K.P. Tiev

Serum CC chemokine ligand-18 predicts lung disease worsening in systemic sclerosis

Elevated serum CC chemokine ligand (CCL)18 reflects lung fibrosis activity in systemic sclerosis (SSc) and could be an early marker of lung function worsening. Therefore, we sought to evaluate whether serum CCL18 levels at baseline could predict worsening of lung disease in SSc. In this prospective study, 83 SSc patients were analysed longitudinally over a 4-yr observation period for the risk of occurrence of combined deleterious events, defined as a 10% decrease from baseline of total lung capacity or forced vital capacity % predicted, or death, according to serum CCL18 at inclusion. Receiver operating characteristic (ROC) curve analysis was performed for prediction of events during the first year after inclusion. The best cut-off level of serum CCL18 for prediction of a combined event within the follow-up period was 187 ng·mL−1, with 53% sensitivity and 96% specificity (area under the ROC curve 0.86; p<0.001). After a mean±sd follow-up of 33.7±10.8 months, a higher rate of disease progression occurred in the group with serum CCL18 levels >187 ng·mL−1. The adjusted hazard ratio was 5.36 (95% CI 2.44–11.75; p<0.001). In summary, serum CCL18 is an accurate predictive biomarker for the identification of patients with a higher risk of subsequent scleroderma lung disease worsening.

Severity of scleroderma lung disease is related to alveolar concentration of nitric oxide

The alveolar concentration of exhaled nitric oxide (CA,NO) is increased in patients with systemic sclerosis (SSc), but whether this increase is related to the severity of interstitial lung disease (ILD) in SSc has not yet been investigated. In total, 58 SSc patients prospectively underwent pulmonary function tests (PFTs), echocardiogram and fibrosis scoring on pulmonary computed tomography (CT). Patients were divided into two groups according to the presence (or not) of ILD. Measurements of CA,NO were assessed in all SSc patients and compared with those obtained in 19 healthy volunteers. Relationships were sought between CA,NO PFTs and CT scan fibrosis scores. Overall, CA,NO was significantly increased in SSc patients (median (range) 6.2 (3.8–9.9) ppb) as compared with controls (2.0 (1.2–3.0) ppb). Among SSc patients, CA,NO was significantly higher in patients with ILD compared with patients without ILD (n = 33, 7.5 (5.2–11.9) ppb versus n = 25, 4.9 (3.1–7.0) ppb, respectively). CA,NO was inversely related to total lung capacity (r =  −0.34) and the diffusing capacity of the lung for carbon monoxide (r =  −0.37) and was directly related to CT scan fibrosis scores (r = 0.36). An increased alveolar concentration of exhaled nitric oxide could, at least in part, either reflect or contribute to the severity of lung disease and could be used to noninvasively assess the extent of interstitial lung disease in systemic sclerosis.

RhoA/Rho-kinase activation promotes lung fibrosis in an animal model of systemic sclerosis

ABSTRACT Background: Systemic sclerosis (SSc) is a connective-tissue disease characterized by vascular injury, immune-system disorders, and excessive fibrosis of the skin and multiple internal organs. Recent reports found that RhoA/Rho-kinase (ROCK) pathway is implicated in various fibrogenic diseases. Intradermal injection of hypochlorous acid (HOCl)-generating solution induced inflammation, autoimmune activation, and fibrosis, mimicking the cutaneous diffuse form of SSc in humans. Our study aimed firstly to describe pulmonary inflammation and fibrosis induced by HOCl in mice, and secondly to determine whether fasudil, a selective inhibitor of ROCK, could prevent lung and skin fibroses in HOCl-injected mice. Methods: Female C57BL/6 mice received daily intradermal injection of hypochlorous acid (HOCl) for 6 weeks to induce SSc, with and without daily treatment with fasudil (30 mg·kg−1·day−1) by oral gavage. Results: HOCl intoxication induced significant lung inflammation (macrophages and neutrophils infiltration), and fibrosis. These modifications were prevented by fasudil treatment. Simultaneously, HOCl enhanced ROCK activity in lung and skin tissues. Inhibition of ROCK reduced skin fibrosis, expression of α-smooth-muscle actin and 3-nitrotyrosine, as well as the activity of ROCK in the fibrotic skin of HOCl-treated mice, through inhibition of phosphorylation of Smad2/3 and ERK1/2. Fasudil significantly decreased the serum levels of anti-DNA-topoisomerase-1 antibodies in mice with HOCl-induced SSc. Conclusions: Our findings confirm HOCl-induced pulmonary inflammation and fibrosis in mice, and provide further evidence for a key role of RhoA/ROCK pathway in several pathological processes of experimental SSc. Fasudil could be a promising therapeutic approach for the treatment of SSc.

Increased exhaled nitric oxide precedes lung fibrosis in two murine models of systemic sclerosis.

Exhaled nitric oxide (NO) is increased as a result of lung inflammation, which in turn causes subsequent interstitial lung disease in patients with systemic sclerosis (SSc). However, the exact time course of inflammatory and fibrotic changes in the SSc lung has not yet been described. Our objective was to assess the chronological evolution of lung inflammatory and fibrotic processes in mice pre-treated with hypochlorous acid (HOCl) or bleomycin. C57BL/6 mice were randomized into three groups receiving subcutaneous injections of HOCl, bleomycin, or PBS for 2, 4 or 6 weeks. Exhaled NO (eNO) was measured at the end of each injection period and after 2 resting weeks without injection (8 week group). Mice were then sacrificed to obtain skin and lung tissues to measure fibrotic changes and NO synthases (NOS) expression. Increased eNO, inducible NOS and nitrotyrosine expression in bronchial epithelium, lung neutrophils and macrophages were observed at early phases in both HOCl- and bleomycin-treated mice. Conversely, lung vascular endothelial NOS expression decreased significantly at 6th and 8th weeks. Skin fibrosis was significantly increased from the 4th week and lung fibrosis from 6th week. We conclude that lung inflammation occurs early after injury as reflected by increased exhaled NO and inducible NOS expression, and precedes fibrotic changes in skin and lungs of mice pre-treated with bleomycin and HOCl. Early detection and treatment of pulmonary inflammation might be useful in preventing subsequent occurrence of lung fibrosis in SSc patients.