1. Acute inflammation and chemical mediators of inflammation Pooja Sharma Moderator: Dr Biman saikia

5. The components of acute and chronic inflammatory responses: circulating cells and proteins, cells of blood vessels, and cells and proteins of the extracellular matrix. Structural Fibrous proteins Adhesive glycoproteins: (Fibronectin and laminin)

7. The nomenclature used to describe inflammation in different tissues employs the tissue name and the suffix “- itis ” e.g pancreatitis meningitis pericarditis arthritis

8. Acute inflammation involves: alteration of vascular caliber (vasodilation leads to increased blood flow) changes of microvasculature (increased permeability for plasma proteins and cells) emigration of leukocytes from microcirculation (leukocyte activation leads to elimination of offending agent)

12. A critical function of the vascular inflammatory response (stasis and vascular permeability) is to deliver leukocytes to the site of injury in order to clear injurious agents Neutrophils are commonly the first inflammatory cells (first 6-24 hours) recruited to a site of inflammation. Extravasation of leukocytes is a coordinated event of: margination rolling, adhesion, transmigration (diapedesis) migration.

15. Four families of adhesion molecules are involved in leukocyte migration Selectins E-selectin (endothelium) P-selectin (endothelium & platelets) L-selectin (leukocytes) Ligands are sialylated glycoproteins (e.g Sialylated Lewis X) which are linked to mucin-like glycoproteins:PSGL-1,GlyCAM-1 , ESL-1, CD34 Immunoglobulin family ICAM-1 (intercellular adhesion molecule 1) VCAM-1 (vascular adhesion molecule 1) Are expressed on activated endothelium Ligands are integrins on leukocytes Integrins (  +  chain) Heterodimeric molecules VLA-4 (  1 integrin) binds to VCAM-1 LFA1 and MAC1 (CD11/CD18) =  2 integrin bind to ICAM Expressed on leukocytes Mucin-like glycoproteins Heparan sulfate (endothelium) Ligands for CD44 on leukocytes

16. Regulation of endothelial and leukocyte adhesion molecules. Intracytoplasmic endothelial granules P-selectins – bind leukocytes Role – leukocyte rolling Induces expression of E-sectins, ICAM-1 and VCAM-1 in endothelial cells LFA-1 (leukocytes) – low to high affinity by chemokines secreted by endothelial cells

17. Leukocyte activation..

18. Leukocytes follow towards the site of injury in the tissue along a chemical gradient of chemo-attractants in a process called chemotaxis. Exogenous and endogenous stimuli can act as chemoattractants Exogenous: bacterial product (e.g N- formyl-methionyl peptides Endogenous: anaphylatoxins (C5a), leukotrienes (LTB4), chemokines (e.g IL-8) Most chemotactic agents signal via G-protein-coupled 7 transmembrane receptors leading to the activation of phospholipase C resulting in intracellular Ca2+ release and activation of small GTPases (Rac,Rho, cdc42) . This leads to actin/myosin polymerization and a morphological response with directional filopodia formation

19. Rac, Rho and cdc42 and the morphological response

20. While signaling of chemo-attractants induces a morphological response and locomotion of neutrophils, pattern recognition receptors or opsonin receptors induce neutrophil and macrophage effector functions Pattern recognition receptors recognize CD14 LPS Toll-like receptor endotoxins, CpG, dsRNA, bacterial proteoglycans Mannose receptor bacterial carbohydrates Scavenger receptors lipids Opsonin-receptors recognize CR1 complement product C3b Fc  receptor IgG coated pathogens

23. Phagocytosis of a particle (e.g., bacterium) involves attachment and binding of Fc and C3b to receptors on the leukocyte membrane, engulfment, and fusion of lysosomes with phagocytic vacuoles, followed by destruction of ingested particles within the phagolysosomes.

