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VEGFR1-TK Signaling Attenuates Pulmonary Fibrosis Formation Through SDF-1/CXCR7/CXCR4 Axis
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A2364 - VEGFR1-TK Signaling Attenuates Pulmonary Fibrosis Formation Through SDF-1/CXCR7/CXCR4 Axis
Author Block: H. Amano1, Y. Mastui2, Y. Ito1, M. Majima1; 1Pharmacology, Kitasato University, Sagamihara, Japan, 2Thoracic Surgery, Kitasato University, Sagamihara, Japan.
(Background)
Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with poor prognosis. Fibroblast proliferation amplified levels of extracellular matrix deposition and increased angiogenesis. It is reported that Vascular Endothelial Growth Factor (VEGF), known as the most potent angiogenesis stimulate factor, directly link to fibrogenesis. VEGF interact with VEGF receptors (VEGFRs), VEGFR1 and VEGFR2. We had reported that the expression of VEGFR-1 was enhanced on day 14 and the percentage of fibrosis area in the lung was significantly suppressed in VEGFRTK knockout mice (TKKO) (2017 ATS Washington DC). In this time, we further estimated precise mechanism of VEGFR1 TK signaling on Bleomycin (BLM) induced pulmonary fibrosis model.
(Material and Methods)
Six weeks old male C57Bl/6 (Wild type) and TKKO were used. BLM and control group were received a single intratracheal injection of 50 μl of saline solution (control saline) or 10 μg /g of BLM in 50 μl of saline solution. Dynamic compliance and elastance were measured using a flexiVent instrument. The expressions of SDF-1, CXCR4 and CXCR7 in the lung were estimated by real time PCR.
(Results)
The dynamic compliance was suppressed and increased elastance in WT compared to TKKO. The expression of CD31, specific marker for endothelial cell, was enhanced on day 7 and 14 in WT compared to TKKO. The mRNA and protein level of Stromal cell derived factor-1 (SDF-1) in the lung was enhanced on day 7, 14 and 21 in WT compared to TKKO.
SDF-1 binds to two known receptors, C-X-C chemokine receptor type 4(CXCR4) and CXCR7. The expression of CXCR7, mediated angiogenesis, was enhanced on day 7 and 14 in WT but not in TKKO. In addition, the expression of CXCR4 was enhanced on day 14 and 21 in WT. In WT, The dynamic compliance was enhanced and suppressed elastance in CXCR4 antibody treated mice compared to control IgG antibody treated mice but not in TKKO.
These results indicated that SDF-1/CXCR7/CXCR4 axis induced the fibrosis formation following after BLM was depended on VEGFR1-TK signaling.
Author Block: H. Amano1, Y. Mastui2, Y. Ito1, M. Majima1; 1Pharmacology, Kitasato University, Sagamihara, Japan, 2Thoracic Surgery, Kitasato University, Sagamihara, Japan.
(Background)
Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with poor prognosis. Fibroblast proliferation amplified levels of extracellular matrix deposition and increased angiogenesis. It is reported that Vascular Endothelial Growth Factor (VEGF), known as the most potent angiogenesis stimulate factor, directly link to fibrogenesis. VEGF interact with VEGF receptors (VEGFRs), VEGFR1 and VEGFR2. We had reported that the expression of VEGFR-1 was enhanced on day 14 and the percentage of fibrosis area in the lung was significantly suppressed in VEGFRTK knockout mice (TKKO) (2017 ATS Washington DC). In this time, we further estimated precise mechanism of VEGFR1 TK signaling on Bleomycin (BLM) induced pulmonary fibrosis model.
(Material and Methods)
Six weeks old male C57Bl/6 (Wild type) and TKKO were used. BLM and control group were received a single intratracheal injection of 50 μl of saline solution (control saline) or 10 μg /g of BLM in 50 μl of saline solution. Dynamic compliance and elastance were measured using a flexiVent instrument. The expressions of SDF-1, CXCR4 and CXCR7 in the lung were estimated by real time PCR.
(Results)
The dynamic compliance was suppressed and increased elastance in WT compared to TKKO. The expression of CD31, specific marker for endothelial cell, was enhanced on day 7 and 14 in WT compared to TKKO. The mRNA and protein level of Stromal cell derived factor-1 (SDF-1) in the lung was enhanced on day 7, 14 and 21 in WT compared to TKKO.
SDF-1 binds to two known receptors, C-X-C chemokine receptor type 4(CXCR4) and CXCR7. The expression of CXCR7, mediated angiogenesis, was enhanced on day 7 and 14 in WT but not in TKKO. In addition, the expression of CXCR4 was enhanced on day 14 and 21 in WT. In WT, The dynamic compliance was enhanced and suppressed elastance in CXCR4 antibody treated mice compared to control IgG antibody treated mice but not in TKKO.
These results indicated that SDF-1/CXCR7/CXCR4 axis induced the fibrosis formation following after BLM was depended on VEGFR1-TK signaling.
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