The TGF-beta-pseudoreceptor BAMBI is strongly expressed in COPD lungs and regulated by nontypeable Haemophilus influenzae.
BACKGROUND
Nontypeable Haemophilus influenzae (NTHI) may play a role as an infectious trigger in the pathogenesis of chronic obstructive pulmonary disease (COPD). Few data are available regarding the influence of acute and persistent infection on tissue remodelling and repair factors such as transforming growth factor (TGF)-beta.


METHODS
NTHI infection in lung tissues obtained from COPD patients and controls was studied in vivo and using an in vitro model. Infection experiments were performed with two different clinical isolates. Detection of NTHI was done using in situ hybridization (ISH) in unstimulated and in in vitro infected lung tissue. For characterization of TGF-beta signaling molecules a transcriptome array was performed. Expression of the TGF-pseudoreceptor BMP and Activin Membrane-bound Inhibitor (BAMBI) was analyzed using immunohistochemistry (IHC), ISH and PCR. CXC chemokine ligand (CXCL)-8, tumor necrosis factor (TNF)-alpha and TGF-beta expression were evaluated in lung tissue and cell culture using ELISA.


RESULTS
In 38% of COPD patients infection with NTHI was detected in vivo in contrast to 0% of controls (p < 0.05). Transcriptome arrays showed no significant changes of TGF-beta receptors 1 and 2 and Smad-3 expression, whereas a strong expression of BAMBI with upregulation after in vitro infection of COPD lung tissue was demonstrated. BAMBI was expressed ubiquitously on alveolar macrophages (AM) and to a lesser degree on alveolar epithelial cells (AEC). Measurement of cytokine concentrations in lung tissue supernatants revealed a decreased expression of TGF-beta (p < 0.05) in combination with a strong proinflammatory response (p < 0.01).


CONCLUSIONS
We show for the first time the expression of the TGF pseudoreceptor BAMBI in the human lung, which is upregulated in response to NTHI infection in COPD lung tissue in vivo and in vitro. The combination of NTHI-mediated induction of proinflammatory cytokines and inhibition of TGF-beta expression may influence inflammation induced tissue remodeling.
Drömann
Daniel
D
Medical Clinic III, University of Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Germany. daniel.droemann@uk-sh.de
Rupp
Jan
J
Rohmann
Kristina
K
Osbahr
Sinia
S
Ulmer
Artur J
AJ
Marwitz
Sebastian
S
Röschmann
Kristina
K
Abdullah
Mahdi
M
Schultz
Holger
H
Vollmer
Ekkehard
E
Zabel
Peter
P
Dalhoff
Klaus
K
Goldmann
Torsten
T
D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020869:Gene Expression Profiling; D006193:Haemophilus influenzae / Q000302:isolation & purification*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D018836:Inflammation Mediators / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D046509:Tissue Culture Techniques; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C485671:BAMBI protein, human; C508606:CXCL8 protein, human; D018836:Inflammation Mediators; D016209:Interleukin-8; D008565:Membrane Proteins; D018125:Receptors, Transforming Growth Factor beta; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha