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.

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Background Respiratory failure is a life-threatening and unpredictable complication of systemic sclerosis (SSc). A study was undertaken to assess the value of alveolar nitric oxide (NO) in predicting the risk of lung function deterioration leading to respiratory failure or death in patients with SSc. Methods 105 patients with SSc were enrolled in this prospective cohort and were followed longitudinally over a 3-year period during which the risk of occurrence of deleterious events was analysed according to alveolar concentration (C A NO), conducting airway output (J 9 aw NO) and fractional concentration (F E NO 0.05 ) of exhaled NO measured at inclusion. Comparison was made between each NO parameter to predict the occurrence of deleterious events, defined as a 10% decrease in total lung capacity or forced vital capacity from baseline, or death. Results The area under the receiver operating characteristic curve of C A NO to predict the occurrence of the combined events was 0.84 (95% CI 0.76 to 0.92; p<0.001), which was significantly higher than those of J 9 aw NO and F E NO 0.05 (p<0.001). A cut-off of C A NO of 5.3 ppb had a sensitivity of 88% and a specificity of 62% for the prediction of the occurrence of combined events during follow-up, and was validated in an independent cohort of patients with SSc.

Endothelial dysfunction is one of the main consequences of the toxic effects of cigarette smoke on the vascular system. Increasing evidence suggests that the small G-protein RhoA and its downstream effectors, the Rho-kinases (ROCKs), are involved in systemic endothelial dysfunction induced by cigarette smoke. This study aimed to evaluate the role of the RhoA/ROCKs pathway in pulmonary artery endothelial function in current smokers with normal lung function.Lung tissues were obtained from nonsmokers and smokers who underwent lobectomy for lung carcinoma. Arterial relaxation in response to acetylcholine (ACh) was assessed in isolated pulmonary arterial rings. Protein expressions and activities of endothelial nitric oxide synthase (eNOS), ROCKs and the myosin phosphatase subunit 1 (MYPT-1) were sought.Relaxation in response to ACh was significantly lower in smokers as compared with nonsmokers (n58 in each group), consistent with reduced eNOS activity in the former compared with the latter. eNOS protein expression remained, however, the same in both groups. Expression of ROCKs, guanosine triphosphate-RhoA and phosphorylated MYPT-1 were significantly increased in smokers compared with controls.Pulmonary endothelial dysfunction is present in smokers whose lung function has not yet been impaired. Reduced activity of eNOS accounts at least in part for this endothelial dysfunction. Increased expression and activity of ROCKs accounts for another part through direct or indirect inhibition of the Rho-A/ROCKs pathway on nitric oxide synthesis and sustained pulmonary vasoconstriction through inhibition of myosin phosphatase.

Objective. Systemic sclerosis (SSc) is characterized by microvascular damage, fibrosis of skin and visceral organs, and autoimmunity. Previous studies have shown that angiotensin II is involved in the synthesis of type I collagen. We investigated whether the blockade of angiotensin II receptor type I (AT 1 ) by irbesartan reduces skin and lung fibrosis in 2 murine models of SSc. Methods. SSc was induced by daily intradermal injection of HOCl into the backs of BALB/c mice (HOCl-induced SSc). Mice were treated daily with irbesartan by oral gavage.Results. Irbesartan reduced dermal thickness, collagen concentration, Smad2/3, and ␣-smooth muscle actin expression, as well as fibroblast proliferation and H-Ras expression in the skin of mice with HOClinduced SSc. Mice treated with irbesartan also displayed less lung fibrosis, less inflammation, and a lower concentration of collagen in the lungs than untreated mice. Exhaled nitric oxide, inducible nitric oxide synthase, and 3-nitrotyrosine expression in the lungs were decreased following irbesartan treatment. Moreover, irbesartan reduced the number and the proliferation of splenic B and T cells and the serum levels of anti-DNA topoisomerase I autoantibodies.Conclusion. Irbesartan, an AT 1 antagonist, prevents fibrosis and inflammation and inhibits nitric oxide production in HOCl-induced models of systemic fibrosis. Our findings extend the indication of an AT 1 antagonist to SSc patients with diffuse fibrosis, especially those with lung involvement.

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Recent evidence suggests that activation of RhoA/Rho-kinase accounts for systemic and pulmonary endothelial dysfunction in smokers with normal lung function. However, its role in patients with chronic obstructive pulmonary disease (COPD) has not yet been investigated. The aim of this study was to evaluate the regulation of RhoA/Rho-kinase pathway and pulmonary endothelial dysfunction in patients with COPD. Pulmonary arteries were obtained from nonsmokers (control subjects) and patients with nonhypoxemic and hypoxemic COPD (n = 6–7/group). Endothelium-dependent and -independent relaxations were evaluated by acetylcholine and sodium nitroprusside, respectively. Gene and protein expressions of endothelial nitric oxide synthase (eNOS) were measured by RT-PCR, Western blot, and immunohistochemistry. Nitrate, cGMP, and endothelin-1 (ET-1) concentrations, as well as Rho-kinase activity were measured by ELISA. Protein expressions of total RhoA and GTP-RhoA were measured by Western blot and pull-down assay, respectively. Endothelium-dependent relaxation, and nitrate and cGMP levels were significantly reduced in pulmonary arteries of COPD patients as compared with control subjects. Conversely, activity of RhoA/Rho-kinase was increased in pulmonary arteries of COPD patients as compared with control subjects. In patients with COPD, pulmonary endothelial dysfunction was related to the downregulation of eNOS activity and upregulation of RhoA/Rho-kinase activity.