Systemic Lupus Erythematosus and Lung Involvement: A Comprehensive Review.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with multiorgan manifestations, including pleuropulmonary involvement (20-90%). The precise mechanism of pleuropulmonary involvement in SLE is not well-understood; however, systemic type 1 interferons, circulating immune complexes, and neutrophils seem to play essential roles. There are eight types of pleuropulmonary involvement: lupus pleuritis, pleural effusion, acute lupus pneumonitis, shrinking lung syndrome, interstitial lung disease, diffuse alveolar hemorrhage (DAH), pulmonary arterial hypertension, and pulmonary embolism. DAH has a high mortality rate (68-75%). The diagnostic tools for pleuropulmonary involvement in SLE include chest X-ray (CXR), computed tomography (CT), pulmonary function tests (PFT), bronchoalveolar lavage, biopsy, technetium-99m hexamethylprophylene amine oxime perfusion scan, and (18)F-fluorodeoxyglucose positron emission tomography. An approach for detecting pleuropulmonary involvement in SLE includes high-resolution CT, CXR, and PFT. Little is known about specific therapies for pleuropulmonary involvement in SLE. However, immunosuppressive therapies such as corticosteroids and cyclophosphamide are generally used. Rituximab has also been successfully used in three of the eight pleuropulmonary involvement forms: lupus pleuritis, acute lupus pneumonitis, and shrinking lung syndrome. Pleuropulmonary manifestations are part of the clinical criteria for SLE diagnosis. However, no review article has focused on the involvement of pleuropulmonary disease in SLE. Therefore, this article summarizes the literature on the epidemiology, pathogenesis, diagnosis, and management of pleuropulmonary involvement in SLE.

Globotriaosylceramide induces lysosomal degradation of endothelial KCa3.1 in fabry disease.

OBJECTIVE: Globotriaosylceramide (Gb3) induces KCa3.1 downregulation in Fabry disease (FD). We investigated whether Gb3 induces KCa3.1 endocytosis and degradation. APPROACH AND RESULTS: KCa3.1, especially plasma membrane-localized KCa3.1, was downregulated in both Gb3-treated mouse aortic endothelial cells (MAECs) and human umbilical vein endothelial cells. Gb3-induced KCa3.1 downregulation was prevented by lysosomal inhibitors but not by a proteosomal inhibitor. Endoplasmic reticulum stress-inducing agents did not induce KCa3.1 downregulation. Gb3 upregulated the protein levels of early endosome antigen 1 and lysosomal-associated membrane protein 2 in MAECs. Compared with MAECs from age-matched wild-type mice, those from aged α-galactosidase A (Gla)-knockout mice, an animal model of FD, showed downregulated KCa3.1 expression and upregulated early endosome antigen 1 and lysosomal-associated membrane protein 2 expression. In contrast, no significant difference was found in early endosome antigen 1 and lysosomal-associated membrane protein 2 expression between young Gla-knockout and wild-type MAECs. In aged Gla-knockout MAECs, clathrin was translocated close to the cell border and clathrin knockdown recovered KCa3.1 expression. Rab5, an effector of early endosome antigen 1, was upregulated, and Rab5 knockdown restored KCa3.1 expression, the current, and endothelium-dependent relaxation. CONCLUSIONS: -Gb3 accelerates the endocytosis and lysosomal degradation of endothelial KCa3.1 via a clathrin-dependent process, leading to endothelial dysfunction in FD.

Modified mandibulotomy technique to reduce postoperative complications: 5-year results.

PURPOSE: To review the 5-year outcomes of our modified mandibulotomy technique. Retrospective review of a tertiary level oral cancer center. MATERIALS AND METHODS: During a 5-year period, 30 patients who had a uniform surgical technique consisting of a lower lip-splitting, modified stair-step osteotomy with thin saw blade and osteotome after plate-precontouring and combination fixation with monocortical osteosynthesis (miniplate) and bicortical osteosynthesis (maxiplate and bicortical screws), with at least 14 months postoperative follow-up, were selected and reviewed retrospectively. RESULTS: There were 8 women and 22 men with an average age of 56.5 years. All the patients involved malignancies were squamous cell carcinoma. The main primary sites of the those who underwent a mandibulotomy were the tonsil, the base of tongue, the oral tongue, the retromolar pad area, and others. Others included buccal cheek, floor of mouth, and soft palate. 23 patients received postoperative radiation therapy, and among whom 8 patients also received chemotherapy. Total four (13%) mandibulotomy-related complications occurred, only two (6.7%) requiring additional operation under general anesthesia. CONCLUSION: Our modified mandibulotomy meets the criteria for an ideal mandibulotomy technique relatively well because it requires no intermaxillary fixation, can precise preserve the occlusion in a precise way, allows early function, requires no secondary procedures, and has few complications.

Contradictory Effects of Superoxide and Hydrogen Peroxide on KCa3.1 in Human Endothelial Cells.

