Hydroxysteroid Dehydrogenase activity and the vitamin D axis in acute lung injury - mechanistic and functional importance.

羟基类固醇脱氢酶活性和维生素 D 轴在急性肺损伤中的机制和功能重要性。

• 批准号: MR/L002736/1
• 负责人: David Thickett
• 金额: $ 44.2万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL002736%2F1
• 关键词: Hydroxysteroid; Dehydrogenase; activity; vitamin; axis

Patients who get infection may develop an exaggerated response that results in damage to organs including the lung. In the lung this is known as acute lung injury. Acute lung injury can occur due to a variety of insults including smoke inhalation, trauma as well as bacterial and viral infection. It causes the lu8ngs to fill up with water and this means that patients' breathing becomes very laboured. These patients therefore need care in the intensive care unit including support with their breathing (mechanical ventilation). The death rate associated with this happening is about 35-45%. Even those who survive acute lung injury have considerable recuperation periods and reduced quality of life 12 months afterwards.In this application we present extensive novel research findings that identify two endocrine abnormalities in patients with ALI- namely defective 11-beta hydroxysteroid dehydrogenase type 1 (HSD-1) activity within the lungs and severe vitamin D deficiency. By using animal models of lung injury we have found that HSD-1 deficiency in genetically modified mice results in exaggerated and persistent inflammatory lung damage. Intriguingly, the HSD-1 deficient mice are very vitamin D deficient which may account for some of the exaggerated lung damage. The link between the activity of HSD-1 (which generates active steroid hormones within tissues such as the lung) and vitamin D is previously unrecognised.The aims of this research are therefore to study why vitamin d levels are low in animals with the HSD-1 gene knocked out. We will establish if this vitamin D deficiency is functionally important by studying the levels of calcium and bone density in these animals over 6 months. We will ascertain through a series of experiments the mechanism of these mice becoming vitamin D deficient. In addition, we will test the ability of HSD-1 KO mice to resist infectious models of pneumonia and gut infection (peritonitis) as clinically relevant models. We will replace the vitamin D deficiency in the HSD-1 KO mice to establish if this can reduce lung injury. In order to translate our findings in mice we will establish whether there is a link between urinary measures of HSD-1 in a cohort of patients with or at risk of acute lung injury (expected low HSD-1 activity markers in urine). This research should therefore expand our knowledge about the interactions between the local tissue production of active steroid cortisol and vitamin D. If our hypotheses are correct this research would provide a rationale for treating patients with acute lung injury with vitamin D or a therapy perhaps cell based to boost HSD-1 activity in inflamed tissues.

感染的患者可能会出现过度反应，导致包括肺部在内的器官受损。在肺部，这被称为急性肺损伤。急性肺损伤可能因多种损伤而发生，包括吸入烟雾、外伤以及细菌和病毒感染。它会导致肺部充满水，这意味着患者的呼吸变得非常费力。因此，这些患者需要在重症监护室接受护理，包括呼吸支持（机械通气）。与这种情况相关的死亡率约为 35-45%。即使是那些在急性肺损伤中幸存下来的人，也需要相当长的恢复期，并且 12 个月后生活质量会下降。在本申请中，我们提出了广泛的新颖研究结果，确定了 ALI 患者的两种内分泌异常，即肺内 11-β 羟基类固醇脱氢酶 1 型 (HSD-1) 活性缺陷和严重维生素 D 缺乏。通过使用肺损伤动物模型，我们发现转基因小鼠中 HSD-1 缺乏会导致过度且持续的炎症性肺损伤。有趣的是，HSD-1 缺陷小鼠的维生素 D 严重缺乏，这可能是肺损伤严重的部分原因。 HSD-1（在肺等组织内产生活性类固醇激素）的活性与维生素 D 之间的联系此前尚未被认识到。因此，本研究的目的是研究为什么 HSD-1 基因被敲除的动物体内维生素 D 水平较低。我们将通过在 6 个月内研究这些动物的钙和骨密度水平来确定这种维生素 D 缺乏是否具有重要的功能。我们将通过一系列实验来查明这些小鼠维生素D缺乏的机制。此外，我们将测试HSD-1 KO小鼠抵抗肺炎和肠道感染（腹膜炎）感染模型作为临床相关模型的能力。我们将替换 HSD-1 KO 小鼠中维生素 D 缺乏症，以确定这是否可以减少肺损伤。为了将我们的发现转化为小鼠，我们将确定一组患有或有急性肺损伤风险的患者的尿液 HSD-1 测量值之间是否存在关联（尿液中预期 HSD-1 活性标记物较低）。因此，这项研究应该扩大我们对局部组织产生的活性类固醇皮质醇和维生素 D 之间相互作用的认识。如果我们的假设正确，这项研究将为使用维生素 D 或基于细胞的疗法来治疗急性肺损伤患者提供理论依据，以增强发炎组织中的 HSD-1 活性。

项目成果

Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS).

• DOI: 10.1136/thoraxjnl-2014-206680
• 发表时间: 2015-07
• 期刊: Thorax
• 影响因子: 10
• 作者: Dancer RC;Parekh D;Lax S;D'Souza V;Zheng S;Bassford CR;Park D;Bartis DG;Mahida R;Turner AM;Sapey E;Wei W;Naidu B;Stewart PM;Fraser WD;Christopher KB;Cooper MS;Gao F;Sansom DM;Martineau AR;Perkins GD;Thickett DR
• 通讯作者: Thickett DR

Real-time assessment of neutrophil metabolism and oxidative burst using extracellular flux analysis.

• DOI: 10.3389/fimmu.2023.1083072
• 发表时间: 2023
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Grudzinska, Frances S.;Jasper, Alice;Sapey, Elizabeth;Thickett, David R.;Mauro, Claudio;Scott, Aaron;Barlow, Jonathan
• 通讯作者: Barlow, Jonathan

Predicting the pulmonary effects of long-term e-cigarette use: are the clouds clearing?

• DOI: 10.1183/16000617.0121-2021
• 发表时间: 2022-03-31
• 期刊: EUROPEAN RESPIRATORY REVIEW
• 影响因子: 7.5
• 作者: Davis, Lauren C.;Sapey, Elizabeth;Thickett, David R.;Scott, Aaron
• 通讯作者: Scott, Aaron

Dysregulated Neutrophil Phenotype and Function in Hospitalised Non-ICU COVID-19 Pneumonia.

• DOI: 10.3390/cells11182901
• 发表时间: 2022-09-16
• 期刊: CELLS
• 影响因子: 6
• 作者: Belchamber, Kylie B. R.;Thein, Onn S.;Hazeldine, Jon;Grudzinska, Frances S.;Faniyi, Aduragbemi A.;Hughes, Michael J.;Jasper, Alice E.;Yip, Kay Por;Crowley, Louise E.;Lugg, Sebastian T.;Sapey, Elizabeth;Parekh, Dhruv;Thickett, David R.;Scott, Aaron
• 通讯作者: Scott, Aaron

Role of CD248 as a potential severity marker in idiopathic pulmonary fibrosis.

• DOI: 10.1186/s12890-016-0211-7
• 发表时间: 2016-04-14
• 期刊: BMC pulmonary medicine
• 影响因子: 3.1
• 作者: Bartis D;Crowley LE;D'Souza VK;Borthwick L;Fisher AJ;Croft AP;Pongrácz JE;Thompson R;Langman G;Buckley CD;Thickett DR
• 通讯作者: Thickett DR