2006 Fiscal Year Final Research Report Summary
Production of an allergic inflammation model using human lungs resected by a surgical operation and its application to drug discovery for the treatment of asthma
| Project/Area Number |
17590478
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied pharmacology
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| Research Institution | Fukuoka University |
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Principal Investigator |
ABE Masayoshi Fukuoka University, School of Medicine, Associate Professor, 医学部, 助教授 (80131803)
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| Project Period (FY) |
2005 – 2006
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| Keywords | allergy / asthma / clinical pharmacology / drug discovery / tissue preservation / super-cooling / mediators |
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| Research Abstract |
In order to resolve a problem concerning species differences in pharmacological science, we tried to make an inflammation model using human lung tissues obtained from patients with lung cancer after surgical resection. When the chopped lung fragments passively sensitized with human IgE were incubated with anti-human IgE antibody, a significant amount of cysteinyl-leukotrienes (cysLTs) was generated in comparison with the control (without anti-IgE). The addition of human C3a or C5a alone did not generate cysLTs. The co-addition, however, of C5a at doses of 1.0 ng/ml to the anti-IgE antibody further potentiated cysLT production. Consequently, an allergic inflammation model in which complement activation was involved as a pathophysiological mechanism was produced. Either a novel C5a receptor complementary peptide or a C5a receptor antagonist inhibited cysLT production in a dose-dependent manner by the human lung fragments following the anaphylactic reaction in the presence of 1 ng/ml C5a.
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Since there are consideable species differences in primary structure of anaphylatoxins and those receptors, this model using human lung tissues may be valuable to perform screening for a novel drug. In contrast, the shortage of suitable human tissues and lack of methods for stable preservation are hindering to produce an adequate model using human tissues. After lung tissues were obtained from patients with lung cancer, they were kept at -5℃ or 4℃ for as many as 5 days, and then they were histologically and biochemically examined. Although the tissues preserved at-5℃ had an almost normal morphology with intact cilia on bronchial epithelium and normal endothelium, the tissues stored at 4℃ showed degradation of these structures. Single-stranded DNA, a sign of DNA cleavage, was frequently noted in tissues stored at 4℃, but only rarely observed at -5℃. A significant amount of cysLTs was generated by anaphylactic reaction from tissues stored at 5℃ for 3 days, but there was no response to antibody stimulation from tissues at 4℃. Therefore, such the novel preservation of human tissues as super-cooling system may facilitate availability of human tissues in medical science. Less
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