Shin Kurosawa

Anesthetics, immune cells, and immune responses

General anesthesia accompanied by surgical stress is considered to suppress immunity, presumably by directly affecting the immune system or activating the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Along with stress such as surgery, blood transfusion, hypothermia, hyperglycemia, and postoperative pain, anesthetics per se are associated with suppressed immunity during perioperative periods because every anesthetic has direct suppressive effects on cellular and neurohumoral immunity through influencing the functions of immunocompetent cells and inflammatory mediator gene expression and secretion. Particularly in cancer patients, immunosuppression attributable to anesthetics, such as the dysfunction of natural killer cells and lymphocytes, may accelerate the growth and metastases of residual malignant cells, thereby worsening prognoses. Alternatively, the anti-inflammatory effects of anesthetics may be beneficial in distinct situations involving ischemia and reperfusion injury or the systemic inflammatory response syndrome (SIRS). Clinical anesthesiologists should select anesthetics and choose anesthetic methods with careful consideration of the clinical situation and the immune status of critically ill patients, in regard to long-term mortality, morbidity, and the optimal prognosis.

Inhalation anesthetics induce apoptosis in normal peripheral lymphocytes in vitro

Background The authors hypothesized that perioperative lymphocytopenia is partially caused by apoptosis of lymphocytes induced by inhalation anesthetics. Therefore, they evaluated whether sevoflurane and isoflurane induce apoptosis of normal peripheral lymphocytes. Methods Normal peripheral blood mononuclear cells were exposed to sevoflurane and isoflurane, and the percentages of apoptotic lymphocytes was measured by Annexin V-fluorescein isothiocyanate–7-amino actinomycin D flow cytometry after 24 h of exposure (0.5, 1.0, and 1.5 mm) and after 6, 12, and 24 h of exposure (1.5 mm). The percentages of lymphocytes with caspase 3–like activity were also measured after 24 h of exposure (1.5 mm). Results The percentages of apoptotic lymhocytes were increased in a dose-dependent manner (controls: 5.1 ± 1.4%; sevo-flurane: 7.3 ± 1.3% [0.5 mm], 9.1 ± 1.5% [1.0 mm], 12.6 ± 2.1% [1.5 mm]; isoflurane: 7.5 ± 1.6% [0.5 mm], 10.5 ± 1.5% [1.0 mm], 16.3 ± 2.7% [1.5 mm]) after 24 h of exposure and in a time-dependent manner (controls: 1.2 ± 0.4% [6 h], 3.4 ± 0.7% [12 h], 5.6 ± 1.2% [24 h]; sevoflurane: 1.8 ± 0.4% [6 h], 6.4 ± 1.2% [12 h], 11.3 ± 2.2% [24 h]; isoflurane: 2.6 ± 0.5% [6 h], 8.8 ± 1.5% [12 h],16.0 ± 1.9% [24 h]) at the concentration of 1.5 mm. The percentages of lymphocytes with caspase 3–like activity were increased (controls: 10.0 ± 1.1%; sevoflurane: 13.8 ± 1.2%; isoflurane: 17.0 ± 1.3%). Conclusions Both sevoflurane and isoflurane induced apoptosis in peripheral lymphocytes in dose-dependent and time-dependent manners in vitro.

Increased circulating endothelial microparticles in COPD patients: a potential biomarker for COPD exacerbation susceptibility

Rationale The influence of COPD exacerbation on the endothelium is not completely understood. Circulating endothelial microparticles (EMPs) are membrane vesicles in circulating blood that are shed by activated or apoptotic endothelial cells. Objective To compare EMP numbers in stable COPD patients with those during and after exacerbation. Methods We examined the EMP numbers in 80 stable COPD patients, 27 patients with exacerbated COPD, and 20 healthy non-COPD volunteers. EMPs were defined as CD144+ MPs (VE-cadherin EMPs), CD31+/CD41− MPs (PECAM EMPs), CD146 MPs (MCAM EMPs) and CD62E+ EMPs (E-selectin EMPs) as analysed by FACS. Von Willebrand factor (vWF) expression was utilised to identify the origins of the EMPs. Results VE-cadherin, PECAM and E-selectin EMP numbers were significantly higher in the stable COPD patients than in the non-COPD volunteers, and they were significantly higher in the patients with exacerbated COPD than in the stable COPD patients. The majority of these increased EMPs were vWF-negative, indicating a pulmonary capillary origin. Baseline E-selectin EMP levels were significantly higher in COPD patients who experienced frequent exacerbations than in those who did not have frequent exacerbations (p<0.001). Twenty-eight days after the onset of exacerbation, E-selectin EMP levels returned to those observed in stable COPD patients, whereas PECAM EMP levels remained high. MCAM EMP numbers were not elevated in stable or exacerbated-COPD patients. Conclusions Endothelial damage, mainly in pulmonary capillaries, occurs during exacerbation and continues even after clinical symptoms disappear. Higher baseline E-selectin EMP levels may indicate COPD patients who are susceptible to exacerbation.

Anesthesia in patients with cancer disorders

PURPOSE OF REVIEW Along with the increasing population of elderly people in developed countries, anesthesiologists have increasing opportunities to anesthetize cancer patients in their routine work. However, no guideline of anesthesia procedures for cancer patients is available even though guidelines of operative procedures have been formulated for different types of cancer. This review provides recent findings related to the optimal choice of anesthetics and adequate anesthesia management for cancer patients. RECENT FINDINGS The intrinsic weapon fighting cancer cells is competent immune cells, particularly CD4+ T helper 1-type cells, CD8+ cytotoxic T cells, and natural killer cells. However, surgical inflammation, some anesthetics, and inadvertent anesthesia management suppress these effector cells and induce suppressive immune cells, which render cancer patients susceptible to tumor recurrence and metastasis after surgery. SUMMARY Accumulated basic and clinical data suggest that total intravenous anesthesia with propofol, cyclooxygenase antagonists, and regional anesthesia can decrease negative consequences associated with perioperative immunosuppression. Volatile anesthesia, systemic morphine administration, unnecessary blood transfusions, intraoperative hypoxia, hypotension, hypothermia, and hyperglycemia should be avoided.

Impaired endothelial progenitor cell mobilization and colony-forming capacity in chronic obstructive pulmonary disease

Background and objective:  Recent studies suggest that there is endothelial impairment in both the systemic and pulmonary circulations of patients with COPD. Endothelial progenitor cells (EPC) are mobilized into the circulation by physiological stressors such as surgery, and are thought to play a role in the repair of damaged endothelium. There has been a steady increase in the frequency of surgery among COPD patients, due to the incidence of complications and lung cancer; however, the mobilization of EPC during lung resection has not been examined. We evaluated whether the mobilization and proliferation of EPC are impaired in COPD patients.

Cesarean section and primary pulmonary hypertension: the role of intravenous dexmedetomidine

Primary pulmonary hypertension is a fatal disease that frequently becomes evident in pregnancy. The management of pregnant women with primary pulmonary hypertension poses a number of difficult problems, especially where regional anesthesia is considered to be contraindicated. A 30-year-old woman who developed primary pulmonary hypertension at 23 weeks of pregnancy was transferred to our hospital. Systolic pulmonary artery pressure and plasma brain natriuretic peptide levels were markedly elevated. Nitric oxide inhalation and prostacyclin prevented the progression of cardiac failure and reduced both plasma brain natriuretic peptide and pulmonary artery pressure. Cesarean section was performed at 32 weeks under general anesthesia. A combination of nitric oxide, prostacyclin, nitroglycerin, and dobutamine were administered during surgery. Intravenous dexmedetomidine was specifically used during emergence and recovery from anesthesia. This provided effective pain relief and hemodynamic stability. Throughout the clinical course, brain natriuretic peptide levels was monitored and used as an indicator of cardiac failure.

Differences in the released endothelial microparticle subtypes between human pulmonary microvascular endothelial cells and aortic endothelial cells in vitro.

ABSTRACT Circulating endothelial microparticles (EMPs) are membrane vesicles that are shed into the blood stream from activated or apoptotic endothelial cells. We previously reported that circulating EMP numbers significantly increased in stable chronic obstructive pulmonary disease (COPD) patients and during exacerbation compared with healthy control subjects. However, different types of circulating EMPs with distinct time profiles were detectable during exacerbations. We hypothesized that the released EMP subtypes correlated with differences in the inflammatory stimuli and the endothelial cell type. We compared the EMP subtypes from human aortic endothelial cells (Aortic ECs) and human lung microvascular endothelial cells (Pulmonary microvascular ECs) released in response to various stimuli, including proinflammatory cytokines (TNFα), oxidative stress (H2O2), and cigarette smoke extracts (CSE) in vitro. We defined circulating EMPs by the expression of endothelial antigens: CD144+ MPs (VE-cadherin EMPs), CD31+/CD41− MPs (PECAM EMPs), CD62E+ MPs (E-selectin EMPs), and CD146+ MPs (MCAM EMPs). E-selectin EMPs were released from both pulmonary microvascular and aortic ECs in response to TNFα but not to H2O2 or CSE stimulation. The amount of MCAM EMPs released from pulmonary microvascular ECs differed significantly between the cells stimulated with H2O2 and those stimulated with CSE. VE-cadherin EMPs were only released from aortic ECs, whereas PECAM EMPs were released exclusively from pulmonary microvascular ECs. The EMP subtypes released differ in vitro among TNFα, H2O2, and CSE stimulation as well as between pulmonary microvascular and aortic ECs. The differences in circulating EMP subtypes may reflect a condition or site of endothelial injury and may serve as markers for endothelial damage in COPD patients.

Compensatory thrombopoietin production from the liver and bone marrow stimulates thrombopoiesis of living rat megakaryocytes in chronic renal failure.

Background/Aims: Decreased thrombopoiesis has been ascribed a role in the pathogenesis of uremic bleeding in chronic renal failure (CRF). However, serum thrombopoietin (TPO) levels are usually elevated in CRF patients, suggesting increased thrombopoiesis. The aim of this study was to determine the thrombopoietic activity in CRF. Methods: Male Sprague-Dawley rats that underwent 5/6 nephrectomy were used as the model of CRF. Age-matched sham-operated rats were used as controls. Single megakaryocytes were isolated from the rat bone marrow, and their size distribution was examined. Megakaryocyte membrane invaginations were monitored by confocal imaging of di-8-ANEPPS staining, and patch clamp whole-cell recordings of membrane capacitance. TPO gene expression was assessed in various tissues. Results: Circulating platelet counts and the number of large megakaryocytes were increased in the bone marrow of CRF rats. Massive di-8-ANEPPS staining and increased membrane capacitance in large megakaryocytes demonstrated increased membrane invaginations. Unaffected Kv1.3-channel currents per cell surface area demonstrated unaltered channel densities. TPO transcription was decreased in the renal cortex but increased in the liver and bone marrow of CRF rats. Conclusion: Increased thrombopoiesis in CRF was thought to be a reactive mechanism to platelet dysfunction. Increased TPO production from the liver and bone marrow compensated for decreased production from damaged kidneys.

The effective removal of proinflammatory cytokines by continuous hemofiltration with a polymethylmethacrylate membrane following severe burn injury: report of three cases.

The serum levels of proinflammatory cytokines were investigated in three patients with severe burn injuries complicated by sepsis and pulmonary edema, who were treated with continuous hemofiltration (CHF) using a polymethylmethacrylate (PMMA) membrane. All patients had suffered burn injuries to more than 30% of their total body surface area (TBSA) and had burn indexes of 20 or more. Both interleukin (IL)-6 and tumor necrosis factor-α were detectable in one patient, while the serum IL-6 levels were elevated in the remaining two patients. The serum cytokines decreased 24h after the initiation of CHF. Determinations of IL-6 in inflow and outflow blood samples as well as in the filtration fluid revealed that IL-6 was ultrafiltrated and/or adsorbed by the filter. Two of the three patients did not survive. Nevertheless, the results of this study indicate that since burn injuries are frequently associated with hypercytokinemia, the removal of cytokines by CHF with a PMMA membrane may be effective in the management of severe burn injuries.

Overexpression of Delayed Rectifier K+ Channels Promotes In situ Proliferation of Leukocytes in Rat Kidneys with Advanced Chronic Renal Failure

Leukocytes, such as lymphocytes and macrophages, predominantly express delayed rectifier K+ channels (Kv1.3), and the channels play crucial roles in the activation and proliferation of the cells. Since lymphocytes are activated in patients with end-stage renal disease (ESRD), the channels expressed in those cells would contribute to the progression of renal fibrosis in advanced-stage chronic renal failure (CRF). In the present study, using a rat model with advanced CRF that underwent 5/6 nephrectomy followed by a 14-week recovery period, we examined the histopathological features of the kidneys and the leukocyte expression of Kv1.3-channels and cell cycle markers. Age-matched sham-operated rats were used as controls. In the cortical interstitium of advanced CRF rat kidneys, leukocytes proliferated in situ and overexpressed Kv1.3 channel protein in their cytoplasm. Treatment with margatoxin, a selective Kv1.3-channel inhibitor, significantly suppressed the number of leukocytes and the progression of renal fibrosis with a significant decrease in the cortical cell cycle marker expression. This study demonstrated for the first time that the number of leukocytes was dramatically increased in rat kidneys with advanced CRF. The overexpression of Kv1.3 channels in the leukocytes was thought to contribute to the progression of renal fibrosis by stimulating cell cycling and promoting cellular proliferation.