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Keratinocyte Growth Factor-2 Ameliorates Acute Lung Injury by Activating the PI3K/Akt Survival Signal and Reducing Prevalence of Th17 and Treg Cells Via Inhibition of NF-κB Signal
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A2968 - Keratinocyte Growth Factor-2 Ameliorates Acute Lung Injury by Activating the PI3K/Akt Survival Signal and Reducing Prevalence of Th17 and Treg Cells Via Inhibition of NF-κB Signal
Author Block: J. Bi, L. Wang, C. Bai, J. Zhou, Y. Song; Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
RATIONALE: Acute lung injury (ALI) is characterized by alveolar injury, inflammation, and infiltration of inflammatory cells. Although the protective effects of keratinocyte growth factor-2 (KGF-2) on ALI have been defined, the mechanisms remain unclear.
METHODS: Healthy adult male C57BL/6 mice were intratracheally injected with either 5 mg/kg lipopolysaccharides (LPS) dissolved in phosphate buffer solution ( PBS ) or an equal volume of vehicle. To investigate the role of KGF-2 in lung injury induced by LPS, KGF-2 (5 mg/kg) mixed with LPS or PBS, was intratracheally injected. To clarify the role of NF-κB pathway, 20 µg/kg BAY 11-7082, the inhibitor of IκBα phosphorylation, was injected intraperitoneally 30 min prior to LPS administration. Mice were euthanized 1, 2, 6, and 10 days after LPS administration or 2 days after KGF-2 treatment. Blood samples were collected by removing the eyeball. The lung lobes were prepared for histological examination, wet-to-dry (W/D) weight ratio, lung single cell for flowcytometry, western blotting, and quantitative real-time polymerase chain reaction(RT-PCR). Bronchoalveolar lavage fluid (BALF) also was collected.
RESULTS: Peak lung injury occurred on day 6 after the LPS challenge, with resolution on day 10. We also observed a progressive influx of CD4+CD25+Foxp3+T cells (Treg) into the lungs and spleen on day 1, which peaked on day 6, and was maintained at high levels on day 10. The percentage of Th17 cells in lung tissues and blood was higher in the ALI group than in the control group, which peaked on day 2, and returned to nearly normal on day 10. KGF-2 attenuated lung injury by inhibiting the prevalence of Th17 and Treg cells through signal transducer and activator of transcription (STAT)3 and STAT5 dysfunction and NF-κB signal, and improved survival rate by activating the PI3K/Akt signal.
CONCLUSIONS:These results illustrated a new mechanism of KGF-2 on ALI by inhibiting Th17 and Treg mediated by STAT3/STAT5-NF-κB, and activating the PI3k/Akt signal.
Author Block: J. Bi, L. Wang, C. Bai, J. Zhou, Y. Song; Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
RATIONALE: Acute lung injury (ALI) is characterized by alveolar injury, inflammation, and infiltration of inflammatory cells. Although the protective effects of keratinocyte growth factor-2 (KGF-2) on ALI have been defined, the mechanisms remain unclear.
METHODS: Healthy adult male C57BL/6 mice were intratracheally injected with either 5 mg/kg lipopolysaccharides (LPS) dissolved in phosphate buffer solution ( PBS ) or an equal volume of vehicle. To investigate the role of KGF-2 in lung injury induced by LPS, KGF-2 (5 mg/kg) mixed with LPS or PBS, was intratracheally injected. To clarify the role of NF-κB pathway, 20 µg/kg BAY 11-7082, the inhibitor of IκBα phosphorylation, was injected intraperitoneally 30 min prior to LPS administration. Mice were euthanized 1, 2, 6, and 10 days after LPS administration or 2 days after KGF-2 treatment. Blood samples were collected by removing the eyeball. The lung lobes were prepared for histological examination, wet-to-dry (W/D) weight ratio, lung single cell for flowcytometry, western blotting, and quantitative real-time polymerase chain reaction(RT-PCR). Bronchoalveolar lavage fluid (BALF) also was collected.
RESULTS: Peak lung injury occurred on day 6 after the LPS challenge, with resolution on day 10. We also observed a progressive influx of CD4+CD25+Foxp3+T cells (Treg) into the lungs and spleen on day 1, which peaked on day 6, and was maintained at high levels on day 10. The percentage of Th17 cells in lung tissues and blood was higher in the ALI group than in the control group, which peaked on day 2, and returned to nearly normal on day 10. KGF-2 attenuated lung injury by inhibiting the prevalence of Th17 and Treg cells through signal transducer and activator of transcription (STAT)3 and STAT5 dysfunction and NF-κB signal, and improved survival rate by activating the PI3K/Akt signal.
CONCLUSIONS:These results illustrated a new mechanism of KGF-2 on ALI by inhibiting Th17 and Treg mediated by STAT3/STAT5-NF-κB, and activating the PI3k/Akt signal.
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