Interleukin-10 Therapy for Bronchopulmonary Dysplasia

Interleukin-10 治疗支气管肺发育不良

• 批准号: 6966139
• 负责人: DENNIS DAVIDSON
• 金额: $ 8.25万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6966139
• 关键词: apoptosis; bronchopulmonary dysplasia; chemokine; cord blood; cysteine endopeptidases; dexamethasone; drug screening /evaluation; enzyme activity; flow cytometry; human tissue; inflammation; interleukin 10; light microscopy; lipopolysaccharides; microarray technology; monocyte; neutrophil; respiratory disorder chemotherapy; tissue /cell culture

DESCRIPTION (provided by applicant): The long-term objective of this project is to develop new, safe and effective anti-inflammatory medication for the prevention or treatment of bronchopulmonary dysplasia (BPD). Our preliminary work, in vitro, suggests that exogenous interleukin-10 (IL-10) may be a novel substitute for the effective but unsafe regimens of past dexamethasone (DEX) therapy for BPD. The early development of BPD involves the recruitment of polymorphonuclear leukocytes (PMNs), followed by monocytes (MONOs), in association with chemokine release. Our preliminary work in LPSstimulated PMNs and MONOs of the newborn, has demonstrated that IL-10 is as potent as DEX, on an equimolar basis, with regard to inhibition of chemokine release. We have also shown that nuclear factor-KB (NF- KB), a pro-inflammatory and anti-apoptotic, pivotal transcription factor is activated by LPS, involving different mechanisms in PMNs compared to MONOs. Furthermore DEX but not IL-10 inhibits NF-KB activity, but paradoxically DEX inhibits PMN apoptosis, while the effect of IL-10 on apoptosis in the newborn is unknown. Our central hypothesis is that IL-10, via its selective molecular actions, as well as selective properties of apoptosis, will lead to more effective and safer therapy for newborns developing BPD compared to DEX. The first specific aim is to test the hypothesis that IL-10 promotes apoptosis, in vitro, as opposed to DEX, in LPS-stimulated PMNs and MONOs of the newborn. Apoptotis will be measured by cell morphology (light microscopy), caspase-3 activity, and annexin binding (flow cytometry). The second specific aim is to test the hypothesis that IL-10 is a more selective regulator of genes that control inflammation and apoptosis, compared to DEX, in LPS-activated PMNs and MONOs of the newborn. High density oligoarrays correlating to timepoints and doses of dexamethasone or IL-10 used in specific aim 1 and our preliminary chemokine studies will be employed. Our studies will provide the urgently needed, scientific underpinnings, that may advance pre-clinical testing of IL-10 for BPD or lead to further molecular studies that define critical anti-inflammatory and apoptic genes in PMNs and MONOs of the newborn.

描述（由申请人提供）：该项目的长期目标是开发新的，安全有效的抗炎药，以预防或治疗支气管肺发育不良（BPD）。我们在体外的初步工作表明，外源白介素10（IL-10）可能是BPD过去地塞米松（DEX）治疗的有效但不安全方案的新颖替代品。 BPD的早期发展涉及募集多形核白细胞（PMN），其次是单核细胞（MONOS），与趋化因子释放有关。我们在新生儿的LPS刺激性PMN和单声道中的初步工作表明，对于抑制趋化因子释放，IL-10在等效的基础上与Dex一样有效。我们还表明，核因子-KB（NF-KB），一种促炎和抗凋亡，关键转录因子，通过LPS激活，与MONOS相比涉及PMN的不同机制。此外，DEX但IL-10不抑制NF-KB活性，但矛盾的是DEX抑制PMN的凋亡，而IL-10对新生儿凋亡的影响尚不清楚。我们的中心假设是，与DEX相比，IL-10通过其选择性分子作用以及凋亡的选择性特性将导致对新生儿进行BPD的更有效和更安全的疗法。第一个具体目的是检验以下假设：在LPS刺激的新生儿PMN和单声道中，IL-10在体外促进凋亡，而不是DEX。凋亡将通过细胞形态（光学显微镜），caspase-3活性和膜联蛋白结合（流式细胞仪）来测量。第二个具体目的是检验以下假设：与DEX相比，在LPS激活的PMN和Newborn的Monos中，IL-10是控制炎症和凋亡的基因的更具选择性调节因子。高密度的寡聚仪与特定AIM 1中使用的时间点和地塞米松或IL-10的剂量相关，将采用我们的初步趋化因子研究。我们的研究将提供急需的科学基础，这些基础可能会推进IL-10的临床前测试，或者导致进一步的分子研究，这些研究定义了新生儿PMN和Monos中关键的抗炎和凋亡基因。