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Hiroaki Harada

Publications and source records attributed to Hiroaki Harada.

11 recordsLinked to original sources
PubMed2006

Shortened lifespan of nematode Caenorhabditis elegans after prolonged exposure to heavy metals and detergents.

The acute toxicities of heavy metals and detergents have been well examined with respect to several endpoints, such as mortality, for application to toxicity tests for environmental assessments. However, chronic influences of these agents on multicellular organisms still need to be determined. Here we studied long-term effects on the lifespan of a free-living nematode, Caenorhabditis elegans, resulting from prolonged exposure to heavy metals or detergents, as well as short-term inhibitory effects on reproduction and growth. These agents inhibited growth of hatched larvae and reproductive capacity in a concentration-dependent manner. They also effectively shortened the lifespan of the adult nematode over the same concentration range. Since toxic effects on both growth and lifespan were observed over similar concentration ranges, where acute toxicities in various endpoints are detected, the shortening of the lifespan can be used as a new endpoint for the assessment of various ecotoxic agents.

Animals↗
PubMed2006

Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its downstream target genes.

Carbon monoxide (CO), an endogenous cytoprotective product of heme oxygenase type-1 regulates target thrombotic and inflammatory genes in ischemic stress. Regulation of the gene encoding early growth response 1 (Egr-1), a potent transcriptional activator of deleterious thrombotic and inflammatory cascades, may govern CO-mediated ischemic lung protection. The exact signaling mechanisms underlying CO-mediated cytoprotection are not well understood. In this study we tested the hypothesis that inhibition of mitogen-activated protein kinase-dependent Egr-1 expression may be pivotal in CO-mediated ischemic protection. In an in vivo isogeneic rat lung ischemic injury model, inhaled CO not only diminished fibrin accumulation and leukostasis and improved gas exchange and survival but also suppressed extracellular signal-regulated kinase (ERK) activation, Egr-1 expression, and Erg DNA-binding activity in lung tissue. Additionally, CO-mediated inhibition of Egr-1 reduced expression of target genes, such as tissue factor, serpine-1, interleukin-1, and TNF-alpha. However, CO failed to inhibit serpine-1 expression after unilateral lung ischemia in mice null for the Egr-1 gene. In RAW macrophages in vitro, hypoxia-induced Egr-1 mRNA expression was ERK-dependent, and CO-mediated suppression of ERK activation resulted in Egr-1 inhibition. Furthermore, CO suppression of ERK phosphorylation was reversed by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one but was insensitive to cAMP-dependent protein kinase A inhibition with H89 and NO synthase inhibition with l-nitroarginine methyl ester. This finding indicates that CO suppresses ERK in a cGMP-dependent but cAMP/protein kinase A- and NO-independent manner. Together, these data identify a unifying molecular mechanism by which CO interrupts proinflammatory and prothrombotic mediators of ischemic injury.

Animals↗
PubMed2006

Obligatory role for interleukin-13 in obstructive lesion development in airway allografts.

The pathogenesis of bronchiolitis obliterans (BO), a common and devastating obliterative disorder of small airways following lung transplantation, remains poorly understood. Lesions are characterized in their early stages by lymphocyte influx that evolves into dense fibrotic infiltrates. Airway specimens taken from patients with histological BO revealed infiltrating myofibroblasts, which strongly expressed the signaling chain of the high affinity interleukin-13 (IL-13) receptor IL-13Ralpha1. Because IL-13 has proinflammatory and profibrotic actions, a contributory role for IL-13 in BO development was examined using murine models of orthotopic and heterotopic tracheal transplantation. Compared with airway isografts, allografts exhibited a significant increase in relative IL-13 mRNA and protein levels. Allogeneic tracheas transplanted into IL-13-deficient mice were protected from BO in both transplant models. Flow cytometric analysis of orthotopic transplant tissue digests revealed markedly fewer infiltrating mononuclear phagocytes and CD3(+) T lymphocytes in IL-13-deficient recipients. Furthermore, protection from luminal obliteration, collagen deposition, and myofibroblast infiltration was observed in heterotopic airways transplanted into the IL-13(-/-) recipients. Transforming growth factor-beta1 expression was significantly decreased in tracheal allografts into IL-13(-/-) recipients, compared to wild-type counterparts. These human and murine data implicate IL-13 as a critical effector cytokine driving cellular recruitment and subsequent fibrosis in clinical and ex-perimental BO.

Adult↗
PubMed2005

Reciprocal regulation of airway rejection by the inducible gas-forming enzymes heme oxygenase and nitric oxide synthase.

Obliterative bronchiolitis (OB) develops insidiously in nearly half of all lung transplant recipients. Although typically preceded by a CD8(+) T cell-rich lymphocytic bronchitis, it remains unresponsive to conventional immunosuppression. Using an airflow permissive model to study the role of gases flowing over the transplanted airway, it is shown that prolonged inhalation of sublethal doses of carbon monoxide (CO), but not nitric oxide (NO), obliterate the appearance of the obstructive airway lesion. Induction of the enzyme responsible for the synthesis of CO, heme oxygenase (Hmox) 1, increased carboxyhemoglobin levels and suppressed lymphocytic bronchitis and airway luminal occlusion after transplantation. In contrast, zinc protoporphyrin IX, a competitive inhibitor of Hmox, increased airway luminal occlusion. Compared with wild-type allografts, expression of inducible NO synthase (iNOS), which promotes the influx of cytoeffector leukocytes and airway graft rejection, was strikingly reduced by either enhanced expression of Hmox-1 or exogenous CO. Hmox-1/CO decreased nuclear factor (NF)-kappaB binding activity to the iNOS promoter region and iNOS expression. Inhibition of soluble guanylate cyclase did not interfere with the ability of CO to suppress OB, implicating a cyclic guanosine 3',5'-monophosphate-independent mechanism through which CO suppresses NF-kappaB, iNOS transcription, and OB. Prolonged CO inhalation represents a new immunosuppresive strategy to prevent OB.

Animals↗
PubMed2005

Functional advantage after radical segmentectomy versus lobectomy for lung cancer.

BACKGROUND: Although several reports have recently demonstrated that segmentectomy for small-sized N0 lung cancer leads to recurrence and survival rates equivalent to those associated with lobectomy, controversy regarding the postoperative functional advantage in the former over the latter still persists. The purpose of this study was to evaluate the degree of postoperative functional loss in patients undergoing segmentectomy or lobectomy for lung cancer. METHODS: We analyzed patients able to tolerate lobectomy, who underwent radical segmentectomy (n = 38) or lobectomy (n = 45) for non-small-cell lung cancer. Functional testing included forced vital capacity, forced expiratory volume in 1 second, and anaerobic threshold measured preoperatively and at 2 and 6 months after surgery. RESULTS: Preoperative function tests showed no differences between segmentectomy and lobectomy patients. A positive and significant correlation was found between the number of resected segments versus loss of forced vital capacity (r = 0.518, p < 0.0001 at 2 months; r = 0.604, p < 0.0001 at 6 months) and loss of forced expiratory volume in 1 second (r = 0.492, p < 0.0001 at 2 months; r = 0.512, p < 0.0001 at 6 months). The postoperative reduction of forced vital capacity (p = 0.0006) and forced expiratory volume in 1 second (p = 0.0007) was significantly less in the segmentectomy group; however, a marginally significant benefit was observed in this group for anaerobic threshold (p = 0.0616). CONCLUSIONS: The extent of removed lung parenchyma directly affected that of postoperative functional loss even at 6 months after surgery, and segmentectomy offered significantly better functional preservation compared with lobectomy. These results indicate the importance of segmentectomy for early staged lung cancer.

Carcinoma, Non-Small-Cell Lung↗
PubMed2004

Division of the pulmonary ligament after upper lobectomy is less effective for the obliteration of dead space than leaving it intact.

PURPOSE: To investigate whether division of the pulmonary ligament after upper lobectomy obliterates dead space. METHODS: Thirty-five patients scheduled to undergo upper lobectomy (23 right, 12 left) were randomly assigned to two groups, according to whether the inferior pulmonary ligament was divided (11 right, 12 left) or preserved (6 right, 6 left). To assess upward movement of the nonoperated lobes, plain chest X-ray films (posterior-anterior) were done at end-inspiration preoperatively and 1 month postoperatively, and the ratio of dead space in the longitudinal axis was measured. To assess the change in the angle of the main bronchus, chest X-ray tomography films were done preoperatively and 1 month postoperatively. The angles formed by the main bronchus and the truncus intermedius on the right side, and by the main bronchus and the lower bronchus on the left side, were measured, and the postoperative changes were calculated. RESULTS: The dead space ratio did not differ significantly between the divided group and the preserved group (3.5% vs 5.5%) or between sides. The change in the angle of the main bronchus did not differ significantly between the two groups on either the right (36.4 degrees vs 36.3 degrees) or the left side (72.5 degrees vs 60.0 degrees). CONCLUSION: Division of the pulmonary ligament after upper lobectomy is less effective for the obliteration of dead space than leaving it intact.

Bronchial Fistula↗
PubMed2004

Management of air leak after pulmonary resection.

