Cystic fibrosis (CF) is characterized by airway neutrophilic inflammation and impaired tissue remodelling and repair associated with abnormal matrix metalloproteinase (MMP) expression [Gaggar et al (2011) Eur Respir J. 38(3):721-7]. MMPs can also modulate cytokine activity, which plays a pivotal role in inflammatory and immune responses [Manicone et al (2008) Semin Cell Dev Biol. 19(1):34-41]. Ubiquitously expressed proprotein convertase, furin can cleave and activate a wide range of pathogenic substrates, including several MMPs. This study therefore, aimed to investigate whether inhibition by a novel, highly selective furin inhibitor, BOS-857 would modulate downstream MMP activity.

Fully differentiated primary CF human bronchial epithelial cells (CF HBECs) were treated with BOS-857 and the basolateral medium collected. A Proteome Profiler Human Protease Array Kit (R&D Systems) was used to detect changes in 35 protease targets in the presence of lipopolysaccharide (LPS) (+/-BOS-857) for 48 hours. Levels of interleukin-8 (IL-8), MMP-1, and MMP-3 was measured by ELISA. MMP-2 and MMP-9 activity was measured by gelatin zymography.

Levels of IL-8 secretion remained relatively unchanged between BOS-857 treated and untreated CF HBECs. Treatment with BOS-857 however, reduced the secretion of MMP-1, MMP-2, MMP-3, and MMP-9. Eight of the nine MMPs detected by the array that were stimulated with LPS were modulated upon treatment with BOS-857.

Furin inhibition appears to inhibit several MMPs which are commonly upregulated in people with CF, overexpression of which may play a role in fibrotic processes characteristic of chronic pulmonary disease.