血管内皮増殖因子ＶＥＧＦ系を基軸とする、敗血症性多臓器不全の治療戦略の研究

2014 Fiscal Year Research-status Report

• Project/Area Number: 25462812
• Research Institution: University of Tsukuba
• Principal Investigator: JESMIN Subrina 筑波大学, 医学医療系, 助教 (60374261)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 医学 / 外科系臨床医学 / 救急医学 / 集中治療学 / 敗血症

Outline of Annual Research Achievements

We completed two years of current project. In Ist year, we mainly concentrated to explore the role of VEGF (Vascular endothelial growth factor) in the pathogenesis of lung injury and cardiac dysfunction in sepsis. In 2nd year, we made diabetic sepsis model and investigated VEGF expression in heart with other experiments. From our previous studies, we know that cardiac VEGF is downregulated in diabetic animals and this downregulation is aggravated when diabetic animals become septic. Endothelin blockade has potential role in reversing the downregulated VEGF cascade in heart tissues in diabetic septic animals. Again, we found that blockade of endothelin significantly normalizes the downregulation of VEGF in lung tissues in sepsis. In addition, protease activated receptor-2 and the blockade of TNF-alpha normalized the downregulated pulmonary VEGF expression in sepsis rat models. Treatment with landiolol, a selective ultra short acting beta blocker significantly reversed the decreased VEGF expression in heart tissues in sepsis with a potential impact on hemodynamics. This landiolol treatment has also significantly reversed the altered VEGF expression in sepsis liver tissues with mild morphological injuries. Thus, we state that aberrant expression of VEGF in sepsis organ complications are influenced by several factors including diabetes, endothelin system, protease activated receptors, beta adrenergic receptors and inflammatory cytokines.

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

The current research is on right track both from the contexts of time line and the amount of research activities scheduled to be done (100% done with target milestone achievement). In last two years, we understood a number of mechanisms responsible for the aberrant VEGF expression in various organ complications in sepsis. These mechanisms at least shed some light to the VEGF pathobiology in organ complication development in sepsis. In last two years, we used five types of pharmacological drug interventions in sepsis animals at various time points with various doses and systematically checking the effects of those drug treatments on VEGF expression in important sepsis-induced organ dysfunction (lung, heart, kidney, liver, brains). In addition, in 2nd year, we started to explore the role of diabetes in organ complications of sepsis in the context of VEGF pathobiology. We investigated in depth both protein and gene expression of target molecules to be assessed in the present study with respective organ function and morphology both in 1st and 2nd years of this project.
Systematically we studied the role of VEGF in organ complication in sepsis not only by using rat models but also other animal models like rabbit and mice, generating longer duration of sepsis models, using various techniques of sepsis induction, using animal models of both the compensatory and decompensatory phases of sepsis. We made more than 10 international publications from these research findings (four of them are in press now).

Strategy for Future Research Activity

Since the start of this project, we have used several pharmacological approaches to reverse the organ specific VEGF expression alteration in sepsis of several duration and doses. In 1st year of this project, we mainly concentrated to the exploration of role of VEGF in pulmonary and cardiac dysfunction in septic models with various pharmacological interventions. In the 2nd year, we largely examined the effect of diabetes on aberrant VEGF expression in septic organ complications specially heart tissue. In 3rd year of this project, we will continue to study the effects of diabetes to the pathogenesis of sepsis organ complication. We also will concentrate to brain and kidney tissues investigation in context of VEGF pathobiology in sepsis models. We will dissect the molecular mechanisms through in vitro cell culture either primary or secondary. Various gene silencing technologies will be used. Human sample analysis: In collaboration of our another current project on sepsis (Kiban B by Professor Satoshi Gando) organ specimens (brain, heart, lung, liver, kidney) obtained at autopsy from individuals divided into two study groups (Sepsis group: Patients with a well-documented medical history and diagnosis of sepsis in vivo, according to the definition of the ACCP/SCCM Consensus Conference, all patients suffer the course of multiple organ failure due to sepsis; Control group: Autopsy cases with death due to various natural and unnatural causes, none of the individuals included in this study group should have a medical history of a septic condition prior to death).

Causes of Carryover

This fiscal year we could not buy VEGF genetically manipulated animals for sepsis induction because of the large volumes of other animal research works of this project.

Expenditure Plan for Carryover Budget

Next fiscal year we will use that unused money from this year to generate VEGF genetically manipulated sepsis models.

Research Products

• [Journal Article] Dual blockade of endothelin action exacerbates up-regulated VEGF angiogenic signaling in the heart of lipopolysaccharide-induced endotoxemic rat model. (2014)
  • Author(s): Oki M, Jesmin S, Islam MM, Mowa CN, Khatun T, Shimojo N, Sakuramoto H, Kamiyama J, Kawano S, Miyauchi T, Mizutani T.
  • Journal Title: Life Sci. Volume: 118 Pages: 364-369
  • DOI: 10.1016/j.lfs.2014.02.008.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effects of protease activated receptor (PAR)2 blocking peptide on endothelin-1 levels in kidney tissues in endotoxemic rat mode. (2014)
  • Author(s): Jesmin S, Shimojo N, Yamaguchi N, Mowa CN, Oki M, Zaedi S, Sultana SN, Rahman A, Islam M, Sawamura A, Gando S, Kawano S, Miyauchi T, Mizutani T.
  • Journal Title: Life Sci. Volume: 102 Pages: 127-133
  • DOI: 10.1016/j.lfs.2014.03.013.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Assessment of circulatory and pulmonary endothelin-1 levels in a lavage-induced surfactant-depleted lung injury rabbit model with repeated open endotracheal suctioning and hyperinflation. (2014)
  • Author(s): Kamiyama J, Jesmin S, Sakuramoto H, Shimojo N, Islam MM, Khatun T, Oki M, Kawano S, Mizutani T.
  • Journal Title: Life Sci. Volume: 118 Pages: 370-378
  • DOI: 10.1016/j.lfs.2014.04.001.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Significant reversal of cardiac upregulated endothelin-1 system in a rat model of sepsis by landiolol hydrochloride. (2014)
  • Author(s): Seki Y, Jesmin S, Shimojo N, Islam MM, Rahman MA, Khatun T, Sakuramoto H, Oki M, Sonobe A, Kamiyama J, Hagiya K, Kawano S, Mizutani T.
  • Journal Title: Life Sci. Volume: 118 Pages: 357-363
  • DOI: 10.1016/j.lfs.2014.04.005.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Potential amelioration of upregulated renal HIF-1alpha-endothelin-1 system by landiolol hydrochloride in a rat model of endotoxemia. (2014)
  • Author(s): Ogura Y, Jesmin S, Yamaguchi N, Oki M, Shimojo N, Islam MM, Khatun T, Kamiyama J, Sakuramoto H, Hagiya K, Kawano S, Mizutani T.
  • Journal Title: Life Sci. Volume: 118 Pages: 347-356
  • DOI: 10.1016/j.lfs.2014.05.007.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] ＬＰSＳ誘発性敗血症性腎障害へのβ1遮断薬の影響―腎組織の炎症系とEndothelin系からの考察― (2014)
  • Author(s): 1.山口直人, Jesmin S, 小倉吉保, 下條信威, 山木万里郎, 鹿野直人, 大瀬寛高, 水谷太郎.
  • Organizer: 第５６回茨城腎研究会
  • Place of Presentation: 茨城
  • Year and Date: 2014-06-17 – 2014-06-17