24. Killing and degradation 1. Oxygen dependent mechanism 2. Oxygen independent mechanism occur through the action of substances in leukocyte granules e.g. BPI (bactericidal permeability increasing proteins), Lysozymes, Lactoferrins, major basic proteins and endotoxins

26. Increased Erythrocyte Sedimentation Rate as a result of the presence of acute phase reactants ESR = rate at which erythrocytes settle out of unclotted blood in one hour Normally, Erythrocytes are very buoyant and settle slowly Erythrocytes are negatively charged and repel each other (no aggregation occurs) In presence of acute phase reactants (fibrinogen) erythrocytes aggregate due to loss of their negative charge resulting in increased sedimentation ESR is a widely performed test to detect occult processes and monitor inflammatory conditions

29. Clinical Examples of Leukocyte-Induced Injury

31. www.nature.com/.../ images/nature01324-f1.2.jpg Allergic Reaction with swelling of the larynx

32. Bacterial pneumonia

33. Peptic ulcer An ulcer is a local defect of mucosal lining produced by shedding of necrotic tissue Peptic ulcers are produced by an imbalance between gastro-duodenal defense mechanisms and the damaging force 70% of all ulcers are due to H. pyolri infection which initiates a strong inflammatory response

34. Septicemia with disseminated intravascular coagulation due to Meningococca l Infection Invasion of the bloodstream by Neisseria meningitides leads to widespread vascular injury with endothelial necrosis, thrombosis and peri-vascular hemorrhage. Hemorrhage as it is seen in the skin can occur in all organs

35. Defects in Leukocyte Functions

36. Immunodeficiency Diseases caused by deficiencies or defects in phagocytes (neutrophils and macrophages) Lack of neutrophil/macrophage numbers or defect of their function can lead to live threatening infectious diseases, particularly with bacterial and fungal pathogens Clinically most common: bone marrow suppression with decreased cell numbers (leukopenia) due to tumor infiltrate or chemotherapy resulting in myelosuppression (>500 neutrophils /  l is considered very severe) However, inherited defects of adhesion, phago-lysosome- and microbicidal functions have been found

37. Wiskott-Aldrich Syndrome: a Trafficking defect of antigen presenting cells WAS – Syndrome Recurrent infections Eczema Thrombocytopenia

39. Leukocyte adhesion deficiencies (LAD 1 and 2) Neutrophils unable to aggregate Leukocytes unable to leave the circulatory system Neutrophil counts are commonly twice the normal level even without an ongoing infection (Leukocytosis) Clinical findings: History of delayed separation of umbilical cord Severe peridontitis Recurrent bacterial and fungal infections of oral and genital mucosa (enteric bacteria, staph, candida, aspergillus) Infected foci contain few neutrophils (no pus) and heal poorly LAD 2 immunodeficiency is less severe , however the defect is associated with growth retardation, dysmorphy and neurological deficits NEJM: Vol. 343: No 23, pp1703-1714

41. Chronic granulomatous disease = defect of NADPH oxidase system Clinical findings: Recurrent infections with catalse-positve microorganisms ( S. aureus, Burgholderia cepacia, aspergillus spec., nocardia spec., and Serratia marrcescens ) Recurrent infections of lungs, soft tissue and other organs (typical is infection of nares, and gingivitis) Appearance of fever and clinical signs of infection may be delayed Excessive formation of granuloma in all tissues NEJM: Vol. 343: No 23, pp1703-1714

43. Defect of the formation and function of neutrophil granules Chediak-Higashi Syndrome Clinical features: recurrent bacterial infections with S. aureus and beta hemolytic streptoc.; Peripheral nerve defects (nystagmus and neuropathy) Mild mental retardation and partial ocular and cutaneous albinism Platelet dysfunction and severe peridonatal disease Mild neutropenia and normal immunoglobulins NEJM: Vol. 343: No 23, pp1703-1714 Normal PMN Abnormal PMN

45. Outcomes of acute inflammation: resolution, healing by fibrosis, or chronic inflammation

50. Eicosanoids can mediate virtually every step of inflammation Action Metabolite Vasoconstriction Thromboxane A2, Leukotrien C4, D4, E4 Vasodilation PGI2, PGE1, PGE2, PGD2 Increased vascul. permeab . LTC4, LTD4, LTE4 Chemotaxis, leuko. adhesion LTB4, 5-HETE, lipoxins Bronchospasm Leukotriene C4, D4, E4

52. Kinin-Bradykinin System Bradykinin increases vascular permeability, contraction of smooth muscles, vasodilation and pain Kallikrein is a potent activator of factor XII, is chemotactic and can directly convert C5 to C5a (HMWK)

55. Major effects of interleukin-1 (IL-1) and tumor necrosis factor (TNF) in inflammation

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