1. Chemotaxis - Clinical approaches Chemotaxis - Clinical approaches Dr. habil. Kőhidai László 2011.

2. Chemotaxis and infections (1) Acute skin lesionscytokine release IL-8 Acute skin lesionscytokine release IL-8 TNF ill. IL-6 are NOT released ! Pseudomonas aeruginosa - formation of biofilms Pseudomonas aeruginosa - formation of biofilms Klebsiella pneumoniae - chemotactic activity is decreased Klebsiella pneumoniae - chemotactic activity is decreased Burellosis- chemotactic and phagocytotic activity of cells decreased Burellosis- chemotactic and phagocytotic activity of cells decreased (6 months follow-up study)

3. Chemotaxis in infections (2) Helicobacter pylori-gastric ulcer Helicobacter pylori-gastric ulcer porin 30kD porin 30kD rapid effect decreased chemotaxis 3h incubationTNF 18h incubationg-IF, GM-CSF, IL-8, IL-3, IL-4

4. Chemotaxis and infections (3) AIDS HIV reservoirs cells: monocyte, macrophage organ: CNS, lung, periph.blood, liver (The time of replication cycle of virus differes in the different cells – it is different from lymphocyte) Cell-physiological functions damaged: cytokine (chkemokine) synthesis chemotaxisphagocytosis 2 mths4 yrs chtx.-19%-32% phagocyt. -6%-18%

5. Diseases influencing physiological chemotactic responsiveness (1) AtherosclerosisLDL-oxLDL-gly LDL-gly chemotaxis (monocyte) cytokine secretion thrombocyte aggregation AmyloidosisAmyloid deposits chr. haemodialysis  2-microglobulin chemotaxis TNF IL-1 IL-6 (monocyte) (macrophage)

6. Diseases influencing physiological chemotactic responsiveness (2) Glycogen storage diseases bacterial infections are frequentchemotaxis Ca 2+ O- + G-CSF chemotaxis decreased Ca 2+ norm. O - norm. Cystic fibrosisAut. rec. 7q31 lung- LTB4 BUT effect of LTB4 and IL-8 sputum - IL-8on chemotaxis is inverse ? receptor down-regulation ? number of IL-8 rec. is 1/3 of normal (22.000/cell)

7. Diseases influencing physiological chemotactic responsiveness (3) Lung sarcoidosis and fibrosis Lung sarcoidosis and fibrosis levels of MCP-1 and IL-8 influx of are increasedneutrophils and monocytes Kartagener syndromedynein defficiency decreased chemotaxis

8. Diseases influencing physiological chemotactic responsiveness (4) Rheumatoid arthritischronic inflammation IL-8 increased chemotaxis VEGF (administration of IL-8 can mimic R.A. in experiments) Asthma bronchialeparoxismal constriction of airways basophils increased chemotaxis biogenic amines are released

9. Primer inflammations (1) Peritonitis- ATP levels in lymphocytes - decreased chemotactic activity - decreased chemotactic activity - decreased - in macrophages chemokinetic activity expressed – induced by MIP-1 expressed – induced by MIP-1 Uveitis (inflammation of the middle layer of the eye) chemotaxis is CD11/CD18-dependent PeriodontitisTNF ands IL-1 levels of sera are increased IL-1 increases chemotaxis of neutrophils and the reabsorption of bones

10. Periodontitislevels of TNF and IL-1 in sera are increased IL-1 neutrophil chemotais bone reabsorption PGE1inhibits development of inflammation IGF, FGF, PDGF chemotaxisproliferationdifferentiation + regeneration of osteoblasts Primer inflammations (2)

11. Neutrophil defect of newborns 1 - 8 dayschemotaxis - decreased 13 - 14 dayschemotaxis - normalized 1 - 2 day chemokinetic act. - normal after 3rd day chemotactic act. - decreased REASON: - low level expression of CD11 integrin - low level expression of L selectin

12. Diseases of circulatory system (1) Circulatory diseases of the heart Ischemic heart diseases – transient or lasting occlusion of coronary vascularsmoothmuscle chemoattractants: fibrinogen (free) - chemotx. fibrinogen (bound) - haptotax.

13. Diseases of circulatory system (2) ReperfusionRelease of chemoattractants is detectable in the early stage of reperfusion Invasion of neutrophils guided by E selectins

14. Diseases of circulatory system (3) Peripherial blood vessels Angiogenesis proliferationchemotaxismorphogenesis Thrombospondin 1 (TSP1): inhibits chemotaxis and morphogenesis inhibits chemotaxis and morphogenesis Reperfusion -strats 24h after a min. 3 hrs occlusion - chemotaxis of PMN cells Blood vessels in brain - ischemia results release of FGF - starts chemotaxis, mitosis, differentiation and angiogenesis

15. Diabetes - increased chemokinetic activity of PMN - antidiabeticums used in therapy can decrease the chemokinetic activity Primer hypothyreosis - bacterial infections are frequent - cell adhesion is increased - chemokinetic activity is decreased Sclerosis multiplex - bacterial infections are frequent - decreased cell adhesion chemotaxis chemotaxis phagocytosis phagocytosis bactericid effects bactericid effects

16. Psoriasis monocytemacrophage TGFb adhezionchemotaxis Edema in lungs, pmeumothorax(PTX) increased levels of IL-8 and LTB4 Hodgkin-disease decreased chemotaxis

17. TumoursMelanoma endothelin-1 (ET-1) perivascular chemokinetic effect Myelomaproduction of fMLP-like, chemotactic factor Human leukemia expression of MAC-1 inegrin Therapy retinoic acid  -4-integrin expression is decreased chemotaxis decreased (231-28) chemoinvasion decreased (132-2)

18. Toxic diseases (1) Alcohol acute: Kupffer cellschtx.increased acute: Kupffer cellschtx.increased neutrophil2-3 xfurther fMLF rec.120.000200.000 (K=65.000) 3 h24 h (even 30mM ethanol is effective !!!) chronic: phagocyte disfunction chronic: phagocyte disfunction Nicotine - TNF and IL-6 levels are decreased - IL-8 level is increased -function of phagocyte function (macrophages) is affected (macrophages) is affected

19. Quarz, ozone, NO 2 quarzchemotaxis decreased, TNF-level increased ozone TNF-level increased NO 2 chemotaxis decreased, TNF-level decreased Asbestos IL-1IL-8Chtx. increased TNF  Methyl~ Hg, Si-lactate release of reactive oxygen radicals decreased neutrophil chemotaxis Mutagenes (benzpyren, 12-dimethyl benzantracen) increased chemotaxis and chemoinvasiveness Toxic diseases (2)

20. BUT Hypnosis Chemotaxis X