Reactive oxygen species (ROS) are generated in various cells, including vascular smooth muscle and endothelial cells, and regulate ion channel functions. KCa3.1 plays an important role in endothelial functions. However, the effects of superoxide and hydrogen peroxide radicals on the expression of this ion channel in the endothelium remain unclear. In this study, we examined the effects of ROS donors on KCa3.1 expression and the K(+) current in primary cultured human umbilical vein endothelial cells (HUVECs). The hydrogen peroxide donor, tert-butyl hydroperoxide (TBHP), upregulated KCa3.1 expression, while the superoxide donors, xanthine/xanthine oxidase mixture (X/XO) and lysopho-sphatidylcholine (LPC), downregulated its expression, in a concentration-dependent manner. These ROS donor effects were prevented by antioxidants or superoxide dismustase. Phosphorylated extracellular signal-regulated kinase (pERK) was upregulated by TBHP and downregulated by X/XO. In addition, repressor element-1-silencing transcription factor (REST) was downregulated by TBHP, and upregulated by X/XO. Furthermore, KCa3.1 current, which was activated by clamping cells with 1 µM Ca(2+) and applying the KCa3.1 activator 1-ethyl-2-benzimidazolinone, was further augmented by TBHP, and inhibited by X/XO. These effects were prevented by antioxidants. The results suggest that hydrogen peroxide increases KCa3.1 expression by upregulating pERK and downregulating REST, and augments the K(+) current. On the other hand, superoxide reduces KCa3.1 expression by downregulating pERK and upregulating REST, and inhibits the K(+) current. ROS thereby play a key role in both physiological and pathological processes in endothelial cells by regulating KCa3.1 and endothelial function.

NADPH oxidase 2-derived superoxide downregulates endothelial KCa3.1 in preeclampsia.

Endothelial dysfunction is associated with KCa3.1 dysfunction and contributes to the development of hypertension in preeclampsia. However, evidence of endothelial KCa3.1 dysfunction in the vascular system from women with preeclampsia is still lacking. Therefore, we examined whether endothelial KCa3.1 dysfunction occurs in vessels from women with preeclampsia. We compared KCa3.1 and NADPH oxidase (NOX) expression in umbilical vessels and primary cultured human umbilical vein endothelial cells (HUVECs) from normal (NP; n=17) and preeclamptic pregnancy (PE; n=19) and examined the effects of plasma from NP or PE on KCa3.1 and NOX2 expression in primary cultured HUVECs from NP or human uterine microvascular endothelial cells. The endothelial KCa3.1 was downregulated, and NOX2 was upregulated, in umbilical vessels and HUVECs from PE, compared with those from NP. In addition, HUVECs from PE showed a significant decrease in KCa3.1 current. Plasma from PE induced KCa3.1 down regulation, NOX2 upregulation, phosphorylated-p38 mitogen-activated protein kinase downregulation, and superoxide generation, and these effects were prevented by antioxidants (tempol or tiron), NOX2 inhibition, or anti-lectin-like oxidized low-density lipoprotein (LDL) receptor 1 (LOX1) antibody. Oxidized LDL and the superoxide donor xanthine/xanthine oxidase mixture induced KCa3.1 downregulation. In contrast, plasma from PE did not generate hydrogen peroxide, and the hydrogen peroxide donor tert-butylhydroperoxide induced KCa3.1 upregulation. These results provide the first evidence that plasma from PE generates superoxide via a LOX1-NOX2-mediated pathway and downregulates endothelial KCa3.1, which may contribute to endothelial dysfunction and vasculopathy in preeclampsia. This suggests KCa3.1as a novel target for patients with preeclampsia.

P2X7 receptor-dependent ATP-induced shedding of CD27 in mouse lymphocytes.

The ATP-gated P2X7 cell surface receptor belongs to the P2X purinoreceptor family, and is expressed abundantly by immune cells. This receptor is involved in several inflammatory and immunological processes, including the secretion of IL-1 by activated macrophages. Here, we demonstrate that CD27, a cell surface molecule, which is involved in the interaction between immune cells and implicated in the immunological memory of the T and B cells, is released rapidly upon treatment with low ATP concentrations, via the activation of the P2X7 receptor. The surface expression of CD27 on the T and B cells has been shown to be down-regulated as the result of ATP treatment, and the soluble form of CD27 was detected readily in the supernatants of splenocytes, which were cultured along with ATP treatment. The shedding of CD27 was blocked by KN-62, a chemical P2X7 inhibitor, and was also efficiently triggered by treatment with 2,3-O-(4-benzoyl-benzoyl)-ATP. The shedding of CD27 from mouse splenic T cells was observed to occur within 5 min of treatment with 300 microM ATP, whereas treatment with PMA or ionomycin was not determined to trigger the shedding of CD27 until treatment had been applied for a period of at least 2 h. The ATP-induced shedding of CD27 was inhibited by treatment with the matrix metalloprotease inhibitor, GM6001, but not by treatments with BAPTA-AM, wortmannin, SB202190, or PD 98059. Therefore, we concluded that P2X7 receptor stimulation by extracellular ATP results in rapid CD27 shedding via protease activation.