Budesonide/formoterol enhances the expression of pro Surfactant Protein-B in lungs of COPD patients

Soo Jung Um, Stephen Lam, Harvey Coxson, Shu Fan Paul Man, Don D Sin, Soo Jung Um, Stephen Lam, Harvey Coxson, Shu Fan Paul Man, Don D Sin

Abstract

Rationale & aim: Pulmonary surfactants are essential components of lung homeostasis. In chronic obstructive pulmonary disease (COPD), surfactant expression decreases in lungs whereas, there is a paradoxical increase in protein expression in plasma. The latter has been associated with poor health outcomes in COPD. The purpose of this study was to determine the relationship of surfactants and other pneumoproteins in bronchoalveolar lavage (BAL) fluid and plasma to airflow limitation and the effects of budesonide/formoterol on this relationship.

Methods: We recruited (clinical trials.gov identifier: NCT00569712) 7 smokers without COPD and 30 ex and current smokers with COPD who were free of exacerbations for at least 4 weeks. All subjects were treated with budesonide/formoterol 400/12 µg twice a day for 4 weeks. BAL fluid and plasma samples were obtained at baseline and the end of the 4 weeks. We measured lung-predominant pneumoproteins: pro-Surfactant Protein-B (pro-SFTPB), Surfactant Protein-D (SP-D), Club Cell Secretory Protein-16 (CCSP-16) and Pulmonary and Activation-Regulated Chemokine (PARC/CCL-18) in BAL fluid and plasma.

Results: BAL Pro-SFTPB concentrations had the strongest relationship with airflow limitation as measured by FEV1/FVC (Spearman rho=0.509; p=0.001) and FEV1% of predicted (Spearman rho= 0.362; p=0.028). Plasma CCSP-16 concentrations were also significantly related to airflow limitation (Spearman rho=0.362; p=0.028 for FEV1% of predicted). The other biomarkers in BAL fluid or plasma were not significantly associated with airflow limitation. In COPD subjects, budesonide/formoterol significantly increased the BAL concentrations of pro-SFTPB by a median of 62.46 ng/ml (p=0.022) or 48.7% from baseline median value.

Conclusion: Increased severity of COPD is associated with reduced Pro-SFTPB levels in BAL fluid. Short-term treatment with budesonide/formoterol increases these levels in BAL fluid. Long term studies will be needed to determine the clinical relevance of this observation.

Conflict of interest statement

Competing Interests: Budesonide and formoterol are marketed by AstraZeneca, the funder of this study. DDS has received research grants from AstraZeneca and Boerhinger Ingelheim over the past 36 months. He has received honoraria for speaking engagements from Merck and AstraZeneca and has sat on advisory boards for Merck, Takeda, Novartis, AstraZeneca and Almirall. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Figure 1. The relationship between baseline BAL…
Figure 1. The relationship between baseline BAL pro-SFTPB and lung function.
Significant relationship is noted between baseline BAL pro-SFTPB and FEV1% predicted, as well as between baseline pro-SFTPB and FEV1/FVC ratio.
Figure 2. BAL and plasma biomarkers at…
Figure 2. BAL and plasma biomarkers at baseline and 4 weeks after budesonide/formoterol treatment in COPD patients.
Budesonide/formoterol significantly increased the BAL concentrations of pro-SFTPB. Data are presented as median with interquartile range and outliers are shown.
Figure 3. The relationship between baseline plasma…
Figure 3. The relationship between baseline plasma CCSP-16 and lung function.
Significant relationship is noted between baseline plasma CCSP-16 and FEV1% predicted.

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