Inflammation (acute and chronic); gross and microscopic appearance. Phagocytosis, cells engaged in inflammation, chemical mediators of inflammation Markéta Hermanová General features of inflammation nA benefitial host response to foreign invadors and necrotic tissue; but itself capable of causing tissue damage n nMain component of inflammation: vascular reaction (vascular and exudative phase) and a cellular response (activated by mediators of inflammation derived from plasma protein and various cells) n nInflammatory response (5 Rs): -Recognition of the injurious agent -Recruitment of leukocytes -Removal of the agent -Regulation of the response -Resolution (repair) n nOutcome of acute inflammation: -Elimination of the noxious stimulus, decline of the reaction, resolution-repair -Persistent injury resulting in chronic inflammation -Extensive destruction of the tissue resulting in scarring Acute inflammation: rapid response to injury or microbes and other foreign substances nStimuli for acute inflamation: nInfections (bacterial, viral, fungal, parasitic) nTrauma and physical and chemical agents nTissue necrosis (e.g. ischamic infarctions) nForeign bodies nImmune reactions (=hypersensitivity reactions) against environmental substances or against self tissues → immune-mediated inflammatory disease Macroscopis appearance of acute inflammation (Celsus signs) nRedness (rubor) nHeat (calor) nSwelling (tumor) nPain (dolor) nLoss of function (function laesa) Early stages of acute inflammation nChanges in vascular caliber and flow -vasodilatation – induced by chemical mediators (e.g. histamin) – causes erythema and stasis n nIncreased vascular permeability and formation of the protein rich fluid exudate -induced by histamine, kinins, … → gaps between endothelial cells (by direct or leukocyte induced injury, by increased passage through the epithelium) n nFormation of the cellular exudate -emigration of the neutrophils polymorphs into the extravascular space) n nResponses of lymphatic vessels n- increased lymph flow; secondary (reactive) lymphangitis, lymphadenitits n extravasation_of_leukocytes Leukocyte recruitment to sites of inflammation nLeukocytes recruited from the blood into extravascular tissues – migrate to the site of infection or tissue injury – are activated to perform their functions n nLeukocyte recruitment – multistep process: -Margination, loose attachment to and rolling on endothelium (selectins) -Firm attachment to endothelium (integrins) -Migration through inter-endothelial spaces – diapedesis (chemokines) -Migration in interstitial tissues toward chemotactic stimulus – chemotaxis - nCytokines produced by macrophages and other cells (TNF, IL-1) promote expression of selectins and integrins ligands on endothelium; promote directional migration of leukocytes n nNeutrophils predominate in the early inflammatory infiltrate and are later replaced by macrophages Leukocyte recruitment to sites of inflammation Chemotactic stimuli nBacterial products nCytokines (chemokine family) nComponents of complement system (C5a) nProducts of lipooxygenase pathway (LTB4) n n Leukocyte effector function nLeukocytes eliminate microbes and dead cells by phagocytosis (with destruction on phagolysosomes) nDestruction caused by free radicals (ROS, NO) generated in activated leukocytes and lysosomal enzymes nEnzymes and ROS may be released into the extracellular environment nInflammation is also capable of damaging normal tissues (the pathologic consequences of inflammation) Phagocytosis nRecognition and attachment of the particle to the ingesting leukocyte n nEngulfment , with subsequent formation of phagocytic vacuole n nKilling and degradation of the ingested material n 16-08a_phagocytosis_1 Phagocytosis n Cells involved in inflammation – components of cellular exudate nLeukocytes – neutrophils nEosinophils, basophils nLymphocytes nPlasma cells nMacrophages nHeparinocytes, mast cells nPlatelets nFibroblasts nErythrocytes PBBasophil •basophil •lymphocyte Histiocyte-100x-website-arrow •Macrophages - histiocytes Mast-cell-and-basophil-100x-website-arrow •Mast cell Plasma cell •Plasma cell eo104le_eosinophil ly100le_lymphocyte th100le_platelet Activation of macrophages M1 •M2 M1 •M2 T and B lymphocytes obr 3 B- a T- a makrof.gif obr 2 - T-makrofágy.jpg Mediator Source Principal action Cell-derived Histamine Mast cells, basophils, platelets VD, ↑permeability, ↑endotel. activation Serotonine Platelets VD, ↑permeability Prostaglandins Mast cells, leukocytes VD, pain, fever Leukotriens Mast cells, leukocytes ↑permeability,CHT,leu adhesion+activ. Platelet-activating factor Leukocytes, endothelial cells VD, ↑P, leu adhesion+activ., CHT,degranulation,... Nitric oxide Endothelium, macrophages vascular SM relax., microbes killing Cytokines (TNF, IL-1) Leukocytes ↑endotel. activation, systemic acute phase damage Reactive oxygen species Macrophages, lymphocytes,.. Microbes killing,tissue damage Chemokines Leukocytes, macrophages CHT, leu activation Plasma protein-derived