Role of Sialidase in Pulmonary Host Defenses and Acute Lung Injury

唾液酸酶在肺宿主防御和急性肺损伤中的作用

• 批准号: 7866681
• 负责人: Alan S. Cross
• 金额: $ 46.82万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7866681
• 关键词: Accounting; Acids; Acute Lung Injury; Address; Adherence; Adhesions; Adult Respiratory Distress Syndrome; Affect; Affinity; Alveolar; Animal Model; Aspirate substance; Bacteria; Binding; Blood capillaries; Breathing; Cathepsin G; Cell Adhesion; Cell Adhesion Molecules; Cell Communication; Cell Surface Receptors; Cell surface; Cells; Cessation of life; Charge; Complex; Coupled; Data; Defense Mechanisms; Diffuse; Elastases; Embryo; Endothelial Cells; Endothelium; Environment; Epithelium; Equilibrium; Event; Excision; Free Radicals; Gases; Glycoconjugates; Host Defense; Human; ICAM1 gene; ITGAM gene; ITGB2 gene; Immune response; In Vitro; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Injury; Invaded; Lead; Length of Stay; Leukocyte Elastase; Leukocyte Trafficking; Leukostasis; Ligands; Lung; Mammalian Cell; Mediating; Microbe; Modeling; Modification; Molecular; Mus; N-Acetylneuraminic Acid; Neuraminidase; Organ; PECAM1 gene; Pathway interactions; Pattern recognition receptor; Peptide Hydrolases; Peptides; Permeability; Phosphorylation; Principal Investigator; Process; Production; Protein Isoforms; Proteins; Reactive Oxygen Species; Regulation; Role; Sialic Acids; Sialyltransferases; Signal Transduction; Site; Stimulus; Surface; Syndrome; Testing; Tissues; Toll-like receptors; Tyrosine Phosphorylation; base; cadherin 5; capillary; collagenase; cytokine; in vivo; in vivo Model; inhibitor/antagonist; interstitial; kidney cell; killings; lung injury; macromolecule; microbial; migration; neutrophil; novel therapeutic intervention; overexpression; programs; response; restoration; sialylation; toll-like receptor 4; trafficking

DESCRIPTION (provided by applicant): Polymorphonuclear leukocytes (PMN) protect the lung against microbial infection; however, an excessive or prolonged influx of PMNs may cause tissue damage. Acute lung injury is characterized by widespread inflammatory changes, including diffuse PMN infiltration, with injury to both lung epithelium and endothelium. We established that the removal of sialyl residues from the surface of PMNs and endothelial cells (EC) by an endogenous PMN sialidase is critical to normal PMN trafficking. Further, we find that desialylation of the Toll-like receptor (TLR) 4 complex enhances LPS-induced cytokine production, while restoration of sialyl residues by sialyltransferases (ST) may restore the basal state. The overall hypothesis to be tested is that sialidases and STs regulate innate immune responses in the lung, and the balance achieved will dictate whether or not the innate immune response develops into acute lung injury. To address this central hypothesis, we propose the following: In Specific Aim 1 we will define which form(s) of PMN sialidase(s) (neul and neu3) regulates adherence to and migration across human lung microvascular EC by overexpression and knockdown of specific neu proteins. In Specific Aim 2 we will define the substrates for PMN sialidase in PMNs and ECs and assess how their sialylation status affects PMN adhesion in vitro and trafficking in vivo. Since PMNs induce signaling cascades in ECs, in Specific Aim 3 we will examine whether an "appropriate" level of PMN sialidase-induced tyrosine phosphorylation of EC proteins opens the EC-EC paracellular pathway sufficiently for transendothelial migration without protein leak, while at levels that exceed this threshold, if there will be loss of EC barrier function. A "two-hit" model of acute lung injury has been proposed whereby a combination of LPS and chemotactic peptide promotes lung injury. In Specific Aim 4, we will examine the role of sialidase in sensitizing the pulmonary vasculature to circulating LPS and lung injury. The molecular mechanism(s) by which desialylation promotes signaling through the TLR4/MD2/CD14 complex will be examined, as well as the ability of STs to downregulate this response. The ability of sialidase inhibitors to reverse acute lung injury will be studied in vivo in a murine model of pulmonary leukostasis. Since inhibitors of sialidase are commercially available, these studies will provide the experimental rationale for testing a new therapeutic approach to the treatment of lung injury.

