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Time-Dependent Alterations of VEGF and Its Signaling Molecules in Acute Lung Injury in a Rat Model of Sepsis

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Abstract

Molecular mechanisms of sepsis-associated acute lung injury (ALI) are poorly defined. Since vascular endothelial growth factor (VEGF) is a potent vascular permeability and mitogenic factor, it might contribute to the development of ALI in sepsis. Thus, using lipopolysaccharide (LPS)-induced (15 mg/kg, intraperitoneal) endotoxemic rat model, we studied the timeline (1, 3, 6, and 10 h) of pulmonary VEGF expression and its signaling machinery. Levels of pulmonary VEGF and its angiogenic-mediating receptor, Flk-1, were downregulated by LPS in a time-dependent manner; levels of plasma VEGF and its permeability-mediating receptor, Flt-1, in contrast, was upregulated with time. In addition, blockade of Flt-1 could improve the downregulated pulmonary VEGF level and attenuate the elevated plasma and pulmonary levels of TNF-α, followed by improvement of arterial oxygenation and wet-to-dry weight ratio of the lung. Expression of signaling, pro- and or apoptotic factors after LPS administration were as follows: phosphorylated Akt, a downstream molecule was downregulated time dependently; endothelial nitric oxide synthase levels were significantly reduced; pro-apoptotic markers caspase 3 and Bax were upregulated whereas levels of Bcl-2 were downregulated. The present findings show that VEGF may play a role through the expression of Flt-1 in LPS-induced ALI. Moreover, downregulation of VEGF signaling cascade may account for LPS-induced apoptosis and impaired physiological angiogenesis in lung tissues, which in turn may contribute to the development of ALI induced by LPS.

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ACKNOWLEDGEMENTS

This work was supported by a grant-in-aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan (22406025, 21249086, and 20790296). The authors greatly thank Dr. Nobutake Shimojo for his excellent advices.

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Authors and Affiliations

  1. Division of Gene Therapeutics, National Center for Global Health and Medicine, Tokyo, Japan

    Subrina Jesmin, A. M. Shahidul Islam, S. Nusrat Sultana, Yoshio Iwashima & Michiaki Hiroe

  2. Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine, N15 W7, Kita-ku, Sapporo, Japan

    Subrina Jesmin, Sohel Zaedi, Takeshi Wada & Satoshi Gando

  3. Health and Disease Research Center for Rural Peoples, Dhaka, Bangladesh

    Subrina Jesmin, Sohel Zaedi, A. M. Shahidul Islam & S. Nusrat Sultana

  4. Center for Medical Sciences, Ibaraki Prefectural University of Health Sciences, Ibaraki, Japan

    Subrina Jesmin, Sohel Zaedi & Naoto Yamaguchi

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  1. Subrina Jesmin
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Correspondence to Satoshi Gando.

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Jesmin, S., Zaedi, S., Islam, A.M.S. et al. Time-Dependent Alterations of VEGF and Its Signaling Molecules in Acute Lung Injury in a Rat Model of Sepsis. Inflammation 35, 484–500 (2012). https://doi.org/10.1007/s10753-011-9337-1

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