chemotaxis - clinical approaches chemotaxis - clinical approaches dr. habil. kőhidai lászló 2011

Chemotaxis Chemotaxis

- Clinical approaches - Clinical approaches

Dr. habil. Kőhidai LászlóDr. habil. Kőhidai László2011.2011.

Chemotaxis and infections (1)Chemotaxis and infections (1)

Acute skin lesionsAcute skin lesions cytokine release cytokine release IL-8IL-8TNF ill. IL-6 are NOTTNF ill. IL-6 are NOT released ! released !

Pseudomonas aeruginosaPseudomonas aeruginosa - - formation offormation of biofilmsbiofilms Klebsiella pneumoniaeKlebsiella pneumoniae - - chemotactic activity is chemotactic activity is

decreaseddecreased

BurellosisBurellosis - - chemotactic and phagocytoticchemotactic and phagocytotic activity of cells activity of cells decreased decreased

(6 months follow-up study)(6 months follow-up study)

Chemotaxis in infections (2)Chemotaxis in infections (2)

Helicobacter pyloriHelicobacter pylori -- gastric ulcergastric ulcer

porin 30kDporin 30kD

rapid effect rapid effect decreased chemotaxisdecreased chemotaxis

3h incubation3h incubation TNFTNF

18h incubation18h incubation gg-IF, GM-CSF, -IF, GM-CSF, IL-8, IL-3, IL-4IL-8, IL-3, IL-4

Chemotaxis and infections (3)Chemotaxis and infections (3)

AIDSAIDS

HIV reservoirsHIV reservoirscells:cells: monocyte, macrophage monocyte, macrophageorgan: CNS, lung, periph.blood, liverorgan: CNS, lung, periph.blood, liver

(The time of replication cycle of virus differes in the (The time of replication cycle of virus differes in the different cells – it is different from lymphocyte)different cells – it is different from lymphocyte)

Cell-physiological functions damaged:Cell-physiological functions damaged:cytokine (chkemokine) synthesiscytokine (chkemokine) synthesischemotaxischemotaxisphagocytosisphagocytosis 2 mths2 mths 4 yrs4 yrs

chtx.chtx. -19%-19% -32%-32%phagocyt.phagocyt. -6%-6% -18%-18%

Diseases influencing physiological Diseases influencing physiological chemotactic responsiveness (1)chemotactic responsiveness (1)

AtherosclerosisAtherosclerosis LDL-oxLDL-ox LDL-glyLDL-gly

LDL-glyLDL-glychemotaxis (monocyte)chemotaxis (monocyte)cytokine secretioncytokine secretionthrombocyte aggregationthrombocyte aggregation

AmyloidosisAmyloidosis Amyloid depositsAmyloid deposits

chr. haemodialysischr. haemodialysis 2-microglobulin2-microglobulin

chemotaxis chemotaxis TNF IL-1 IL-6TNF IL-1 IL-6(monocyte) (monocyte) (macrophage) (macrophage)


Glycogen storage diseasesGlycogen storage diseases bacterial infections are bacterial infections arefrequentfrequent

chemotaxischemotaxisCaCa2+2+

O-O-+ G-CSF+ G-CSF

chemotaxis chemotaxis decreaseddecreasedCaCa2+2+ norm. norm.OO-- norm.norm.

Cystic fibrosisCystic fibrosis Aut. rec. 7q31Aut. rec. 7q31

lunglung - LTB4 - LTB4 BUTBUT effect of LTB4 and IL-8effect of LTB4 and IL-8 sputum - IL-8sputum - IL-8 on chemotaxis on chemotaxis

is inverseis inverse? receptor down-regulation ? number of IL-8 rec. is 1/3 of normal? receptor down-regulation ? number of IL-8 rec. is 1/3 of normal

(22.000/cell)(22.000/cell)


Lung sarcoidosis and fibrosisLung sarcoidosis and fibrosis

levels of levels of MCP-1 and IL-8MCP-1 and IL-8 influx of influx of are increasedare increased neutrophils and monocytesneutrophils and monocytes

