Responses to exercise in systemic sclerosis-associated interstitial lung disease.

INTRODUCTION: Pulmonary complications in systemic sclerosis (SSc) significantly increase morbidity and mortality. Our aim was to determine the factors limiting exercise capacity in SSc patients with and without interstitial lung disease (ILD), and to identify and quantify abnormalities during exercise that might assist in clinical assessment of this complication. METHODS: Fifteen patients with SSc and ILD (SSc-ILD) were compared with 10 patients with SSc without ILD and 9 age- and sex-matched normal volunteers. Subjects performed symptom-limited incremental treadmill exercise with online measurement of respiratory gas exchange, arterial blood gas sampling and measurement of neurohormones in venous blood. RESULTS: Patients with SSc-ILD had lower exercise capacity than SSc patients without ILD or normal subjects (peak oxygen consumption (PV̇O2 ) (17.1 [4.2] vs. 22.0 [4.7] and 23.0 [5.4] ml kg-1 min-1 , respectively, mean [SD], p < 0.01 ANOVA), but PV̇O2 did not correlate with static pulmonary function measurements. Ventilatory equivalent for CO2 (V̇E/V̇CO2 ; nadir) was higher in SSc-ILD patients than the other two groups (36.6 [8.0] vs. 29.9 [4.4] and 30.0 [2.5], p < 0.005) as were peak exercise dead-space tidal volume ratio (0.44 [0.06] vs. 0.26 [0.09] and 0.26 [0.05], p < 0.001) and peak exercise alveolar-arterial difference (28.9 [16.9] vs. 18.8 [14.0] and 11.5 [6.9] mmHg, p < 0.05). Atrial natriuretic peptide was elevated in both SSc patient groups. CONCLUSIONS: SSc-ILD results in lower exercise capacity than SSc without ILD, and abnormalities of gas exchange are seen. The possible use of cardiopulmonary exercise testing to identify disease and quantify impairment in SSc-ILD merits further study.

SMAD inhibition attenuates epithelial to mesenchymal transition by primary keratinocytes in vitro.

Epithelial to mesenchymal transition (EMT) is a process whereby epithelial cells undergo transition to a mesenchymal phenotype and contribute directly to fibrotic disease. Recent studies support a role for EMT in cutaneous fibrotic diseases including scleroderma and hypertrophic scarring, although there is limited data on the cytokines and signalling mechanisms regulating cutaneous EMT. We investigated the ability of TGF-ß and TNF-α, both overexpressed in cutaneous scleroderma and central mediators of EMT in other epithelial cell types, to induce EMT in primary keratinocytes and studied the signalling mechanisms regulating this process. TGF-ß induced EMT in normal human epidermal keratinocytes (NHEK cells), and this process was enhanced by TNF-α. EMT was characterised by changes in morphology, proteome (down-regulation of E-cadherin and Zo-1 and up-regulation of vimentin and fibronectin), MMP secretion and COL1α1 mRNA expression. TGF-ß and TNF-α in combination activated SMAD and p38 signalling in NHEK cells. P38 inhibition with SB203580 partially attenuated EMT, whereas SMAD inhibition using SB431542 significantly inhibited EMT and also reversed established EMT. These data highlight the retained plasticity of adult keratinocytes and support further studies of EMT in clinically relevant in vivo models of cutaneous fibrosis and investigation of SMAD inhibition as a potential therapeutic intervention.