Inflammatory Response & Biomarkers

1. Inflammatory Response & Biomarkers Melissa Boileau, Andre Juricka, JaspreetShokar, Martha Sutton PHM142 Fall 2012 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

2. Overview • Overview of inflammation • Acute versus chronic • Inflammation process • Treatment of inflammation • NSAIDs • Corticosteroids • Biomarkers • Histamine • TNF-α • IL-6 • Fibrinogen • Summary

3. Inflammation • Characterized by pain, redness, edema and warmth at infection site1 • Bodies defense mechanism to control and contain infection following injury as an innate immune response1 • Non-specific • Why?1 • To bring effector molecules to site of infection • To create a barrier to stop spread of infection • Increase repair of injured site

4. Inflammation • Caused by:3 • Infection • Damage • Foreign bodies (i.e. pollen) Figure 1: Infected ingrown toenail2

5. Acute inflammation3 • Length: • Minutes to days • Cause: • Foreign substance • Physical damage • Infection • Conditions: • Acute bronchitis • Acute appendicitis • Sore throat • Cut or scratch • Outcomes: • Resolution • Develops into abscess • Chronic inflammation

6. Chronic Inflammation3 • Length: • Weeks • Months • Years • Cause: • Acute inflammation • Autoimmune disease • Disease/Conditions: • Asthma • Tuberculosis • Colitis • Crohn’s Disease • Outcomes: • Tissue destruction • Fibrosis • Necrosis

7. Figure 2: Inflammation overview 6

8. Inflammation Figure 3: Initiation of inflammation 1

9. Inflammation Figure4: Cytokine mediation of inflammation 1

10. Resolution of inflammation Figure 5: Resolution of Inflammation 7

11. NSAIDs8 • Such as Ibuprofen and aspirin • Used for both acute and chronic inflammation • Deals with pain and inflammation – does not treat infection

12. NSAIDS8 • Block the cylcooxygenase (COX) enzyme in the inflammatory pathway. • Stops the conversion of arachidonicacid to eicosanoids, a group of biologically active lipids which include important inflammatory mediators such as prostaglandins, thromboxane and leukotrienes • May cause ulcers, kidney failure, reduced healing and increased risk of heart attack

13. Corticosteroids9 • Used for both replacement therapy and pharmacological effect • Mechanism of action • When used at higher doses they lead to the inhibition of phospholipase A2 which is responsible for hydrolyzing the second carbon group of glycerol to release arachidonic acid • Limited supply of arachidonic acid leads to decrease in eicosanoids • Prostaglandins, thromboxanes and leukotrienes

14. Figure 6: NSAID and Corticosteroid use in interrupting inflammation10

15. Biomarkers • A molecule that can be measured that indicates presence of disease.5 - Usually a protein

16. Biomarkers in Inflammation1 Histamine • Directly • Phosphorylation of intracellular adhesion molecules = increased membrane permeability at site of injury (vasoactive) • Blood fluids enter = swelling • Indirectly • Suggested to affect functioning of other local leukocytes • May trigger release of cytokines & mediators • Increased inflammatory response • TNF-α • Mainly produced by macrophages • Endothelial cell activator; pro—inflammatory changes • Increase expression of cell adhesion molecules • Change cell-cell junctions = vascular leak

17. Biomarkers in Inflammation1 • IL-6 • Role in fever & inflammation • Secreted by T cells & macrophages in response to trauma • Stimulate NK cells, enhance lymphocytes & mediate fever • Increase energy mobilization leading to increased body temperature • Helps enhance the response • Fibrinogen • Synthesized by the liver • Involved in clotting (clot blood downstream) • Converted by thrombin to fibrin • Helps contain the pathogen and prevent swelling

18. Summary – Inflammation & biomarkers Inflammation • Acute- minutes –days • i.e. cuts and scratches • Chronic – weeks to years • i.e. Crohn’s Disease Several Biomarkers of Inflammation • Histamine - Phosphorylation of intracellular adhesion molecules = increased membrane permeability at site of injury (vasoactive) • TNF-α–Endothelial cell activation = increased leukocyte adhesion and vascular leak to help contain infection. • IL-6– Important mediators of fever and of the acute phase response. Helps enhance inflammatory response • Fibrinogen - Involved in clotting which helps contain the pathogen and prevent swelling

19. Sources • Murphy K, Travers P, Walport M. 2008. Janeway’sImmunobiology, 7th Ed. New York: Garland Science. 11, 50 – 51, 425 p. • PrimeHealthChannel. 2012. What is an ingrown toenail?. Retrieved October 26, 2012 from http://www.primehealthchannel.com/ingrown-toenail-causes-symptoms-prevention-infection-and-treatment.html • Silbernagl S, Lang F. 2009. Color Atlas of Pathophysiology., 2nd Ed. Stuttgart, Germany:Thieme. 52 p. • McConnell TH. 2007. The Nature of Disease: Pathology for the health professions. Baltimore: Lippincott Williams & Wilkins. 44 p. • Lawrence E. 2008. Henderson’s Dictionary of Biology, 14th Ed. England: Pearson Benjamin Cummings. 76 p. • ADMIT. Mechanisms of acute and chronic inflammation in Asthma. 2012. Retrieved October 26, 2012 from http://www.admit-online.info/nl/achtergrond-informatie-ademhaling/pathofysiologie/ • Soehnlein O, Lindborn L. 2010. Phagocyte partnership during the onset and resolution of inflammation. Nat Rev Immuno 10:427-439 • Shah S, Metha V. 2012. Controversies and advances in non-steroidal anti-inflammatory drug (NSAID) analgesia in chronic pain management. Postgrad Med Journal: 88,(1036), 73-78. • Gomersall C. 1999. Corticosteroids , The Dept of Anaesthesia & Intensice care CUHK. Retrieved October 26, 2012 from http://www.aic.cuhk.edu.hk/web8/corticosteroids.htm • Hamilton Birney M, Durston S, Brady CL, FrangesEZ,Bruchak KT, Fuhrman L, Carrillo C, Grant JA, Clark SH, Haynes NH and others. 2005. Pthaophysiology: A 2-in-1 Reference for Nurses. Ambler, PA: Lippincott Williams & Willkins. 64 p.