Complement Plasma (produced in liver) Chemotaxis,opsonization,VD Kinins Plasma ↑permeability, VD, pain,… Proteases activated during coagulation Plasma Endothelial activation, leukocyte recruitment Arachidonic acid metabolites (Eicosanoids) Action Eicosanoid Vasodilatation PGI2, PGE1, PGE2, PGD2 Vasoconstriction Thromboxane A2, leukotrienes C4, D4, E4 Increased vascular permeability Leukotrienes C4, D4, E4 Chemotaxis, leukocyte adhesion Leukotrienes B4 The lipooxygenase and cyclooxygenase pathway. Membrane phospolipids are converted to arachidonic acid through the action of phospolipases, which is further metabolised through cyclooxygenase and lipooxygenase pathways. The cyclooxygenases convert the arachidonic acid to unstable cylcloendoperoxides, which are converted to prostaglandins, prostacyclin and thromboxanes. The lipoxygenases metabolise arachidonic acid through hydroperoxyeicosatetraenoic acids (HPETEs) to leukotrienes. Major cell-derived mediators of inflammation – summary: nVasoactive amines: histamine, serotonine; VD, ↑permeability n nArachidonic acid metabolites: prostaglandines and leukotriens; vascular reaction, chemotaxis,… n nCytokines: IL-1, TNF, chemokines,…; multiple effects in leukocytes recruitment and migration n nReactive oxygen species: tissue damage, microbial killing n nNitric oxide: VD, microbial killing n nLysosomal enzymes: microbial killing, tissue damage n Plasma protein-derived mediators of inflammation nComplement proteins: n activation of complement→generation of multiple breakdown products→chemotaxis, opsonization, phagocytosis, cell killing n nCoagulation proteins: n activated factor XII triggers: clotting, kinin and complement cascades, fibrinolytic system n nKinins: n produced by proteolytic cleavage of precursors: mediate vascular reaction, pain n Defects in leukocyte function nBone marrow suppression – decreased leukocyte numbers nMetabolic diseases (DM – abnormal leukocyte function) nMalignancy, sepsis, immunodeficiencies, leukemia, anemia, malnutrition, hemodialysis nGenetic disorders: -Defects in leukocyte adhesion and migration through endothelium, defective phagocytosis and generation of an oxidative burst (LAD-1, LAD-2: absence of sialyl-Lewis X (oligosaccharide on leukocytes that binds to selectins on activated endothelium)) -Defects in microbicidal activity (chronic granulomatous disease, AR, X-linked – genetic defect responsible for lack of ROS; MPO deficiency) -Defects in phagolysosome formation (Chediak-Higashi syndrome – AR, disordered intracellular trafficing to organelles) - - n Classification of inflammation: nacute nchronic n nGranulomatous (specific) nnon-granulomatous (non-specific) n Non-specific inflammation n (leucocytes, lymphocytes, macrophages; non-specific granulation tissue): n -Alterative -Exsudative -Proliferative n Inflammation – microscopic appearance ðALTERATION: n tissue damage - regressive changes, necrosis n ðEXUDATION: n vascular leakage of protein-rich fluid and blood cells n Inflammation – microscopic appearance ðPROLIFERATION: n proliferation of fibroblasts and capillaries n formation of granulation and fibrous tissue û ðIMMUNE RESPONSE: n antigen presentation n T and B-lymphocytes reaction n production of antibodies by plasma cells n memory cells Morphologic patterns of acute inflammation nSerous inflammation nCatarrhal inflammation nFibrinous inflammation; pseudomembranes, ulcers nHaemorrhagic inflammation nNon-suppurative (lymphoplasmocytic) inflammation nSuppurative (purulent) inflammation, abscess nNecrotizing (gangrenous) inflammation n Non-suppurative inflammation – lymphoplasmocytic – interstitial myocarditis myokarditis 40x myokarditis 200x Suppurative (purulent) inflammation: purulent meningitis and absceding bronchopneumonia meningitis1 plíce povrch abscesy Fibrinous pericarditis. perikarditis 20x plíce 100x Chronic inflammation nChronic inflammation developing from acute inflammation (e.g. chronic osteomyelitis,…) n nPrimary chronic inflammation -Resistance of infective agents to phagocytosis and intracellular killing (tbc, leprosy, brucellosis,…) -Foreign body reactions -Some autoimmune diseases -Specific diseases of unknown etiology (IBD,…) -Primary granulomatous diseases (sarcoidosis, reaction to beryllium,…) n Chronic inflammation nProlonged duration – prolonged host response to persistent stimulus n→ active inflammation+tissue injury+healing n nInfiltration with mononuclear cells (macrophages, plasma cells, lymphocytes) n nTissue destruction (by products of the inflammatory cells) n nRepair (new vessel proliferation and fibrosis) Growth factors involved in regeneration and repair associated with inflammation nEpidermal growth factor (EGF) n(regeneration of epithelial cells) nTransforming growth factor alpha and beta (TGF) n(regeneration of epithelial cells) nPlatelet-derived growth factor(PDGF) n(stimulation of fibroblasts proliferation, collagen synthesis) nFibroblast growth factor(FGF) n(stimulation of fibroblasts proliferation, angiogenesis, regeneration