A phosphatidylinositol 3-kinase inhibitor strongly suppressed pulmonary vascular remodeling of allergic vasculitis in a murine model.

OBJECTIVES: We investigated the effects of pan-class I PI3K inhibitor, ZSTK474 on vascular remodeling using a murine model of allergic vasculitis with eosinophil infiltration. METHODS: C57BL/6 mice were sensitized with OVA. The positive controls were exposed to aerosolized OVA daily for 7 days. The other group of mice were administered ZSTK474 (30 mg/kg, p.o. daily) in parallel with daily exposure to aerosolized OVA for 7 days. On the 3rd and 7th day, bronchoalveolar lavage (BAL) was performed and the lungs were excised for pathological analysis. Cell differentials were determined and the concentrations of IL-4, IL-5, IL-13 and TGF-ßin BAL fluid were measured. RESULTS: The total cell numbers and eosinophil numbers in BALF were greatly reduced in the ZSTK474-treated group on the 3rd and 7th day after exposure to OVA. The numbers of total white blood cells and eosinophils in the peripheral blood were significantly reduced in the ZSTK474-treated group on the 3rd and 7th day after exposure to OVA. The concentrations of IL-4, IL-5, and IL-13 in BAL fluids were also reduced significantly on the 3rd day in the ZSTK474-treated group. The concentrations of TGF-ß in BAL fluids were also reduced significantly on the 3rd and 7th day in the ZSTK474-treated group. The pathological scores reduced significantly in the ZSTK474-treated group compared to the control group. CONCLUSION: The PI3K inhibitor, ZSTK474 suppressed pulmonary vascular remodeling in the murine model of allergic vasculitis with eosinophil infiltration. PI3K signal transduction may have a critical role in the immunological process that induces allergic vasculitis.

Detection of cerebral microvascular lesions using 7 T MRI in patients with neuropsychiatric systemic lupus erythematosus.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is speculated to be caused by disturbed microcirculation of the central nervous system. However, characteristic imaging findings of NPSLE have not been established. Hence, we investigated whether high-resolution images obtained using ultrahigh field MRI at 7 T can detect microcerebrovascular lesions in patients with NPSLE that have never been detected by conventional MRI. We prospectively examined 20 patients with SLE, including five with NPSLE, using a 7 T MRI scanner. High-resolution two-dimensional T2-weighted images and high-resolution three-dimensional T1-weighted images (T1WIs) before and after the administration of contrast agents were obtained. On the high-resolution T1WIs obtained at 7 T, minute punctate/linear hyperintense lesions in subcortical and/or cortical areas were found in four (80%) NPSLE patients and one (7%) non-NPSLE patient. Further, the minute punctate enhanced lesions in these areas were found on contrast-enhanced T1WIs in only three (60%) NPSLE patients. These findings suggesting microvascular thrombi or inflammation were significantly more frequent in NPSLE than in non-NPSLE patients (P=0.001). In contrast, other imaging findings, laboratory findings, and clinical characteristics were not different between the two groups. High-resolution T1WIs obtained at 7 T can detect minute lesions, indicating intracerebral microvascular lesions in patients with NPSLE.