OBJECTIVE: We prospectively evaluated the efficacy of water seal in the management of air leak after pulmonary resection. METHODS: Eighty-seven patients who underwent lobectomy were enrolled. Air leak was qualitatively described on each postoperative day using a six-grade scale. All chest tubes were continuously suctioned at a negative pressure of 12 cm H2O until the morning of postoperative day (POD) 1. Switch was made to water seal if the air leak was graded as "minor at expiration" or lower. This procedure is referred to as "the water seal challenge". RESULTS: On POD 1, 58 patients had air leaks. The water seal challenge was attempted on POD 1.6+/-1.0. While 45 patients (78%) continued to receive the water seal, the remaining 13 patients were switched to suctioning at -5 cm H2O followed by the successful second water seal challenge within 3 days from the first challenge. The air leak stopped 3.1+/-3.0 days after the application of the water seal in the 58 patients. None of the following correlated with the duration of air leak: preoperative pulmonary function tests, type of lobectomy, age, and gender. Only the leak grade on POD 0 correlated significantly with the duration of air leaks (p<0.0001). CONCLUSION: These results show that water seal is a safe and effective management option for air leak during the early postoperative period.

Adult↗
PubMed2004

Prediction of morbidity after lung resection with risk factors using treadmill exercise test.

OBJECTIVE: To predict accurate morbidity after lung resection using treadmill exercise test. METHODS: A total of 130 patients (108 men and 22 women, with mean age 67.1+/-11.4 years (range, 34-78 years)) of 1129 patients underwent standard lobectomy were performed both treadmill exercise test and spirometry preoperatively. We measured maximum oxygen uptake/body weight (VO2max/BW) and change in arterial blood oxygen pressure from rest to symptom-limited maximum loading (delta aPaO2) and calculated exercise-induced hypoxemia (delta PaO2/delta VO2/BW), and retrospectively compared these parameters for patients with and without complications. RESULTS: There were five patients with severe postoperative complications, including three requiring use of a respirator, two with home oxygen therapy. %Vital capacity, VC (%, 80.2+/-13.2 vs. 92.5+/-20.9, P=0.026), delta PaO2 (Torr, -29.3+/-4.3 vs. -13.2+/-10.8, P=0.0004), VO2max/BW (ml/min/kg, 16.5+/-2.9 vs. 20.6+/-5.1, P=0.018) and delta PaO2/delta VO2/BW (Torr/ml/min/kg, -1.98+/-0.26 vs. -0.57+/-0.47) were significantly associated with worse outcome. All the five patients with complications had delta PaO2/delta VO2/BW<-1.7. CONCLUSIONS: Treadmill exercise testing is a good method for assessment of cardiopulmonary reserve. Limited resection must be performed if delta PaO2/delta VO2/BW is under -1.7.

Adult↗
PubMed2003

Long-term survival and prognostic factors of five-year survivors with complete resection of non-small cell lung carcinoma.

OBJECTIVE: We analyzed the long-term follow-up data on cancer-related death in 5-year survivors of complete resection of their non-small cell lung cancer and examined the prognostic factors having an impact on subsequent survival. METHODS: Of 848 consecutive patients with proven primary non-small cell carcinoma who underwent complete removal of the primary tumor together with hilar and mediastinal lymph nodes, 421 patients (49.6%) survived 5 years or longer after the initial surgical treatment. Of all the data analyzed, only death related to cancer was treated as death. RESULTS: The median follow-up of 5-year survivors was 84 months from the original treatment (range, 60 to 200 months). Their overall survival rate at 10 years was 91.0%. Multivariable Cox analysis demonstrated that although advanced surgical-pathological stage (P =.0001), nodal involvement (P =.0245), male gender (P =.0313), and non-squamous type of the tumor (P =.0034) were significant, independent, unfavorable prognostic determinants in all patients, none of the variables investigated significantly influenced the long-term survival of 5-year survivors. The rate of recurrence beyond 5 years was much lower compared with that within 5 years. In contrast, the rate of occurrence of new malignancies was unchanged throughout the long-term postoperative period. CONCLUSIONS: Among 5-year survivors of complete resection of non-small cell lung cancer, neither stage, nodal status, sex, nor histologic condition further affected subsequent survival, suggesting that the 5-year interval might be sufficient to declare that a patient with lung cancer has been cured.

Adenocarcinoma↗
PubMed2002

Mediastinal angioleiomyoma.

We report a case of a mediastinal angioleiomyoma. The patient was a 64-year-old previously healthy man. Computed tomographic scan revealed a well-circumscribed tumor with a diameter of approximately 2 cm in the right anterior mediastinum. We removed the tumor through a midline sternotomy. Microscopic examination revealed a highly vascular mesenchymal tumor without cellular dysplasia or mitotic figures.

Angiomyoma↗