Neutrophil Accumulation in Bacterial Pneumonia

细菌性肺炎中的中性粒细胞积聚

• 批准号: 7837294
• 负责人: Samithamby Jeyaseelan
• 金额: $ 29.35万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7837294
• 关键词: Acute Lung Injury; Address; Adult; Adult Respiratory Distress Syndrome; Adverse effects; Affect; Alveolar; Alveolar Macrophages; Attention; Attenuated; Bacteria; Bacterial Infections; Bacterial Pneumonia; CXC Chemokines; CXCL5 gene; Cause of Death; Cell surface; Cells; Cessation of life; Chemotactic Factors; Child; Data; Defense Mechanisms; Dendritic Cells; Development; Disease; Distal; Epithelial; Epithelial Cells; Escherichia coli Infections; Event; Genes; Germ; Goals; Health Expenditures; Host Defense; Human; Immune response; In Vitro; Infection; Inflammation; Inflammation Mediators; Interleukin-17; Interleukin-8B Receptor; Investigation; Knock-out; Laboratories; Lead; Legionella pneumophila; Legionnaires' Disease; Leukocytes; Ligands; Lung; Lung Inflammation; Lung diseases; MAP Kinase Gene; Measures; Mediating; Mediator of activation protein; Modeling; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Natural Immunity; Neutrophil Infiltration; Pathogenesis; Pathway interactions; Play; Pneumonia; Production; Proteins; RIPK2 gene; Recruitment Activity; Relative (related person); Reporting; Respiratory System; Respiratory tract structure; Role; Scheme; Signal Transduction; System; T-Lymphocyte; TNF gene; Time; Toll-like receptors; Type II Epithelial Receptor Cell; United States; Up-Regulation; cell type; chemokine; cytokine; design; in vivo; innovation; interleukin-23; keratinocyte; lung injury; macrophage inflammatory protein 2; mortality; neutrophil; novel; pathogen; public health relevance; receptor; research study; respiratory; response; trafficking; treatment strategy

DESCRIPTION (provided by applicant): Bacterial pneumonia is a leading cause of death. Recruitment of neutrophils into the lungs is one of the most important defense mechanisms in the initial host defense against bacterial infection. However, excessive influx of neutrophils can cause extensive lung injury and ARDS, suggesting that neutrophil influx is tightly regulated. Neutrophil trafficking is primarily dependent on chemokine production by myeloid and resident cells in the lung. In the past, most of the attention has been focused on the role of myeloid cells in neutrophil trafficking. Recently, we reported for the first time that resident alveolar epithelial type (AE) II cells produce the neutrophilic chemokine, CXC chemokine ligand (CXCL) 5, in LPS-mediated lung inflammation. In addition, we showed that CXCL5 blockade attenuated LPS-induced neutrophil influx in the lung. In this proposal, we focus on Legionella pneumophila (Lp), as our preliminary data show that the in vivo depletion of CXCL5, but not other neutrophilic chemokines, such as KC and MIP-2, impairs host defense against Lp despite the fact that depletion of either CXCL5, KC or MIP-2 impairs host defense against E. coli infection. We hypothesize that Lp-induced CXCL5 is a critical mediator of neutrophil influx in the lung and CXCL5 production stimulated by Lp infection involves both direct and indirect cascades. The direct cascade involves interaction of Lp with AEII cells and the indirect cascade involves interaction of Lp with myeloid cells leading to the production of inflammatory mediators, which can then stimulate AEII cells. The Specific Aims of this application are: 1) To directly assess the contribution of CXCL5 to neutrophil influx in Lp pneumonia; 2) To delineate the direct pathways responsible for CXCL5 production in murine and human AEII cells (in vitro) after Lp infection; and 3) To delineate the indirect pathways (in vivo) that mediate CXCL5 production and neutrophil influx in the lung during Lp infection. Overall, the proposed studies focus on the novel pathways responsible for CXCL5 production and neutrophil influx in Lp pneumonia. A unique combination of in vivo (mouse, including CXCL5 knockout) and in vitro (murine AEII and dendritic cells, and human AEII cells) systems will be employed to address the Aims. Elucidation of the mechanisms by which Lp induces CXCL5 production and neutrophil influx in pneumonia will lead to a better understanding of disease pathogenesis and ultimately lead to new strategies to the treatment of lung injury and ARDS in bacterial pneumonia. PUBLIC HEALTH RELEVANCE. Bacterial pneumonia is an important lung disease in both adults and children, and affects more than 1 million adults with 30,000 deaths per year in the United States alone. Despite the fact that some advances have been made in the recent past in understanding bacterial pneumonia, we still do not have effective control measures. Neutrophil, a white blood cell, recruitment to the lungs is one of the important protective mechanisms against respiratory bacterial germs; paradoxically excessive accumulation of neutrophils in response to bacteria can significantly contribute to lung damage. A better understanding of the mechanisms underlying neutrophil influx is crucial to designing novel and innovative treatment strategies to minimize excessive lung inflammation. To investigate the mechanisms by which neutrophils are recruited to the lung, we propose to use a model of lung disease (pneumonia) induced by the germ, Legionella pneumophila. L. pneumophila causes severe pneumonia known as "Legionnaires disease" and is characterized by extensive neutrophil accumulation. We have recently shown the importance of a neutrophil attracting molecule, CXCL5, in the lungs in disease (pneumonia) progression. In this proposal, we will determine the role of CXCL5 in bacterial pneumonia caused by the germ, L. pneumophila. The results from this study will help us understand the role played by CXCL5 in inducing neutrophil accumulation in the lungs in bacterial disease (pneumonia). It is anticipated that these investigations will lead to the development of new and innovative treatment strategies to treat lung diseases via manipulating neutrophil numbers in the lung.

