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  1. Case Study: Carl Wheezer Patient Information: Age: 12 Gender: Male Hobbies: Loves Llamas and Singing Dislikes: Germs, Lima Beans, Food Signs and Symptoms: Wheezing, Shortness of Breath, Coughing, Chest tightness Diagnosis: ASTHMA PHM142 Fall 2013 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

  2. Biochemistry of Asthma Group Members: Ali Musheer Lisa Tran Michelle Duong Jason Yung

  3. What is Asthma? Definition: Respiratory disease involving inflammation of airways and increased resistance to airflow Prevalence of Asthma? Asthma affects ~3 million Canadians (~10% of population) Causes: Multiple Environmental factors (allergens, low air quality) as well as genetic factors Common Stimuli: - Physical Exertion - Stress - Others… (allergens in nature/food)

  4. What Happens to the Airways in an Asthma Attack? Decreased airway diameter due to: • Contracted smooth muscle • Inflammation due to increased permeability of blood vessels

  5. How Does Asthma Work? The Immune Response

  6. Cells Involved: Eosinophils (chronic response) • large contributor to the late-phase response and progression of Asthma • Severity of Asthma relates to the number of Eosinophils the patient has in circulation • Higher numbers = stronger and more severe response

  7. Cells Involved: Basophils (chronicresponse) • Only Basophils and Mast Cells have high affinity receptors for IgE antibody • Both these cells contain histamine • Difference? • Mast Cells are involved in an acute allergic response in Asthma • Basophil is like the circulating form of Mast Cells • it invades tissues and is responsible for the chronic allergic responses in Asthma

  8. Cells Involved: Mast Cells (acute response) Mast Cells • are found close to nerves, blood vessels and lymphatic vessels (in tissues) • this allows them to respond within minutes of exposure to an allergen, or other forms of physical and biological stimuli • are packed with mediators (histamines, cytokines, etc) • these mediate an inflammatory response (vascular permeability) as well as recruiting other cells in mounting the immune response • are activated by IgE receptor activation Mast Cell

  9. Cells Involved: Mast Cells

  10. Histamine Biosynthesis • Modified form of the amino acid Histidine • Histamine is synthesized and stored in Basophils, butmostly Mast Cells, among others • Catalyzed by the enzyme: Histamine Decarboxylase that requires Vitamin B6 • It has undergone a decarboxylation reaction, which in effect, has removed the carboxylic acid releasing CO2 Histidine Decarboxylation Histamine Histamine Decarboxylase

  11. Histamine Release • During an allergic reaction, allergen binds to the IgE (already bound to the mast cell) which leads to degranulation of mast cells • Mast cell degranulation → releasing pre-formed agents such as histamine, leukotrienes, tryptase, chymase • Histamine binds to H1 receptors in smooth muscle cells, leading to contraction and inflammation of the airways

  12. Histamine Receptors Histamine binds to histamine receptors on airway and vascular smooth muscle as well as eosinophils, neutrophils, T and B cells. What: Histamine receptors are G-protein Coupled Receptors @ cell surface H1 receptors (smooth muscle) • H1 activation causes smooth muscle contraction and vasodilation H4 Receptors: • Activation causes accumulation of mast cells and eosinophils at sites of allergic inflammation

  13. Histamine-induced airway inflammation • Histamine causes phosphorylation of intercellular adhesion proteins on vascular endothelial cells, forming gaps, and increasing leakiness. • Plasma, leukocytes and other immune cells enter the tissue and cause swelling. • The infiltration of these cells propagates the inflammatory response.

  14. Histamine-induced smooth muscle contraction SR

  15. How Does Carl Manage? Examples of Drug Classes Used to Treat Asthma: - Sympathomimetics - Steroids - Anticholinergics - Anti-IgE Antibody

  16. Summary Slide - Asthma - Definition: Respiratory disease involving inflammation of airways and increased resistance to airflow - During an asthma attack, inflammation and smooth muscle contraction of the bronchiolar walls result in the narrowing of airways and entrapment of air in the alveoli - Detection of antigen (allergen) leads to production of IgE antibodies that bind to mast cells (acute response) and basophils (chronic response) triggering degranulation → histamine release. Actions of histamine involved in an asthma attack: 1) Histamine binds to G-protein coupled receptors in the airways and pulmonary vasculature to cause bronchiolar smooth muscle contraction 2) Histamine increases permeability of endothelial cells to recruit eosinophils and more mast cells to the tissue, leading to inflammation of airway walls

  17. References Akdis, C. A., Blaser, K. & Jutel, M. (2005). Histamine in chronic allergic responses. J InvestiqAllergolClinImmunol, 15, 1-8. Retrieved from Amin, K. (2012). The Role of Mast Cells in Allergic Inflammation. Respiratory Medicine, 106, 9-14. Retrieved from Barnes, P.J. (1991). Biochemistry of Asthma. Trends in Biochemical Sciences, 16, 365-69. Retrieved from Bochner, B. S., & Lichtenstein, L. M. (1991). The role of basophils in asthma. Ann N Y AcadSci, 629, 48-61. Retrieved from Busse, W. W., Calhoun, & W. J., Sedgwick J. (1991). The role of eosinophils in the pathophysiology of asthma. Ann N Y AcadSci, 629, 62-72. Retrieved from Hart, P. H. (2001). Regulation of the inflammatory response in asthma by mast cells product. Immunol Cell Biol, 79, 149-153. Retrieved from Lin, K.W., Li, J., Finn, P.W. (2011). Emerging pathways in asthma: innate and adaptive interactions. Biochimica et BiophysicaActa, 1810, 1052-1058. Retrieved from Mehta, P. K. & Grriendling K. K. (2007). Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. American Journal of Physiology, 292, C82-C97. Retrieved from Schmidt, D., Ruehlmann, E., Branscheid, D., Magnussen, & H., Rabe, K. F. (1999) Passive sensitization of human airways increases responsiveness to leukotriene C4.  European Respiratory Journal 14(2), 315-319. Retrieved from