EOSINOPHIL AND EOSINOPHIL-DERIVED TGFS IN WOUND HEALING

嗜酸性粒细胞和嗜酸性粒细胞衍生的 TGFS 在伤口愈合中的作用

• 批准号: 3223858
• 负责人: David T Wong
• 金额: $ 23.71万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3223858
• 关键词: antiserum; bioassay; biological models; blocking antibody; cell adhesion molecules; cell type; complementary DNA; eosinophil; hamsters; immunocytochemistry; in situ hybridization; messenger RNA; model design /development; monoclonal antibody; neutralizing antibody; northern blottings; oral mucosa; phenotype; protein biosynthesis; radioimmunoassay; skin; surface antigens; tissue /cell preparation; transforming growth factors; wound healing

The process of wound healing involves a series of carefully orchestrated biological events permitting the host to eliminate the injurious agents and then systematically repair the damages. Various cellular infiltrates and mediators (cytokines and lymphokines) released during wound healing are known to facilitate the healing process. Transforming growth factor-alpha and beta-I (TGF-alpha and TGF-beta-1) are two well-studied multifunctional cytokines known to promote wound healing. Considerable evidence now indicates that there are endogenous cellular sources that deliver these cytokines to wound sites. However, the detailed identities of cytokine producing cells at wound sites remain elusive. Furthermore the molecular mechanisms by which these cells and their secreted cytokines influence the process of wound healing remain incompletely understood. The applicants have recently identified a novel mechanism by which eosinophils can importantly influence the wound healing process: the production of TGF-alpha and TGF-beta-1. Eosinophils are part of the cellular infiltrate typically found in significant numbers in healing wounds. Eosinophils infiltrated into cutaneous wounds of the rabbit and hamster are the major producers of TGF-alpha and TGF-beta-1. Among their many activities, TGF-alpha and TGF-beta-1 together can influence epithelial migration, promote angiogenesis, and tissue remodeling. Based on these findings, we have formulated the hypothesis that the eosinophil and its derived TGFs are responsible for many of the coordinated activities during the wound healing. To test this hypothesis, we wish to pursue the following two specific aims: 1. To establish the skin and oral mucosa of the Syrian hamster as models of cutaneous and oral wound healing. At each site, the kinetics of eosinophil infiltration and their production of TGF-alpha and TGF-beta-1 will be determine by the techniques of in-situ hybridization and immunohistochemistry, using hamster specific reagents (cDNAs and antisera). 2. To evaluate the biological significance of the eosinophil and eosinophil-derived TGFs in wound healing. Using hamster as experimental models for oral and cutaneous wound healing, influx of eosinophils into wound sites will be selectively prevented or reduced by either blocking the adherence of circulating eosinophils to the vascular cellular adhesion molecule- 1 (VCAM- 1) by masking eosinophil cell surface very late activation antigen-4 (VLA-4) using specific monoclonal antibodies (mAb), or by the use of anti-IL-5 mAb to block the development and maturation of eosinophils. The contributions of eosinophil-derived TGF-alpha and TGF-beta-1 to wound healing will be investigated by the administration of specific neutralization antibodies.

伤口愈合的过程涉及一系列精心策划的 生物事件允许宿主消除有害特工 然后系统地修复损失。 各种细胞浸润 在伤口愈合期间释放 已知可以促进康复过程。 改变增长 因子-Alpha和beta-I（TGF-Alpha和TGF-BETA-1）是两个良好的研究 已知可促进伤口愈合的多功能细胞因子。 大量 现在的证据表明，有内源性细胞来源 将这些细胞因子输送到伤口部位。 但是，详细的身份 伤口部位的细胞因子产生细胞的细胞仍然难以捉摸。 此外 这些细胞及其分泌的分子机制 细胞因子影响伤口愈合的过程不完全 理解。 申请人最近确定了一种新型机制 嗜酸性粒细胞可以重要地影响伤口愈合过程： TGF-Alpha和TGF-Beta-1的产生。 嗜酸性粒细胞是 细胞浸润通常在愈合中大量发现 伤口。 嗜酸性粒细胞渗入兔子的皮肤伤口 仓鼠是TGF-Alpha和TGF-BETA-1的主要生产国。 他们中间 许多活动，TGF-Alpha和TGF-BETA-1共同影响 上皮迁移，促进血管生成和组织重塑。 基于这些发现，我们提出了以下假设 嗜酸性粒细胞及其派生的TGF负责许多 伤口愈合期间协调活动。 测试这个 假设，我们希望追求以下两个具体目标： 1。建立叙利亚仓鼠的皮肤和口服粘膜作为模型 皮肤和口腔伤的愈合。 在每个站点，动力学 嗜酸性粒细胞浸润及其产生TGF-Alpha和TGF-BETA-1 将通过原位杂交和 免疫组织化学，使用仓鼠特定试剂（CDNA和 安排）。 2。评估嗜酸性粒细胞的生物学意义和 嗜酸性粒细胞衍生的TGF在伤口愈合中。 使用仓鼠作为实验 口腔和皮肤伤口愈合的模型，嗜酸性粒细胞的涌入 通过两种阻止，将选择性地预防或减少伤口部位 循环嗜酸性粒细胞遵守血管细胞 粘附分子-1（VCAM-1）通过掩盖嗜酸性粒细胞表面非常非常 使用特定单克隆抗体的晚期激活抗原4（VLA-4） （mab），或使用抗IL-5 mAb阻止开发和 嗜酸性粒细胞的成熟。 嗜酸性粒细胞衍生的贡献 TGF-Alpha和TGF-BETA-1至伤口愈合将由 特定中和抗体的给药。