描述（由申请人提供）：细菌性肺炎是死亡的主要原因。将嗜中性粒细胞募集到肺部是最初宿主防御细菌感染的最重要防御机制之一。然而，嗜中性粒细胞的过多流入会导致广泛的肺损伤和ARDS，这表明嗜中性粒细胞的流入受到严格调节。中性粒细胞运输主要取决于肺中髓样和驻留细胞的趋化因子的产生。过去，大多数注意力集中在髓样细胞在中性粒细胞运输中的作用。最近，我们首次报道了在LPS介导的肺炎症中，居民肺泡上皮类型（AE）II细胞产生嗜中性粒性趋化因子CXC趋化因子（CXCL）5。此外，我们表明CXCL5阻断减弱了LPS诱导的肺中性粒细胞流入。 In this proposal, we focus on Legionella pneumophila (Lp), as our preliminary data show that the in vivo depletion of CXCL5, but not other neutrophilic chemokines, such as KC and MIP-2, impairs host defense against Lp despite the fact that depletion of either CXCL5, KC or MIP-2 impairs host defense against E. coli infection.我们假设LP诱导的CXCL5是LP感染刺激的肺和CXCL5产生中嗜中性粒细胞涌入的关键介质涉及直接和间接级联反应。直接的级联反应涉及LP与AEII细胞的相互作用，间接级联反应涉及LP与髓样细胞的相互作用，从而导致炎症介质的产生，从而可以刺激AEII细胞。该应用的具体目的是：1）直接评估CXCL5对LP肺炎中性粒细胞流入的贡献； 2）描述LP感染后鼠和人AEII细胞（体外）中CXCL5产生的直接途径； 3）描绘LP感染期间肺中CXCL5产生和中性粒细胞流入的间接途径（体内）。总体而言，拟议的研究集中于导致LP肺炎中CXCL5产生和中性粒细胞流入的新途径。将使用体内（包括CXCL5敲除）和体外（鼠AEII和树突状细胞以及人AEII细胞）系统的独特组合来解决目标。阐明LP在肺炎中诱导CXCL5产生和中性粒细胞涌入的机制将使人们对疾病发病机理有更好的了解，并最终导致新的策略来治疗肺肺炎中的肺损伤和ARDS。公共卫生相关性。细菌性肺炎是成年人和儿童的重要肺部疾病，仅在美国，每年就会影响超过100万人死亡。尽管最近在了解细菌性肺炎方面已经取得了一些进步，但我们仍然没有有效的控制措施。中性粒细胞是白细胞，募集到肺部是针对呼吸细菌细菌的重要保护机制之一。响应细菌的嗜中性粒细胞的矛盾积累会显着导致肺损伤。更好地理解中性粒细胞流入的机制对于设计新颖而创新的治疗策略以最大程度地减少过度肺部炎症至关重要。为了研究嗜中性粒细胞募集到肺部的机制，我们建议使用胚芽肺炎军团菌诱导的肺疾病模型（肺炎）。肺炎乳杆菌引起严重的肺炎，称为“军团疾病”，其特征是中性粒细胞的积累。最近，我们显示了吸引分子CXCL5在疾病（肺炎）进展中吸引分子CXCL5的重要性。在此提案中，我们将确定CXCL5在细菌肺炎引起的细菌性肺炎中的作用。这项研究的结果将有助于我们了解CXCL5在诱导细菌疾病（肺炎）肺中嗜中性粒细胞积累的作用。预计这些调查将导致通过操纵肺中性粒细胞数量来治疗肺部疾病的新的和创新的治疗策略。