描述（由申请人提供）：多形核白细胞（PMN）保护肺部免受微生物感染；然而，PMN 的过度或长时间流入可能会导致组织损伤。急性肺损伤的特点是广泛的炎症变化，包括弥漫性中性粒细胞浸润，同时损伤肺上皮和内皮。我们确定，内源性 PMN 唾液酸酶从 PMN 和内皮细胞 (EC) 表面去除唾液酸残基对于正常的 PMN 运输至关重要。此外，我们发现Toll样受体（TLR）4复合物的去唾液酸化增强了LPS诱导的细胞因子的产生，而唾液酸转移酶（ST）对唾液酸残基的恢复可能会恢复基础状态。待测试的总体假设是唾液酸酶和 ST 调节肺部的先天免疫反应，所达到的平衡将决定先天免疫反应是否发展为急性肺损伤。为了解决这一中心假设，我们提出以下建议：在具体目标 1 中，我们将定义哪种形式的 PMN 唾液酸酶（neul 和 neu3）通过特定的过表达和敲低来调节人肺微血管 EC 的粘附和迁移。 neu蛋白。在具体目标 2 中，我们将定义 PMN 和 EC 中 PMN 唾液酸酶的底物，并评估它们的唾液酸化状态如何影响 PMN 体外粘附和体内运输。由于 PMN 诱导 EC 中的信号级联，在特定目标 3 中，我们将检查 PMN 唾液酸酶诱导的 EC 蛋白酪氨酸磷酸化的“适当”水平是否足以打开 EC-EC 旁细胞途径，以进行跨内皮迁移而不会出现蛋白质泄漏，同时处于以下水平：超过此阈值，EC屏障功能就会丧失。已经提出了急性肺损伤的“二次打击”模型，其中脂多糖和趋化肽的组合可促进肺损伤。在具体目标 4 中，我们将研究唾液酸酶在使肺血管系统对循环 LPS 和肺损伤敏感中的作用。将检查去唾液酸化通过 TLR4/MD2/CD14 复合物促进信号传导的分子机制，以及 ST 下调这种反应的能力。唾液酸酶抑制剂逆转急性肺损伤的能力将在小鼠肺白细胞停滞模型中进行体内研究。由于唾液酸酶抑制剂可在市场上买到，这些研究将为测试治疗肺损伤的新治疗方法提供实验依据。

项目成果

MUC1 ectodomain is a flagellin-targeting decoy receptor and biomarker operative during Pseudomonas aeruginosa lung infection.

MUC1 胞外域是一种靶向鞭毛蛋白的诱饵受体和生物标志物，在铜绿假单胞菌肺部感染期间发挥作用。

• 发表时间: 2021-11-22
• 影响因子: 4.6
• 作者: Verceles, Avelino C;Bhat, Pavan;Nagaria, Zain;Martin, Destiny;Patel, Harsh;Ntem;Hyun, Sang W;Hahn, Andrea;Jeudy, Jean;Cross, Alan S;Lillehoj, Erik P;Goldblum, Simeon E
• 通讯作者: Goldblum, Simeon E

Neuraminidase 1-mediated desialylation of the mucin 1 ectodomain releases a decoy receptor that protects against Pseudomonas aeruginosa lung infection.

神经氨酸酶 1 介导的粘蛋白 1 胞外域的去唾液酸化会释放一种诱饵受体，从而防止铜绿假单胞菌肺部感染。

• 发表时间: 2019
• 作者: Lillehoj, Erik P;Guang, Wei;Hyun, Sang W;Liu, Anguo;Hegerle, Nicolas;Simon, Raphael;Cross, Alan S;Ishida, Hideharu;Luzina, Irina G;Atamas, Sergei P;Goldblum, Simeon E
• 通讯作者: Goldblum, Simeon E

Changes in polysialic acid expression on myeloid cells during differentiation and recruitment to sites of inflammation: role in phagocytosis.

骨髓细胞在分化和募集到炎症部位过程中聚唾液酸表达的变化：在吞噬作用中的作用。

• DOI: 10.1093/glycob/cwu050
• 发表时间: 2014-09-01
• 期刊: Glycobiology
• 影响因子: 4.3
• 作者: N. Stamatos;Lei Zhang;A. Jokilammi;J. Finne;Wilbur H. Chen;Abderrahman El;A. Cross;K. Hankey
• 通讯作者: K. Hankey

Potential role for alternatively activated macrophages in the secondary bacterial infection during recovery from influenza.

替代激活的巨噬细胞在流感恢复期间继发细菌感染中的潜在作用。

• DOI: 10.1016/j.imlet.2011.10.009
• 发表时间: 2012-01-30
• 期刊: Immunology letters
• 影响因子: 4.4
• 作者: Chen, Wilbur H.;Toapanta, Franklin R.;Shirey, Kari Ann;Zhang, Lei;Giannelou, Angeliki;Page, Carly;Frieman, Matthew B.;Vogel, Stefanie N.;Cross, Alan S.
• 通讯作者: Cross, Alan S.