Kartagener syndromeKartagener syndrome dyneindynein defficiency defficiencydecreaseddecreased chemotaxis chemotaxis


Rheumatoid arthritisRheumatoid arthritis chronic inflammationchronic inflammation

IL-8IL-8increased chemotaxisincreased chemotaxis

VEGFVEGF

(administration of IL-8 can mimic R.A. in experiments)(administration of IL-8 can mimic R.A. in experiments)

Asthma bronchialeAsthma bronchiale paroxismal constriction of airwaysparoxismal constriction of airways

basophilsbasophilsincreasedincreased chemotaxis chemotaxis

biogenic aminesbiogenic amines are released are released

Primer inflammations (1)Primer inflammations (1)

PeritonitisPeritonitis - ATP levels in lymphocytes - - ATP levels in lymphocytes - decreaseddecreased chemotactic activitychemotactic activity - decreased - decreased

-- in macrophages in macrophages chemokinetic chemokinetic activity activity expressed – induced by expressed – induced by MIP-1MIP-1

UveitisUveitis (inflammation of the (inflammation of the middle layer of the eyemiddle layer of the eye))chemotaxis is chemotaxis is CD11/CD18CD11/CD18-dependent-dependent

PeriodontitisPeriodontitis TNF ands IL-1 levels of sera are TNF ands IL-1 levels of sera are increasedincreasedIL-1 increases chemotaxis of neutrophilsIL-1 increases chemotaxis of neutrophilsand the reabsorption of bonesand the reabsorption of bones

PeriodontitisPeriodontitis levels of TNF and IL-1 in sera are levels of TNF and IL-1 in sera are increasedincreased

IL-1IL-1 neutrophil chemotaisneutrophil chemotais

bone reabsorptionbone reabsorption

PGE1PGE1 inhibitsinhibits development of inflammation development of inflammation

IGF, FGF, PDGFIGF, FGF, PDGF

chemotaxischemotaxisproliferationproliferationdifferentiationdifferentiation

++ regeneration of osteoblasts regeneration of osteoblasts

Primer inflammations (2)Primer inflammations (2)

Neutrophil defect of newbornsNeutrophil defect of newborns

1 - 8 days1 - 8 days chemotaxis - chemotaxis - decreaseddecreased

13 - 14 days13 - 14 days chemotaxis - chemotaxis - normalizednormalized

1 - 2 day1 - 2 day chemokinetic act. - chemokinetic act. - normalnormal

after 3rd day after 3rd day chemotactic act. - chemotactic act. - decreaseddecreased

REASON:REASON: - low level expression of CD11 integrin- low level expression of CD11 integrin- low level expression of L selectin- low level expression of L selectin

Diseases of circulatory system (1)Diseases of circulatory system (1)

Circulatory diseases of the heartCirculatory diseases of the heart

Ischemic heart diseasesIschemic heart diseases – transient or lasting occlusion – transient or lasting occlusion of coronaryof coronary

vascular vascular smoothsmoothmusclemuscle

chemoattractants:chemoattractants:

fibrinogen (free) - chemotx.fibrinogen (free) - chemotx.

fibrinogen (bound) - haptotax.fibrinogen (bound) - haptotax.


ReperfusionReperfusion Release of chemoattractants is detectableRelease of chemoattractants is detectablein the earlyin the early stage of reperfusion stage of reperfusion

Invasion of Invasion of neutrophils neutrophils guidedguided byby E selectins E selectins


Peripherial blood vesselsPeripherial blood vessels

AngiogenesisAngiogenesisproliferationproliferationchemotaxischemotaxismorphogenesismorphogenesis

Thrombospondin 1 (TSP1)Thrombospondin 1 (TSP1):: inhibitsinhibits chemotaxis and morphogenesis chemotaxis and morphogenesis

ReperfusionReperfusion -strats 24h after a min. 3 hrs occlusion strats 24h after a min. 3 hrs occlusion - chemotaxischemotaxis of PMN cells of PMN cells

