, eosinophils Cellular response- migration and phagocytosis - chemotaxis - bacterial product that attract phagocytic cells - Margination - phagocytic cells align themselves at endothelial surface - Diapedesis - phagocytic cells deform and squeeze out though opening in the blood vessels - Phagocytosis - the next step is to engulf and kill the invaders Cellular response - phagocytic cells - Neutrophils easily deformable cells first to move out of blood vessels they phagocytose bacteria release their contents to kill it and eventually form pus - Macrophages are blood monocytes they follow the neutrophils and that ingest bacteria virus dead cells and forgotten matter - They also function as A  ntigen presenting cell (apc) and present the antigen of the invaders to other cells of the immune system for further action

Phagocytosis microbial killing - Contact recognition internalisation - Opsonin eg fc and c3b receptors - Cytoskeletal changes engulfment - Phagosomes fuse with lysosomes to produce secondary lysosomes killing by lysosomes and hydrolases myeloperoxidase halide systems Transudates and exudates - Transudates edema fluid containing very little protein resulting from an increase in capillary hydrostatic pressure - Exudates protein rich edema fluid resulting from increase in capillary permeability eg inflammation burn Systemic effects of of acute inflammation Acute phase response - Decrease appetite anorexia malaise tachycardia (increased heart rate), painful swelling in lymph nodes altered sleep patterns Acute phase proteins - C- reactive protein (CRP) (clinically useful), haptoglobin Outcomes of active inflammation - 1. Resolution- restoration to normal, limited injury - Chemical substances neutralization - Normalization of cell permeability - Apoptosis of inflammatory cells - Lymphatic drainage 2. Healing by scar - Tissue destruction - Purulent infl to abscess formation (pus pyogenic membrane, resorption - pseudoxanthoma cells weeks to months - 3. P  rogression to chronic Outcome of acute inflammation ( picture) Chronic inflammation Reasons - Persistent infection of prolonged exposure to irritants (intracell. Serving of agents - tbc) - Repeated acute inflammation (otitis rhinitis) - Primary chronic inflammation low virulence sterile inflammation (silicosis) - Autoimmune reaction(rheumatoid arthritis glomerulonephritis multiple sclerosis Anti inflammatory drugs - Used to treat pain, swelling and redness of inflammation in conditions such as rheumatoid arthritis musculoskeletal conditions and high fever Two main groups - Non steroidal anti inflammatory drugs (nsaids) eg aspirin paracetamol ibuprofen - Glucocorticoids - Eg cortisol prednisolone Non steroidal anti inflammatory drugs - Adverse effects - Gastrointestinal disturbances (major problems) eg vomiting stomach pain/irritation nausea ulcers and gi bleeding skin reaction renal problems - Celecoxib (celebrex) may be used in people with hyperacidity or showing other adverse effects COXIBs are effective at blocking the cox enzymes that leads to pain and inflammation

OEDEMA Microcirculatory exchange in capillary bed - In a healthy person the fluid interchange is balanced and usually there should not be a collection of extra fluid in the interstitial space Distribution of water in body - Approximately 60 of the body weight is water Fluid and haemodynamic derangements - Derangements of either blood supply or fluid balance causes some common disorder - Oedema - Hyperaemia and congestion - Infarction shock Oedema - May be defined as the accumulation of excess fluid in the intercellular (interstitial) tissue spaces or body cavities - Anasarca generalized edema - Hydrothrax accumulation of fluid in the pleural space - pericardial effusion accumulation of fluid in the pericardial space - Ascites accumulation of fluid in the peritoneal sac Transudates and exudates - Transudates -oedema fluid containing very little protein resulting from an increase in capillary hydrostatic pressure - Exudates proteins rich oedema fluid resulting from an increase in capillary permeability eg inflammation burn Hyperaemia and congestion - Hyperaemia increase volume of blood in an organ tissue due to arterial dilation - Congestion- increased volume of blood in organ/ tissue due to impaired venous drainage (obstruction outflow from tissue) Review of microcirculatory exchange - Movement of fluid between blood vessels in the extravascular compartment is determined by two sets of forces - Forces tending to drive fluid out of the blood vessel - Capillary hydrostatic pressure - Osmotic pressure of the interstitial intracellular fluid - Forces drawing fluid or at least trying to hold fluid in the blood vessels - Plasma osmotic pressure - Tissue hydrostatic pressure Diffusion and osmosis - Diffusion is the net movement of molecules in either a gas or a liquid from a region of high concentration to one of lower concentration - Osmosis is the movement of a solvent from an area of a lo  wer concentration (hypotonic solution) to an area of a h  igher solute concentration (hypertonic solution)

