Mikio Ueda

ROLE OF INTERCELLULAR ADHESION MOLECULE 1 IN ACUTE LUNG INJURY INDUCED BY CANDIDEMIA

Candidemia, a complication often affecting immunocompromised patients, is a common cause of acute lung injury. Yeast-phase Candida albicans has been shown to express a protein that is antigenically and structurally related to Mac-1. C. albicans is reported to stimulate intercellular adhesion molecule 1 (ICAM-1)expression on endothelial cells. In this study, the authors examined the role of ICAM-1 in acute lung injury induced by candidemia. The authors cultured rat pulmonary artery endothelial cells (RPAEC)and investigated the effect of anti-ICAM-1antibodies on adhesion of C. albicans to RPAEC. In addition, the authors administered anti-ICAM-1 antibodies to rats to examine the effect of the antibodies on experimentally induced candidemia. Survival rates, lung wet-to-dry (W/D) weight ratios, bronchoalveolar lavage (BAL) fluid, histopathological findings, and colony-forming units (CFUs)of lung C. albicans were examined. The adherence of C. albicans to RPAEC was significantly decreased by anti-ICAM-1 antibodies. Anti-ICAM-1 antibodies significantly increased survival, decreased lung W/D weight ratios, decreased neutrophil counts in the BAL fluid, reduced microscopic lung injury, and decreased the quantity of lung C. albicans. These results indicate that ICAM-1plays a role in adherence of C. albicans to pulmonary vascular endothelial cells, which likely leads to invasion of lung tissue by the organism.Candidemia, a complication often affecting immunocompromised patients, is a common cause of acute lung injury. Yeast-phase Candida albicans has been shown to express a protein that is antigenically and structurally related to Mac-1. C. albicans is reported to stimulate intercellular adhesion molecule 1 (ICAM-1) expression on endothelial cells. In this study, the authors examined the role of ICAM-1 in acute lung injury induced by candidemia. The authors cultured rat pulmonary artery endothelial cells (RPAEC) and investigated the effect of anti-ICAM-1 antibodies on adhesion of C. albicans to RPAEC. In addition, the authors administered anti-ICAM-1 antibodies to rats to examine the effect of the antibodies on experimentally induced candidemia. Survival rates, lung wet-to-dry (W/D) weight ratios, bronchoalveolar lavage (BAL) fluid, histopathological findings, and colony-forming units (CFUs) of lung C. albicans were examined. The adherence of C. albicans to RPAEC was significantly decreased by anti-ICAM-1 antibodies. Anti-ICAM-1 antibodies significantly increased survival, decreased lung W/D weight ratios, decreased neutrophil counts in the BAL fluid, reduced microscopic lung injury, and decreased the quantity of lung C. albicans. These results indicate that ICAM-1 plays a role in adherence of C. albicans to pulmonary vascular endothelial cells, which likely leads to invasion of lung tissue by the organism.

Role of Alveolar Macrophages in Candida-Induced Acute Lung Injury

ABSTRACT Recent studies have shown that alveolar macrophages (AMs) not only act as phagocytes but also play a central role as potent secretory cells in various lung diseases, including pneumonia and acute respiratory distress syndrome. The behavior of AMs during disseminated candidiasis, however, is insufficiently elucidated. This study is the first to report disseminated candidiasis in AM-depleted mice and to analyze the effect of AMs on Candida-induced acute lung injury. While all AM-sufficient mice died by day 2 after infection withCandida albicans, no mortality was observed among AM-depleted mice. Unexpectedly, the CFU numbers of C. albicans isolated from the lungs of AM-depleted mice were significantly higher than those for C. albicans isolated from AM-sufficient mice. The lung wet-to-dry weight ratio was lower for AM-depleted mice than for AM-sufficient mice, although this difference was not significant. We found that bronchoalveolar lavage fluid (BALF) from AM-depleted mice in candidemia contained fewer neutrophils than BALF from AM-sufficient mice. In addition, myeloperoxidase activities in lung homogenates of AM-depleted mice were significantly lower than those in homogenates of AM-sufficient mice. A significant decrease in levels of murine macrophage inflammatory protein 2 (MIP-2), a potent chemoattractant for neutrophils, was noted in lung homogenates from AM-depleted mice compared with levels in homogenates from AM-sufficient mice. Immunohistochemical studies using anti-MIP-2 antibodies revealed that AMs were the cellular source of MIP-2 within the lung during candidemia. We observed that AM depletion decreased levels of AM-derived neutrophil chemoattractant, alleviated acute lung injury during candidemia, and prolonged the survival of mice in candidemia, even though clearance of C. albicans from the lungs was reduced.

Phase II Trial of Weekly Gemcitabine and Split-dose Cisplatin for Advanced Non-small-cell Lung Cancer

OBJECTIVE Cisplatin is widely used for the treatment of non-small-cell lung cancer. However, it can cause unpleasant side effects and also requires prolonged hydration. We conducted a Phase II study of weekly gemcitabine and split-dose cisplatin in patients with advanced non-small-cell lung cancer (NSCLC) in order to reduce toxicity and shorten the time taken by administration. Our aims were to determine the response rate, toxicity and survival time with this regimen in patients with Stage IIIB/IV disease. METHODS Previously untreated patients with Stage IIIB/IV NSCLC were given gemcitabine (1000 mg/m(2)) and split-dose cisplatin (40 mg/m(2)) on days 1 and 8 at 3-week intervals for four cycles. Gemcitabine was administered over the course of 30 min, and cisplatin was over the course of 60 min on the same days on an outpatient basis. RESULTS Forty-five patients were enrolled, and all of them were assessable for response and toxicity. None had a complete response and 17 had a partial response (37.8%), for an overall response rate of 37.8% (95% confidence interval, 25.1-52.4%). The survival rate was 56.5% at 1 year and 38.9% at 2 years, with a median survival time of 15.7 months. Leukopenia, neutropenia, anemia and thrombocytopenia were the most common toxic reactions, with Grade > or = 3 reactions occurring at rates of 35%, 51%, 31% and 13%, respectively. CONCLUSIONS Weekly gemcitabine and split-dose cisplatin is active and well tolerated in patients with Stage IIIB/IV NSCLC, administered on an outpatient basis without requiring prolonged hydration or hospitalization.