Presentation on theme: "Chemical Mediators of Inflammation"— Presentation transcript:
1 Chemical Mediators of Inflammation University of Colorado DenverSchool of MedicineDisease & Defense (Course IDTP5004A)Francisco G. La Rosa, MDAssociate Professor, Department of PathologyUniversity of Colorado Denver, Aurora, Colorado 80045
3 Only some receptors are depicted. Leukocyte activation. Different classes of cell surface receptors of leukocytes recognize different stimuli. The receptors initiate responses that mediate the functions of the leukocytes.Only some receptors are depicted.
4 Click for Movie NECROSIS: A white blood cell dies after a meal Ingesting “leukotoxic”Streptococcus pyogenesClick for Movie
5 “Chemical substances mediate all phases of acute inflammation”Thomas, Lewis ( )Reactions are similar irrespective of tissue or type of injury2. Reactions occur in absence of nervous connections
6 Chemical mediators of inflammation (EC: endothelial cells)
7 Events in Acute Inflammation Vasodilatation:HistamineProstaglandinsNitric oxideIncreased vascular permeability:Anaphylatoxins C3a and C5aKininsLeukotrienes C, D, and EPAFSubstance PEvents in Acute InflammationChemotaxis:Complement fragment C5aLipoxygenase products, lipoxins & leukotrines (LTB4)ChemokinesTissue DamageLysosomal productsOxygen-derived radicalsNitric Oxyde
8 Diversity of Effects of Chemical Mediators Prostaglandins :VasodilationPainFeverPotentiating edemaIL-1 and TNF:Endothelial-leukocyte interactionsLeukocyte recruitmentProduction of acute-phase reactants
11 The red structures are fat globules stained with fat stain (oil red) Adipose tissue showing mast cells around blood vessels and in the interstitial space.Stained with metachromatic stain to identify the mast cell granules (dark blue or purple).The red structures are fat globules stained with fat stain (oil red)
13 Ultrastructure and contents of neutrophil granules, stained for peroxidase activity. The large peroxidase-containing granules are the azurophil granules; the smaller peroxidase-negative ones are the specific granules (SG). N, portion of nucleus.
15 Leukotrienes and Prostaglandins: Potent mediators of inflammation Derived from Arachidonic acid (AA): 20-carbon, unsaturated fatty acid produced from membrane phospholipids.Principal pathways:5-lipoxygenase: Produces a collection of leukotrienes (LT)Cyclooxygenase (COX): Produces prostaglandin H2 (PGH2)PGH2 serves as substratefor two enzymatic pathways:Prostaglandins (PG)Thromboxanes (Tx).
16 Biosynthesis of leukotrienes and lipoxins by cell-cell interaction. AA: arachidonic acid –derived; LTA4: Leukotriene A4; LTC4: Leukotriene C4
18 Functions of nitric oxide (NO) in blood vessels and macrophages, produced by two NO synthase enzymes. NO causes vasodilation, and NO free radicals are toxic to microbial and mammalian cells. NOS: nitric oxide synthase.
23 The activation and functions of the complement system The activation and functions of the complement system. Activation of complement by different pathways leads to cleavage of C3. The functions of the complement system are mediated by breakdown products of C3 and other complement proteins, and by the membrane attack complex (MAC)
25 Production of microbicidal reactive oxygen intermediates within phagocytic vesicles.
26 Click for Movie OXIDATIVE BURST: Neutrophils kill microbes by producing reactive oxygen species,demonstrated here with the dyenitroblue tetrazolium (NBT)Click for Movie
27 Interrelationships between the four plasma mediator systems triggered by activation of factor XII (Hageman factor). Note that thrombin induces inflammation by binding to protease-activated receptors (principally PAR-1) on platelets, endothelium, smooth muscle cells, and other cells.
28 Role of Mediators in Different Reactions of Inflammation VasodilatationProstaglandinsNitric oxideHistamineIncreased vascular permeabilityVasoactive aminesC3a and C5a (through liberating amines)BradykininLeukotrienes C4, D4, E4PAFSubstance PChemotaxis,leukocyte recruitment and activationC5aLeukotriene B4ChemokinesIL-1, TNFBacterial productsFeverPainTissue damageNeutrophil and macrophage lysosomal enzymesOxygen metabolites
29 Summary of Mediators of Acute Inflammation ACTIONMediatorSourceVascular LeakageChemotaxis OtherHistamine and serotoninMast cells, platelets+-BradykininPlasma substratePainC3aPlasma protein via liverOpsonic fragment (C3b)C5aMacrophagesLeukocyte adhesion, activationProstaglandinsMast cells, from membrane phospholipidsPotentiate other mediatorsVasodilatation, pain, feverLeukotriene B4LeukocytesLeukotrienesC4 D4 E4Leukocytes, mast cellsBronchoconstriction, vasoconstrictionPlatelet Activating Factor (PAF)Bronchoconstriction, leukocyte primingIL-1 and TNFMacrophages, otherAcute-phase reactions, endothelial activationChemokinesLeukocytes, othersLeukocyte activationMacrophages, endotheliumVasodilatation, cytotoxicity
30 COX, cyclooxygenase; HETE, hydroxyeicosatetraenoic acid; Generation of arachidonic acid metabolites and their roles in inflammation.The molecular targets of some anti-inflammatory drugs are indicated by a red X.COX, cyclooxygenase; HETE, hydroxyeicosatetraenoic acid;HPETE, hydroperoxyeicosatetraenoic acid.
32 Disclaimer:The images and texts presented in this slide show are solely for educational purposes and not intended for commercial or pecuniary benefit. The images have been obtained from Dr. La Rosa’s personal collection, from text books used during the teaching of this chapter, and from published articles and educational works. Reproduction of these images can be done only for educational use.Reference: USA Copyright Law, Section 110, “Limitations on exclusive rights: Exemption of certain performances and displays”).[Download] the USA Copyright Law version, October 2009.