Abstract
BackgroundNontypeable 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)-β.MethodsNTHI 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-β 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)-α and TGF-β expression were evaluated in lung tissue and cell culture using ELISA.ResultsIn 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-β 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-β (p < 0.05) in combination with a strong proinflammatory response (p < 0.01).ConclusionsWe 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-β expression may influence inflammation induced tissue remodeling.
Highlights
Pulmonary presence of nontypeable Haemophilus influenzae (NTHI) has been implicated as an important infectious trigger in chronic obstructive pulmonary disease (COPD) [1]
Patients and lung tissue The study population consisted of 48 COPD patients who had an indication for lung surgery of peripheral nodules
Lung tissue samples were obtained from lobectomy or atypical resections (COPD patients: lung cancer: n = 39, metastases of extrapulmonary tumors: n = 6, benign nodules: n = 3; controls: n = 11, lung cancer: n = 2, metastases of extrapulmonary tumors: n = 7, benign nodules: n = 2)
Summary
Pulmonary presence of nontypeable Haemophilus influenzae (NTHI) has been implicated as an important infectious trigger in chronic obstructive pulmonary disease (COPD) [1]. The pulmonary inflammatory response is a critical element of the host defense to infection and initiates tissue repair to return the organ to normal function. An accurate balance between host defense and inappropriate tissue damage is essential. 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)-β
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