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Interaktion Wirt Mikroorganismus am Beispiel der Lunge Robert Bals - - PowerPoint PPT Presentation
Interaktion Wirt Mikroorganismus am Beispiel der Lunge Robert Bals - - PowerPoint PPT Presentation
Interaktion Wirt Mikroorganismus am Beispiel der Lunge Robert Bals / Christoph Beisswenger Klinik fr Innere Medizin V - Pneumologie Analogy The host needs to control bacterial colonization and infection early time point late time point
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The host needs to control bacterial colonization and infection
early time point late time point
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The host needs to control bacterial colonization and infection
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Local lymph node Lymphocytes Dendritic cells Bacteria Environmental substances
Homeostasis Barrier disruption
What is the problem in lung disease?
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hBD-2
RT-PCR
hBD-1
RT-PCR
IP-10
RT-PCR
IL-8
[pg/ml]
control 1 1 1 3676
- E. Coli
[107 CFU/ml]
327,4 0,6 59,9 13829
- P. aeruginosa
[107 CFU/ml]
467,8 1,9 34,2 12304 Flagellin
[50 μg/ml]
51,9 0,6 3,03
- PolyI(I:C)
[20 μg/ml]
16 0,9 3104,8 13122 Malp
[1 μg/ml]
8,5 1,3 12,9 6048 IL-1
[5 ng/ml]
53,7 1,3
- 8946
Activation of respiratory epithelial cells by bacterial stressors in vitro
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Activation of respiratory epithelial cells by bacterial stressors in vivo
TLR4 -/- TLR4 -/- TLR2 -/-
- Fig. 3
TLR2 -/- non infected Hi infected WT non infected Hi infected WT
p-p38 p-ATF-2
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TLR4 -/- TLR2 -/- non infected Hi infected WT
p-smad2/3
TLR dependent activation of the TGF-β signaling pathway in vivo
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Knockout of p65 in macrophages (KO) Viable bacteria Epithelial KC expression Murine pneumonia with Pseudomonas aeruginosa
KO WT
Hess et al., ERJ 2009
Immunohistochemistry KC
Macrophages regulate epithelial effector substances
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Airway epithelial cells (primary or cell line) Stimulation with PAMPs Wound healing in vitro ERGF phorsphorylation
Microorganism are not only bad
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Infections as triggers
- f exacerbations
?
Hygiene Hypothesis
Asthma
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Airway epithelial cell (air liquid interface) + Pseudomonas aeruginosa Preincubation with Th2 cytokines Antimicrobial activity
TH2 cytokines inhibit epithelial host defense
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OVA ip OVA ip OVA ip OVA aero plus infection with Pseudomonas aeruginosa
Evaluation
- inflammation
- histopathology
- microbiology
Combination of animal models of allergy and infection
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Infection with
- P. aeruginosa
Allergic airway inflammation (OVA)
Differential cell count
Allergic inflammation inhibits neutrophil influx
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Infection with
- P. aeruginosa
Allergic airway inflammation (OVA) Microbial viability anti-CRAMP Beisswenger et al., JI 2006 anti-CRAMP-immunohistochemistry
Allergic Allergic airway inflammation inhibits pulmonary host defense
PBS / P.a. OVA / P.a.
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Effect of cigarette smoke on innate host defense ? in vitro model clinical studies
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A
5 10 15 20 25 30 35
Reference CS P.a. CS + P.a.
Relative E xpression
hBD-1 hBD-2 p < 0. 01 00 p < 0. 01 00
Differentiated epithelium Infection with P. aeruginosa Smoke exposure vs. Control (mock exposure) Defensin expression (mRNA)
Study of cigarette smoke: smoke inhibits expression of epithelial defensins
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CAP patients Smoker Former-smoker Never smokers Defensin protein levels
Smoking suppresses the innate immune system of the lung
- in CAP patients
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1. Epithelial / lung innate immunity is a network 2. The lung is continousely exposed to microbes 3. Epithelial cells have an important role 4. Presence of microbes is important for asthma, COPD
Summary
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SFB/IR22 Bals Lab 2004 - 2010 Rembert Koczulla Christian Herr Christian Hess Christoph Beißwenger Thomas Damm Tetyana Zakharkina Dong Li Han Gang Jan Hellberg MHH Tobias Welte UCSD Rich Gallo Marburg Harald Renz Michael Lohoff Stefan Bauer Univers Heidelberg Alexander Dalpke LMU München Christian Kupatt Rudolf Rupec TU München Roland Schmid
Email: robert.bals@uks.eu www.uniklinikum-saarland.de/pneumologie
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