Some fluid enters the lymphatics - In a healthy person the fluid interchange is balance and usually there should not be a collection of extra fluid in the interstitial space Causes of pathogenesis of oedema - In a healthy person movement of fluid between blood vessels and extravascular compartment is a balance process and usually there should not be a collection of extra fluid in the interstitial space

- Oedema is a pathologic state with “review of microcirculation exchange” the cause can be explained They are - Increased capillary hydro pressure and Decreased plasma colloid osmotic pressure - Lymphatic obstruction - Increased osmotic pressure of interstitial fluid increase capillary permeability Increased capillary hydrostatic pressure - Congestive cardiac failure - Constrictive pericarditis - Thrombosis - Cirrhosis of liver Reduced plasma colloid osmotic pressure - Diffuse liver disease cirrhosis - Glomerulopathy nephrotic syndrome - Severe protein malnutrition Lymphatic obstruction - Removal of LN and associated lymphatics in cancer - Inflammatory or radiation induced scarring - Milroy's disease (faulty development of lymphatics Increased osmotic pressure of interstitial fluid - Excessive salt intake - Increase tubular resbostion of sodium Increased endothelial permeability - Inflammation trauma - Burn and immunologic reactions - Chemical mediators of inflammation increase cap permeability Types of oedema Non inflammatory oedema - Increased hydrostatic pressure - Reduced plasma osmotic pressure - Lymphatic obstruction - Sodium retention Inflammatory oedema - Increased vascular permeability histamine exudates (protein rich) Clinical manifestation of oedema Ranges of cpnseques depending on location - Weight gain rapid and general weakness - Swelling in affected areas - Dyspnoea and tachypnoea - A decrease in exercise tolerance - Puffy eyes ankles oedema Common disease that causes edema Generalised - Heart failure - Hepatic oedema cirrhosis of the liver - Renal oedema nephrotic syndrome - Malnutrition protein starvation Localised - Venous obstruction (DVT) - Inflation - Lymphatic obstruction - Immunologic reaction

Generalised oedema - Failure of pumping ability of the heat venous hydrostatic pressure and under perfused kidneys retain fluid Hepatic oedema - Occur in cirrhosis of the liver due to - Decreased plasma protein synthesis - Increase regional; venous pressure (portal hypertension) - Lymphatic obstruction - Decreased hepatic inactivation of aldosterone - Oedema first appears in the abdomen (ascites) Renal oedema - Chronic loss of protein in urine - A fall of plasma protein level - Decreased plasma osmotic pressure leading /other renal diseases localised oedema Venous edema, DVT Acute inflammatory oedema - Increase vascular permeability - Increased osmotic pressure of interstitial fluid - Immunologic reaction hypersensitivity reaction Lymphatic obstruction - Surgical removal of lymph nodes - Related bacterial lymphadenitis - filariasis (caused by wucherira bancroft) Pulmonary oedema - Accumulation of fluid in the interstitial spaces of the lungs alveolar capillaries engorged with blood caused by left sided chf or pulmonary capillary injury Clinical manifestation - Dyspnea cyanosis - Moist and cool skin - Productive pink frothy coung - Rapid pulse Cerebral oedema - Swelling of the brain narrowed sulci and flattening of gyri may cause herniation and death - Causes - Brain tramus, Infractions - Obstruction outflow, hypertensive crises HEALING Wonds - Any breach in the surfaces of the body or any tissue disruption usually by physical injury - Abrasion - Contusion crush injury - incision laceration Healing - Healing and repair consists of replacement of dead tissue by viable cells - The process of healing repair involve \ - Regeneration replacement of the dead tissue by parenchymal cells - Replacement replacement of dead cells by connective tissue resulting a scar - Events following wound tissue damage

