Reduced circulating levels of angiotensin-(1--7) in systemic sclerosis: a new pathway in the dysregulation of endothelial-dependent vascular tone control.

OBJECTIVE: Systemic sclerosis (SSc) impairs endothelium-dependent vasodilatation. Among angiotensin I (Ang I)-derived compounds, vasoconstrictor angiotensin II (Ang II) and vasodilator angiotensin-(1-7) (Ang-(1-7)), cleaved from ACE and neutral endopeptidase (NEP) 24.11, respectively, play an important role in vascular tone regulation. Ang-(1-7) may act independently or by activating other vasodilating molecules, such as nitric oxide (NO) or prostaglandin I2 (PGI2). Our aim was to assess, in patients with SSc, circulating levels of Ang I, Ang II and Ang-(1-7), with their metabolising enzymes ACE and NEP, and levels of NO and PGI2, and to correlate them to the main characteristics of SSc. METHODS: Levels of Ang I, Ang II, Ang-(1-7), NEP, ACE, NO and PGI2 were measured in 32 patients with SSc, who were also assessed for humoral and clinical characteristics, and 55 controls. RESULTS: Plasma Ang I, Ang II and Ang-(1-7) levels were lower in patients with SSc than in controls (p<0.001in all cases). When Ang II and Ang-(1-7) levels were expressed as a function of the available Ang I, lower Ang-(1-7) levels in patients with SSc than in controls were confirmed (p<0.001), while no difference was found for Ang II levels. In patients with SSc, the Ang II/Ang-(1-7) ratio indicated a prevalence of Ang II over Ang-(1-7), while in controls Ang-(1-7) was prevalent (p<0.001). Levels of ACE, NEP, NO and PGI2 were lower in patients with SSc than in controls (p<0.05 in all cases). CONCLUSION: In patients with SSc, prevalence of the vasoconstricting Ang II over the vasodilator Ang-(1-7) suggests a dysfunction of the angiotensin-derived cascade that may contribute to dysregulation of vascular tone.

Melatonin is a safe and effective treatment for chronic pulmonary and extrapulmonary sarcoidosis.

Chronic sarcoidosis (CS) is often unresponsive to usual treatments. Melatonin, an immunoregulatory drug, was employed in CS patients in whom usual treatments were ineffective or induced severe side effects. Melatonin was given for 2 yr (20 mg/day in the first year, 10 mg/day in the second year) to 18 CS patients. Pulmonary function tests, chest X rays, pulmonary computed tomography, Ga(67) scintigraphy and angiotensin-converting enzyme (ACE) were assayed at baseline and in the follow-up. Normalization of ACE, improvement of pulmonary parameters and resolution of skin involvement were found in the patients given melatonin. After 24 months of melatonin therapy, hylar adenopathy completely resolved in eight patients and parenchymal lesions were markedly improved in all patients; in the five patients with reduced diffusion capacity of the lung for carbon monoxide, the values normalized after 6 months of therapy and remained stable until month 24. After 24 months, Ga(67) pulmonary and extra-pulmonary uptake was totally normalized in seven patients and, at month 12 months, ACE was normalized in six patients in which the values were high at the baseline. Skin lesions, present in three patients, completely disappeared at month 24 months. No side effects were experienced and no disease relapse was observed during melatonin treatment. Melatonin may be an effective and safe therapy for CS when other treatments fail or cause side effects.

Effect of N-acetyl-L-cysteine on peroxynitrite and superoxide anion production of lung alveolar macrophages in systemic sclerosis.

Lung macrophages may play a relevant role in oxidative processes producing both superoxide anion (O(2)(-)) and NO. In this view, an antioxidant therapy can be useful in the treatment of systemic sclerosis (SSc) patients. N-Acetylcysteine (NAC) is able to expand natural antioxidant defenses by increasing intracellular gluthatione concentration and it has been proposed as an antioxidant therapy in respiratory distress syndromes. The aim of our study was to determine whether lung macrophages obtained from SSc patient bronchoalveolar lavage (BAL) express the inducible form of nitric oxide synthase (iNOS) and whether NAC can reduce the peroxynitrite (ONOO(-)) and O(2)(-) production of these cells. Alveolar macrophages were isolated from BAL of 32 patients and used for the immunocytochemical determination of iNOS, and the production of ONOO(-) and O(2)(-) was measured by fluorimetric or spectrophotometric methods, respectively. Lung macrophages obtained from SSc patients expressed a higher level of iNOS compared to healthy subject cells. NAC preincubation (5 x 10(-5)M, 24h) significantly reduced (-21%) the ONOO(-) production in formyl Met-Leu-Phe (fMLP)-activated cells and slightly reduced it under resting conditions, whereas NAC preincubation was unable to modify the release of O(2)(-) both in basal condition and in fMLP-stimulated cells. We conclude that since SSc lung macrophages express high levels of iNOS and produce a significant quantity of ONOO(-), NAC administration reduces ONOO(-) production and can be an useful treatment to alleviate SSc symptoms.