2007 Fiscal Year Final Research Report Summary
Host defense system in the lung using pulmonary surfactant proteins and Toll-like reosptors
| Project/Area Number |
18390241
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
KUROKI Yoshio Sapporo Medical University, School of Medicine, Professor (70161784)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Hiroki Sapporo Medical University, School of Medicine, Professor (60231396)
TAECAHASHI Motoko Sapporo Medical University, School of Medicine, Associate Professor (00303941)
SHIMIZU Takeyuki Sapporo Medical University, School of Medicine, Assistant Professor (10339137)
MITSUZAWA Hiroaki Sapporo Medical University, School of Medicine, Research Associate (40325874)
NISHITANI Chiaki Sapporo Medical University, School of Medicine, Research Associate (30381255)
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| Project Period (FY) |
2006 – 2007
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| Keywords | pulmonary surfactant / collectin / SP-A / SP-D / Toll-like receptor / pulmonary inflammation / endotoxin / MD-2 |
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| Research Abstract |
The purposes of this project were to investigate the mechanisms by which pulmonary collections, surfactant proteins A and D (SP-A and SP-D), and Toll-like receptor (TISO function against infection and inflammation, and to establish the molecular basis for the clinical application of these proteins. The research results are summarized below.
1. We have found that SP-A and SP-D bind to TLR2, TLR4 and MD-2. SP-A inhibited the binding of smooth LPS on the cells expressing TLR4 and MD-2 and suppresses inflammation elicited by smooth LPS. The functional domain was the carbohydrate recognition domain (CRD) of SP-A, but the collagenase-resistant fragment of SP-A (CRF) in which the collagenous domain was removed bound to TLR4 very weakly and did not inhibit LPS-induced inflammation, indicating that the oligometric structure composed of SP-A octadecamers is important for expressing its function. Unlike SP-A SP-D inhibits inflammation elicited by different serotypes of LPS, rough LPS and smooth LPS. The experiments with SP-A/SP-D chimeric proteins revealed that the cruciform structure of SP-D composed of long collagenous domain was crucial for suppressing inflammation.
2. We have also found that the amino-terminal region of TLR4, Glu24-Lys47, is a site for MD-2 binding. Recombinant soluble forms of the extracellular TLR4 domain and MD-2 were demonstrated to dampen endotoxin-induced pulmonary inflammation in mice.
3. The experiments with TLR4 mutant, TLR4C88A, revealed that MD-2 possesses crucial abilities to express cell surface expression of TLR4 and its N-linked complex type glyoosylation.
4. SP-A and SP-D bound to Mycobacterium avium and induced bacrerial aggregation. SP-D possesses a potent ability to aggregate M. avium compared with SP-A The ligand for SP-D on M. avium was lipoarabinomannan (LAM) and that for SP-Aexisted in the lipid fraction extracted M. avium.
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