- Bleeding vasospasm platelet aggregation → clot formation (on surface skin will form a scab) - Release → - Chemical mediator histamine from the damaged tissue Stages of healing - 1. Acute inflammatory phase initial inflammatory response clear damaged tissue/debris - 2. Proliferative phase granulation tissue formation - 3. Remodeling maturation phase Phase 1 acute inflammatory phase - Bleeding → clotting - Tissue damage → chemical mediators - Vasodilation → increased capillary permeability → which dilutes toxins wall of the area - Infiltration of WBC in the area initially neutrophils and macrophages phagocytose cell debris and pathogens - Prepare the area for reconstruction of new tissue - Chemical mediators stimulate pain receptors Phase 1 acute inflammatory phase - Bleeding → clotting - Tissue damage →chemical mediators vasodilation → increased capillary permeability →which dilutes toxins, wall of the area - Infiltration of WBC in the area initially neutrophils and macrophages phagocytose cell debris and pathogens - Prepare the area for reconstruction of new tissue - Chemical mediators stimulates pain receptors Visible features - Swelling, increase fluid in the area Redness increase blood flow to area increase temperature is increased blood flow to area - Pain chemical mediator (PG) and swelling Phases 2: proliferative fibrocystic regeneration phase - Starts 2 to 3 days after injury and can last as long as 2-3 weeks or more - Granulation tissue forms consists of fibroblasts, collage, new blood vessels and macrophages. Granulation tissue is delicate and bleed easily. - Growth factors from fibroblasts induce - New capillary loops (angiogenesis) - Migration and proliferation of epithelial cells from the cuts ends - Fibroblasts → secrete strands of collagen Macrophages still clearing tissue debris - Epithelial cells continue to grow and migrate to cover the granulation tissue (epithelialization) Granulation tissue - Granulation tissue begins to from early in the process of healing it is a specialized type of soft granular pinkish tissue that bleeds on touch present over the surface of healing inflammation it is the hallmark of healing inflammation Granulation tissue is composed of - Proliferating new blood vessels - fibroblast / myofibroblast - Inflammatory cells - Macrophages - Neutrophils - Eosinophils and lymphocytes - Newly formed blood vessels have got leaky endothelium and granulation tissue is often oedematous

Phases 3 remodeling maturation phase - Begins approximately 3 weeks after injury and can continue for 6 months or more collagen synthesis continues resulting in tissue architecture and increase tensile strength of the wound area - Reorientation - collagen synthesis continues and horizontally - Scar oriented for maximum tensile strength to wound contraction of collages (scar shrinks) - Decrease vascularity (blood vessels decreased) - Fibrosis → scar →scar shrinks and wound reaches 80 % of the tensile strength Factors affects re-epithelialization of wounds - Wounds size and position are important - In superficial wound epithelium spreads quickly from sweat glands and hair follicles than in deeper wound - Location well vascularised areas eg face heal most quickly - Infection poor nutrition poor blood supply etc impede this process - In open wounds it does not occur until a bed of granulation tissue if formed Types of healing Primary union (healing by first intention) - Skins edges are approximated closed as in a surgical wound - Inflammation subsides within 24 hours (redness warmth edema) - Resurfaces within 4 to 7 days Secondary union - Secondary union occurs where the wound is large with loss significant tissue and bacterial contamination (slower healing and more scar tissue) intention tissue loss - burn pressure ulcer severe laceration - Wound left open - Scar tissue forms Primary union steps - Death of limited number of cells the wound gap is immediately filled by clotted blood dehydration of which forming the scab - By 24/48 hours: neutrophils appears at the wound margin as the first inflammatory response epithelial spur grow from each cut margin as single layer and fuse at the ,idle by 24 48 hours - By the 3rd day neutrophils disappeared and replaced and replaced by macrophages granulation tissue begins to appears and invade the space (wind gap) collage appears vertically - By the 5th day more granulation tissue neovascularization abundant collagen appears horizontally - By the 3rd week fibroblast accumulation of collagen vascu;rarity decreased Secondary union healing by second intention - Secondary union occurs where the wound is large and there is bacterial; contamination the large gap contains more tissues debris that has to be removed by macrophages which takes longer time depending upon infection large quantities of granulation tissues require to fill the gap - The most unpleasant outcome of the secondary union is the wound contraction Secondary union healing by 2nd intention - Wound with large gap with infection →more granulation tissue → require long time to heal Complication - Infection wound rupture - Wound contraction - Hypertrophic scar - Keloid excessive formation of collagen - Contracture common in secondary healing with large gap and in burn wound

Factors which affect wound healing - Nutrients 3 food groups for making new materials eg lipids→ membranes proteins → structures cho for providing energy for repair and proliferation of inflammatory cells - Vitamins vit c in collagen formation and vic for epithelial cell formation Delay wound healing - Diabetes mellitus has various effects includes vascular and neutrophil problems - Infection impairs wound healing may lead to dehiscence toxin presence etc - Cortisone has anti inflammatory and immunosuppressive effects - Foreign bodies like glass etc can encourage infection even sutures also impair healing and so usually need to be removed - Ageing usually facter in younger people smoking -...