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Abstract
Background The asthma and chronic obstructive pulmonary disease (COPD) gene, A Disintegrin And Metalloproteinase (ADAM)33, is selectively expressed in mesenchymal cells and its metalloprotease activity has been linked to angiogenesis and airway remodelling. A soluble form of ADAM33 (sADAM33) has been identified in the bronchoalveolar lavage fluid (BALF) of asthmatic patients and its levels inversely correlate with lung function and disease severity. Because tissue remodelling also occurs in pulmonary sarcoid, we hypothesised that sADAM33 is elevated in BALF of patients with this disease which, like asthma, is heterogeneous.
Methods BALF was obtained from healthy controls (n=11) and patients with sarcoid (n=13) using fibre optic bronchoscopy according to current guidelines. After removal of immunoglobulins using Protein A/G and enrichment using Concanavalin A beads, sADAM33 was identified in BALF by Western blotting. A FRET peptide cleavage assay was used to assess ADAM33-like activity in BALF. Lung function (FVC%) and gas transfer (TLCO%) were measured at time of first diagnostic workup.
Results sADAM33 protein in BALF was detected as a 25kDa fragment and levels were significantly increased in samples from sarcoid patients when compared to healthy controls (p<0.05) (Abstract S141 Figure 1A). Levels of sADAM33 were inversely correlated with lung function (FVC % predicted) (p<0.05) and gas transfer (TLCO% predicted) (p<0.01) (Abstract S141 Figure 1B). No difference in sADAM33 enzymatic activity was observed between healthy and sarcoid BALF samples.
Conclusion Release of sADAM33 is increased in sarcoid in association with abnormal lung function. Further studies will be required to determine whether the release of sADAM33 results in dysregulated metalloprotease activity, leading to angiogenesis and pulmonary parenchymal remodelling in pulmonary sarcoid. Since ADAM33 polymorphism is related to reduced lung function in asthma and COPD, this study raises the possibility that there may also be genetic associations between ADAM33 and some forms of pulmonary sarcoid. Finally, the occurrence of sADAM33 in asthma and sarcoidosis and its relation to reduced lung function suggests that it may be a biomarker of pulmonary remodelling in these diseases.