Inflammation copy.pdf PDF

TISSUE INTEGRITY, WOUND HEALING AND THERMOREGULATION Pathophysiology and Pharmacology -Tobi Ajayi  LEARNING OUTCOMES -To understand the body’s three lines of defense. -To understand the process of inflammation, inclu...

TISSUE INTEGRITY, WOUND HEALING AND THERMOREGULATION Pathophysiology and Pharmacology -Tobi Ajayi  LEARNING OUTCOMES -To understand the body’s three lines of defense. -To understand the process of inflammation, including the role of chemical mediators. -Identify the 5 cardinal signs of acute inflammation. -To understand the process of healing and repair after tissue injury. -To be able to differentiate between acute and chronic inflammation. -To understand the mechanisms, risks and benefits of NSAIDS and corticosteroids to trea acute and chronic inflammation. -To understand the pathophysiology and pharmacology of allergic reactions.  mmunity refers to the body's ability to recognize and defend itself against foreign invaders, such as pathogens (bacteria, viruses, fungi) and other harmful substances. Mediated by: Neutrophils, and monocytes/ macrophages. Lymphocytes (T cells, B cells, and Natural Killer cells).  Immunity Innate Immunity Present even before an infection has occurred and that provide the first line of protection from pathogens. Non-specific: doesn't target specific pathogens but responds to general threats. Physical barriers : skin and mucous membranes. Cellular barriers: e.g. phagocytes, cytokines (interferons& interferons). Process barriers: inflammation, opsonins, fever, etc. Adaptive/Acquired Immunity More specific and targeted response. Memory: remembers immune response. Relies on lymphocytes (B cells and T cells), that recognize specific antigens presented by pathogens. Antigens is a foreign substance that provokes an immune response. B cells produce antibodies, while T cells can directly attack infected cells or help regulate the immune response. Takes longer to develop but provides long-lasting protection and memory against specific pathogens.  Blood Basics Blood is a specialized body fluid with 4 main components: plasma, red blood cells, white blood cells, and platelets. Blood’s goal is perfusion of organs, when absent = cellular necrosis (e.g. Stroke). Bloods aids in: Transport of nutrients hormones electrolytes. Clotting: to prevent excess blood loss. Immunity: carrying cells and antibodies that fight infection. bringing waste products to the kidneys and liver, which filter and clean the blood. regulating body temperature (Hypothalamus...vasodilation...heat losss through blood flow).  Blood Basics Plasma 55% of whole blood volume. Contains >90% water, blood proteins, and solutes (electrolytes, nutrients). Cells 45% of whole blood volume. RBCs, WBCs, Platlets. Synthesized via Hemopoiesis (Hematopoiesis)  White Blood cells WBCs are synthesized from hematopoietic stem cells (leukopoiesis). They migrate out of blood vessels into tissues, towards stimulus (chemotaxis). Granulocytes Neutrophils: First responder at the site of injury (within 90 mins). Make up 50-70% of WBC but are short-lived. Phagocytose and digest pathogen then apoptosis. Release inflammatory mediators to recruit more WBC Granules (small particles) are releases upon detection of ‘foreigner’. Eosinophils: respond to parasites (worms) involved in may contain mix of histamine, heparin, toxins to kill invaders, enzymes to synthesize prostaglandins and allergic reactions leukotrienes, signal molecules (cytokines and Mast cells: localized in tissue for allergic responses. chemokines) in different proportions Player in anaphylaxis. Basophils: amplifies allergic response. White Blood Cells Agranulocytes Monocytes: Inactively circulate the bloodstream until chemotaxis signal is received about damage Upon activation, they move into interstitial space as macrophages Macrophages phagocytose invaders and also produce signal molecules to prolong immune response Lymphocytes: Mostly involved in systemic response. T lymphocytes: kill infected or damaged cells & stores memory of the encounter. B lymphocytes secrete antibodies (immunoglobulins) which physically interact with antigens to neutralize or mark them for destruction. Complete Blood Count + Differentials  Inflammation (Innate Immunity) Inflammation(-itis) is the reaction of vascular tissues to harmful stimuli, and is characterized by inflammatory mediators. vascular tissue: tissues that contain blood vessels (veins, arteries, “-itis”: appendicitis, pericarditis, neuritis. capillaries) and lymph vessels. Can be triggered by: tissue injury, allergen, infection r/t pathogens, autoimmune diseases, etc. Variety of physiologic and pathologic responses intended to eliminate the initial cause of cell injury, remove the damaged tissue, and generate new tissue. Inflammation is essential for homeostasis, but dysfunctional inflammatory responses are linked to the pathogenesis of multiple diseases. Bronchial Asthma, generation of atherosclerotic plaques, etc.  