Blood vessels in brainBlood vessels in brain- ischemia results release of FGF- ischemia results release of FGF- starts chemotaxis, mitosis, differentiation and- starts chemotaxis, mitosis, differentiation andangiogenesisangiogenesis

DiabetesDiabetes

- increasedincreased chemokinetic activity of PMN chemokinetic activity of PMN - antidiabeticums used in therapy can - antidiabeticums used in therapy can decreasedecrease the chemokinetic activity the chemokinetic activity

Primer hypothyreosisPrimer hypothyreosis - bacterial infections are frequent- bacterial infections are frequent- cell adhesion is - cell adhesion is increasedincreased- chemokinetic activity is - chemokinetic activity is decreaseddecreased

Sclerosis multiplexSclerosis multiplex - bacterial infections are frequent- bacterial infections are frequent- decreased- decreased cell adhesion cell adhesion

chemotaxischemotaxis phagocytosisphagocytosis bactericid effectsbactericid effects

PsoriasisPsoriasis monocytemonocyte macrophagemacrophageTGFTGFbb

adhezionadhezionchemotaxischemotaxis

Edema in lungs, Edema in lungs, pmeumothorax(PTX)pmeumothorax(PTX)

increased levels of IL-8 and LTB4increased levels of IL-8 and LTB4

Hodgkin-diseaseHodgkin-disease decreased chemotaxisdecreased chemotaxis

TumoursTumours

MelanomaMelanoma endothelin-1 (ET-1)endothelin-1 (ET-1)perivascular chemokinetic effectperivascular chemokinetic effect

MyelomaMyeloma production ofproduction of fMLP-like, chemotactic factor fMLP-like, chemotactic factor

Human leukemiaHuman leukemia expression of MAC-1 inegrin expression of MAC-1 inegrin

TherapyTherapy

retinoic acidretinoic acid -4-integrin expression is decreased-4-integrin expression is decreased

chemotaxis chemotaxis decreaseddecreased(231-28)(231-28)

chemoinvasion chemoinvasion decreaseddecreased(132-2)(132-2)

Toxic diseases (1)Toxic diseases (1)

AlcoholAlcohol

acute: acute: Kupffer cellsKupffer cells chtx.chtx. increasedincreasedneutrophilneutrophil 2-3 x2-3 x furtherfurtherfMLF rec.fMLF rec. 120.000120.000 200.000200.000(K=65.000)(K=65.000)

3 h3 h 24 h24 h

(even 30mM ethanol is effective !!!)(even 30mM ethanol is effective !!!)

chronic: phagocyte disfunctionchronic: phagocyte disfunction

NicotineNicotine - TNF and IL-6 levels are - TNF and IL-6 levels are decreaseddecreased- IL-8 level is- IL-8 level is increased increased

-function of phagocyte function function of phagocyte function (macrophages) is affected(macrophages) is affected

Quarz, ozone, NOQuarz, ozone, NO22

quarzquarz chemotaxis chemotaxis decreaseddecreased, TNF-level , TNF-level increasedincreasedozoneozone TNF-level TNF-level increasedincreasedNONO22 chemotaxischemotaxis decreaseddecreased, TNF-level , TNF-level decreaseddecreased

AsbestosAsbestos IL-1IL-1 IL-8IL-8 Chtx. Chtx. increasedincreasedTNFTNF

Methyl~ Hg, Si-lactateMethyl~ Hg, Si-lactate

release of reactive oxygen radicals release of reactive oxygen radicals decreaseddecreased neutrophil chemotaxis neutrophil chemotaxis

Mutagenes Mutagenes (benzpyren, 12-dimethyl benzantracen)(benzpyren, 12-dimethyl benzantracen)increasedincreased chemotaxis and chemoinvasiveness chemotaxis and chemoinvasiveness

Toxic diseases (2)Toxic diseases (2)

BUTBUTHypnosisHypnosis

ChemotaxisChemotaxis

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chemotaxis - clinical approaches chemotaxis - clinical approaches dr. habil. kőhidai lászló 2011

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