Severe asthma is a chronic lung disease characterized by inflammation, airway hyperresponsiveness (AHR) and airway remodelling with hyperplasia of airway smooth muscle cells (aSMC). Small G proteins of the Rho family (RhoA, Rac1 and Cdc42) are key regulators of smooth muscle functions and we recently demonstrated that Rac1 controls bronchoconstriction. The objective of this study was to assess the role of Rac1 in severe asthma associated airway remodelling.

We have studied the level of Rac1 activation by immunofluorescence in bronchial biopsies from severe asthmatic patients and control patients. In order to identify the role of Rac1 in aSMC remodelling, mice with specific deletion of Rac1 in SMC were sensitized to house dust mite to mimic the characteristics of severe allergic asthma in humans.

Immunofluorescence analysis in human bronchial biopsies revealed an increased Rac1 activity in aSMC from severe asthmatic patients compared to control subjects. The basal proliferation rate of aSMC from severe asthmatics subjects is increased compared to control subjects. We have also observed that bFGF and PDGF-BB, growth factors described to be implicated in airway remodelling, stimulate the proliferation of aSMC from severe asthmatic subjects by 33% and 37% respectively. Moreover, the inhibition of Rac1 by EHT1864 decreased this proliferation by more than 50%. By a biochemical approach we have demonstrated that Rac1 signalling controlled human aSMC proliferation induced by mitogenic stimuli through the STAT3 signalling pathway. In vivo, we have demonstrated that specific deletion of Rac1 in SMC prevents aSMC hyperplasia and hypertrophy.

This study demonstrates that Rac1 is overactive in the airways of patients with severe asthma and is essential for aSMC proliferation and airway remodelling. Inhibition of Rac1 dependant signalling pathway may represent an interesting target for the treatment of severe asthma.