Acute Inflammation exudation: a fluid released by Non-specific and immediate response lasting from a few minutes to several days. an organism through pores or Characterized by the exudation of fluid and plasma components and emigration a wound of leukocytes (predominantly neutrophils) into the extravascular tissues. WBC Aimed primarily at removing the injurious agent and limiting the extent of tissue damage. Inflammation May be triggered by infections, immune reactions, trauma, physical or chemical agents, or tissue necrosis. fibrosis: the thickening and scarring of connective tissue, usually as a result of injury Chronic Inflammation Longer duration, lasting for days to years. Associated with the presence of lymphocytes and macrophages, proliferation of blood vessels, fibrosis, and tissue necrosis.  Cells of Inflammation Endothelial Cells Line the inside of all blood and lymphatic vessels. form a selective permeable barrier between the circulating blood in vessels and the surrounding tissues. Provide barrier to exogenous (microbial) and endogenous inflammatory stimuli. Produce anti-platelet and antithrombotic agents that maintain vessel patency, and vasodilators and vasoconstrictors that regulate blood flow. This means that the body produces certain substances that help keep blood vessels open (anti-platelet and antithrombotic agents), preventing clots from forming inside the vessels. It also produces other substances (vasodilators and vasoconstrictors) that either widen or narrow blood vessels to control how much blood flows through them. These processes help keep the blood moving smoothly and maintain healthy circulation. Regulate leukocyte extravasation by expression of cell adhesion molecules and receptors. extravasation: The leakage WBC of blood, lymph, or other fluid, such as an anticancer drug, from a blood vessel or tube into the tissue around it. Contribute to the regulation and modulation of immune responses through synthesis and release of inflammatory mediators. produce growth factors that stimulate angiogenesis (formation of new vessels). Cells of Inflammation Platelets Aka thrombocytes, are involved in the primary cellular mechanism of hemostasis. Activated platelets also release potent inflammatory mediators, thereby increasing vascular permeability and altering the chemotactic, adhesive, and proteolytic properties of endothelial cells. Activated platelets release strong chemicals that cause inflammation. These chemicals make blood vessels more "leaky" and change how the cells lining the vessels attract, stick to, and break down other cells or substances. Platelet activation is associated with inflammatory diseases: atherosclerosis , multiple sclerosis, stroke.  Cells of Inflammation Neutrophils and Monocytes/Macrophages Leukocytosis is the elevation of circulating WBCs during bacterial infections and tissue injury. Eosinophils, Basophils, Masts Cells. Excessive demands for phagocytes may cause immature neutrophils (bands) to be released from the bone marrow. Eosinophils increase in the blood during allergic reactions, Neutrophils generate oxygen and nitrogen products (H2O2 promoting the release of specific chemical mediators. & NO) that assist in destroying the engulfed debris. Mast cells do not develop until they leave the circulation and Monocytes circulate the bloodstream inactively and act as lodge in tissue sites. Activation of mast cells results in the macrophages upon activation, performing phagocytic release of their contents. functions. Basophils bind an antibody, immunoglobulin E (IgE), to also Monocytes and macrophages produce potent vasoactive trigger release of histamine and other vasoactive agents. mediators, including prostaglandins and leukotrienes, platelet-activating factor, inflammatory cytokines, and growth factors that promote tissue regeneration.  Mast Cells Rich in Histamine and Heparin. Mostly found in connective tissue near blood vessels. Skin, mucosa (eye, nose, GI, etc.) Degranulation may be caused by: Injury, Temperature, Allergens, etc. Primary secretors of histamine, the primary mediator of inflammation associated with allergies.  