of epithelial cells) nInsulin-like growth factor (IGF-1) n(synergistic effect with othe growth factors) nTumor necrosis factor (TNF) n(stimulation of angiogenesis) Granulation tissue: (new vessels proliferation and fibrosis) HE40x Granulation tissue nFormation of granulation tissue = major repair instrument n n In: n healing of wounds, fractures, ulcers; organisation of necrosis, thrombus, and haematoma n n Gross: n soft red tissue, granular surface (capillary loops) n nMicro: n fibrin fibers n inflammatory reaction n fibroblasts, myofibroblasts n starting collagen fibers production n proliferating capillaries – angiogenesis n later intercellular matrix + tissue remodeling, retraction – scar formation n n n n Macroscopic apperance of chronic inflammation nChronic ulcer nChronic abscess cavity nThickening of the wall of a hollow viscus nGranulomatous inflammation nFibrosis n Chronic peptic ulcer in stomach. he40x Microscopic features of chronic inflammation nExudation not prominent nProduction of new fibrous tissue from granulation tissue nContinuing destruction of the tissue+regeneration+repair nCellular reaction in chronic inflammation -macrophages, plasma cells, lymphocytes, eosinophils, mast cells - Chronic inflammatory cells and mediators (I) nMacrophages -derived from circulatin blood monocytes -mononuclear phagocyte system: liver: Kupffer cells; lymph nodes, spleen: sinus histiocytes; CNS: microglia; lungs: alveolar macrophages -Activated by bacterial endotoxins, by cytokines from immune activated T cells (IFN-γ),… -Activated macrophages secrete a variety of biologically active products (acid and neutral proteases, ROS, NO, AA metabolites, IL-1, TNF, GFs influencing proliferation of smooth muscles and fibroblasts) Chronic inflammatory cells and mediators (II) nLymphocytes (B and T) -Interaction with macrophages -TCR on macrophages, produce cytokines (IL-2) stimulating T-cells, which produce cytokines (IFN-γ) activating macrophages -Plasma cells derived from activated B-cells: production of antibodies against persistent antigens n nEosinophils (immune reactions mediated by IgE) -in parasitic infections -in allergies n nMast cells -In both chronic and acute inflammation -IgE coated mast cells release histamins, AA metabolites -Central players in allergic reactions, incl. anaphylactic shock n n Relationship of chronic inflamation and carcinogenesis nIncreased production of ROS, cytokines, pro-inflammatory transcription factors n nMediators if inflammation: -Induction of genetic damage -Induction of cell proliferation -Inhibition of apoptosis -Regulation of tumor angiogenesis n Relationship of chronic inflamation and carcinogenesis nBarrett´s oesophagus – adenocarcinoma of qoesophagus nUlcerative colitis – colorectal cancer nChronic pancreatitis – pancreatic cancer nViral hepatitis B, C – hepatocellular carcinoma nAtrofic gastritis – adenocarcinoma of stomach nChronic gastritis (Helicobacter pylori) – MALT lymphoma and adenocarcinoma of stomach nChronic lymphocytic thyreoiditis – carcinomas and lymhomas of thyroid Granulomatous inflammation nAggregates of activated macrophages (epitheloid) n nNon-immune granulomas (response to foreign bodies, chemicals ) n nImmune granulomas -Necrotizing (tbc) -Non-necrotizing (sarcoidosis) n nPersistent T-cell response n nTuberculosis – n a prototype of granulomatous disease n n n n • • Examples of diseases with granulomatous inflammation disease cause Tissue reaction Tuberculosis Mycobacterium tbc Caseating tubercle –granuloma Leprosy Mycobacterium leprae Noncaseating granuloma, acid-fast bacilli in macrophages Syphilis Treponema pallidum Gumma: enclosing wall of histiocytes, plasma cells infiltrate, central cells necrotic Cat-scratch disease G- bacillus Granuloma with central necrotic debris and neutrohils Sarcoidosis Unknown etiology Noncaseating granuloma with abundant activated macrophages Foreign body granulomas Response to foreign bodies, chemicals (berrylium) Giant cell granulomas (foreign body granulomas) Crohn disease (IBD) Immune reaction against intestinal bacterial, self antigens Occasional noncaseating granuloma in wall of intestine+chronic inflammatory infiltrate Morbus Crohn – noncaseous granuloma in subserous tissue. 100x Tuberculous lymphadenitis. 40x Granulomatou-purulent lymphadenitis – cat scratch disease. granulom nekrot Sarcoidosis of a lymph node granulomat la2 Granulomatous giant cell reaction around foreign bodies. granulom cizí těleso Systemic effects of inflammation nFever n (cytokines (TNF, IL-1) stimulate production of PGs in hypothalamus) nConstitutional symptoms n (malaise, anorexia, nausea, weight loss in chronic inflammation) nProduction of acute phase proteins n (CRP, fibrinogen, SAA – synthesis stimulated by cytokines (IL- 6)) nHaematological changes: leukocytosis, increased erythrocyte sedimentation rate, anaemia nIn some severe infections, septic shock (↓BP, DIC, metabolic abnormalities) nSecondary amyloidosis (in chronic inflammation) Thank you for your attention …