Review of Inflammation https://www.youtube.com/watch? REVIEW OF v=XS30Rnpka8M INFLAMMATORY PROCESS  Vascular Stage AA  Cellular Stage AA  R Redness (rubor) Cardinal Signs of S Swelling (tumor) Inflammation H Heat (Calor) P Pain (Dolor) Loss of Function (functio L laesa) Systemic manifestations (e.g. fever) may also occur when chemical mediators (e.g. cytokines) that are produced at the site of inflammation enter into the circulatory system. Review of Inflammation Blood tests in inflammation Neutrophils Highly responsive to bacteria. Depletion of mature neutrophils cause immature neurophils to be present. Lymphocytes Elevated especially when viruses are present. Eosinophils especially if allergens present. C-reactive protein (CRP) Pro-inflammatory protein, elevated with tissue inflammation  Inflammation in tissue injury Endothelium, tissues, and mast cells: -release inflammatory mediators (histamine, bradykinin, etc). -release pro-inflammatory mediators (cytokines, pyrogens if pathogens present). -synthesize prostaglandins from Arachodonic Acid (fatty acid)  Inflammation in tissue injury Prostaglandins are essential to the inflammatory process, facilitating: -Vasodilation, Increased vascular permeability, pain sensitivity, recruitment of immune cells, Fever induction (PGE2). CycloOxygenase (COX) enzymes are required for prostaglandin synthesis. COX 1 - (present in all tissues) makes prostaglandins that help the blood clot and protect the stomach lining and intestinal tract from digestive acids. COX 2 - only present after injury to make prostaglandins involved in inflammation.  Non-steroidal Anti-Inflammatory Drugs (NSAID) Selective COX Inhibtors Non-Selective COX Inhibitors First gen - block both COX 1 & 2. Target COX-2 MOA. Analgesic, Anti-inflammatory, and Anti-pyretic actions typical of older NSAIDs without adverse effects on the digestive system and blood Side effects of bleeding, gastric coagulation upset, and reduced kidney Prescription only, escept topical creams ‘Black Box’ cardiovascular warning. function from blocking COX-1. Not 1st line therapy E.g. Celecoxib (Celebrex). E.g. Acetylsalicylic Acid (ASA), Ibuprofen, Naproxen, Keterolac, Volateran (Diclofenac), Indomethacin (20x ASA potency). NO ASPIRIN (ASA) FOR KIDS!! Reye Syndrome  LEARNING CHECK! A patient twisted ‘sprained’ her ankle while playing basketball last night. Dx: Soft Tissue injury due to torsion Tx: NSAIDs -Ibuprofrn (PO) + Volteran (top) + ice + elevate, rest  Mast Cells Rich in Histamine and Heparin. Mostly found in connective tissue near blood vessels. Skin, mucosa (eye, nose, GI, etc.) Degranulation may be caused by: Injury, Temperature, Allergens, etc. Primary secretors of histamine, the primary mediator of inflammation associated with allergies.  Inflammation: Histamine Histamine is the primary mediator of inflammation associated with allergic reaction. Released upon mast cells’ contact with allergen (pollen, dust, foods, drugs, etc.)....bind to H1 receptors. Histamine + H1 Receptor = Smooth Muscle contraction: Bronchioles/GI Blood Vessels: Vasodilation & Increased permeability Skin: Wheal (swelling) and Flare (redness) Nerves: Increased sensitivity (urticaria) & Pain Brain: Wakefulness Symptoms of Allergic reaction: Rash, Lacrimation, Runny Nose, Sneezing, Red Eyes, Itchiness.  Inflammation: Histamine https://www.youtube.com/watch?v=y3bOgdvV-_M Treatment of allergies depends on severity of allergic response (Local, Systemic, Anaphylaxis). Allergen testing. Anaphylaxis (Life-threatening): -E.g. Mast cells degranulation+++ ---> Significant histamine release---> Generalized vasodialtion and leakage of blood vessels around the body----> Reduced BP/Angioedema/Bronchioconstriction -Treated with Epinephrine: Bronchiodilation + Vasoconstriction Anti-Histamines Differentiated by specificity to histamine receptors. 1st Generation 2nd Generation Block histamine receptors. Block H1- Histamine Receptor. Very lipid soluble = Cross BBB = CNS Less lipophilic = Decreased CNS effects distribution = Non-drowsy. Recall: Activation of H1 receptor = Fexofenadine (Allegra), Loratadine wakefulness. (therefore this class of anti- (Claritin), Cetrizine (Reactine) histamines cause drowsiness/sedation. E.g. Diphenhydramine (Benadryl), Promethazine.  ANTI-HISTAMINES TOPICAL Eye symptoms: eye drops (e.g. Olopatadine) Skin symptoms: Cream  Development of Medicine Allergen testing Allergy De-sensitization Treatments Aims to make the immune system less Allergen is administered via sensitive to an allergen by allowing it to topical or superficial injection. "get used to" it. Once an allergen(s) is identified, low levels of allergen-specific serum is administered over months/years. Allergy shots have just enough allergens to alert the immune system but not enough to cause allergy symptoms.  Challenges in Drug Development 1 2 3 Local Response Systemic Systemic Life-threaning Patient touches a plant, Patient comes to a The cat allergy worsens. e.g. stinging nettle. friend’s house and a cat is present. S&S: itching, diffused S&S: localized urticaria urticaria throughout, (hives), itching, no S&S: Watery eyes, itchy difficulty breathing, changes to vital signs, eyes, Runny nose, tachycardia. and no other alteration Sneezing, Slightly itchy noted skin throughout Dx: Localized Allergic Reaction Dx: Systemic Allergic reaction Dx: Anaphylaxis Tx: Tx: Tx: Epinephrine (?Route) + Anti- histamines  LEARNING CHECK! Open Lexidrug. -Look up an anti-histamine -Note the Drug Class, Generation, PKPD