Therapeutic Use of High Molecular Weight Hyaluronic Acid in Acute Lung Injury Following Severe Bacterial Pneumonia or Sepsis

高分子量透明质酸在严重细菌性肺炎或脓毒症后急性肺损伤中的治疗用途

• 批准号: 10614496
• 负责人: Perenlei Enkhbaatar
• 金额: $ 15.34万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10614496
• 关键词: Acute Lung Injury; Acute Respiratory Distress Syndrome; Acute respiratory failure; Alveolar; Animal Model; Animals; Anti-Inflammatory Agents; Antibiotics; Asthma; Bacteremia; Bacteria; Bacterial Pneumonia; Binding; Biological; Blood Vessels; Blood-Air Barrier; CD44 gene; Cells; Chronic Obstructive Pulmonary Disease; Clinical Trials; Critical Illness; Data; Dose; Edema; Endothelial Cells; Endothelium; Escherichia coli; Exposure to; Extracellular Matrix; Glycocalyx; Glycosaminoglycans; Growth; HAS2 gene; Human; Hyaluronan; Hyaluronic Acid; Hyaluronidase; Immune; Infection; Inflammation; Inflammation Mediators; Inflammatory; Innovative Therapy; Interleukin-6; Liquid substance; Liver; Lung; Lung diseases; Messenger RNA; Modeling; Molecular Weight; Multiple Organ Failure; Mus; Nitrogen; Organ; Oxygen; Patients; Perfusion; Permeability; Phagocytosis; Phase; Plasma; Pneumonia; Property; Proteins; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas aeruginosa pneumonia; Pulmonary Edema; Pulmonary Hypertension; Pulmonary Inflammation; Research Personnel; Sepsis; Septic Shock; Septicemia; Serum; Severities; Sheep; Site; Spleen; Sterility; Structure; Supportive care; Systemic infection; TNF gene; Therapeutic Effect; Therapeutic Studies; Therapeutic Use Study; Therapeutic Uses; Therapeutic immunosuppression; Tissues; Toxin; Translations; Vascular Endothelium; antimicrobial; clinically relevant; cytokine; ex vivo perfusion; extracellular vesicles; human model; improved; indexing; lung injury; molecular size; mortality; mouse model; novel; pharmacokinetics and pharmacodynamics; pre-clinical; preservation; prevent; receptor; restoration; severe injury; sheep model; smoke inhalation; vesicular release

ABSTRACT Bacterial pneumonia with or without sepsis is among the most common cause of acute respiratory failure in critically ill patients leading to acute respiratory distress syndrome (ARDS). Despite improvements in supportive care and appropriate antibiotic use, mortality from ARDS remains as high as 40%. Therefore, new innovative therapies are needed. Hyaluronan or hyaluronic acid (HA) is normally synthesized as a high molecular weight (HMW) nonsulfated glycosaminoglycan and is a chief component of the extracellular matrix and critical for maintaining the normal structure of alveolar air-blood barrier. In multiple pulmonary disorders including acute lung injury (ALI), asthma, COPD or pulmonary hypertension, HA undergoes degradation by hyaluronidases, reactive oxygen and nitrogen species and inflammatory mediators. The degradation products, low molecular weight (LMW) HA, has inflammatory properties and can decrease endothelial cell barrier function and induce expression of inflammatory mediators. In patients with ARDS, elevated levels of alveolar LMW HA have been associated with increased Lung Injury Score. Surprisingly, HMW HA has biologic properties opposite of LMW HA based primarily due to its molecular size. Therefore, investigators have previously studied the therapeutic use of exogenous administration of HMW HA in lung disorders. Despite promising pre-clinical data, a major limitation for the use of HMW HA for ARDS has remained the concern of giving an immunosuppressive therapy in patients with severe infection. In the current proposal, we hypothesize that administration of HMW HA will further restore major indices of ALI from severe bacterial pneumonia and/or sepsis in part through increased (1) antimicrobial activity and (2) through neutralization of inflammatory extracellular vesicles (EV) released during the exudative phase of ALI. In Aim 1, we will determine the therapeutic effects of HMW HA administration in established mouse models of severe bacterial pneumonia. We hypothesize that the mechanisms underlying the therapeutic effects of HMW HA will be due to increased antimicrobial activity of innate immune cells, binding of inflammatory EVs released early in the exudative phase of ALI, and through the restoration of the endothelial glycocalyx layer. To make the small pre-clinical animal studies more clinically relevant, in Aim 2, we will determine the therapeutic effects of HMW HA administration in an ex vivo perfused human lung injured with severe E.coli or Pseudomonas aeruginosa bacterial pneumonia. And to overcome some of the limitations of the perfused human lung such as a lack of the liver and spleen which are the major sites of HA degradation, in Aim 3, we will determine the therapeutic effects of HMW HA administration in a well-established ovine model of septic shock induced by smoke inhalation and Pseudomonas aeruginosa pneumonia. If successful, HMW HA, an inexpensive, non-immunogenic biologic already in use in clinical trials for other sterile inflammatory pulmonary disorders such as COPD, may prove to be a viable therapy for ARDS and/or sepsis.

摘要 细菌性肺炎伴或不伴败血症是急性呼吸衰竭的最常见原因之一， 重症患者导致急性呼吸窘迫综合征（ARDS）。尽管改善了 支持治疗和适当的抗生素使用，ARDS的死亡率仍然高达40%。因此，新 需要创新疗法。透明质酸或透明质酸（HA）通常作为高浓度的透明质酸合成。 分子量（HMW）的非硫酸化糖胺聚糖，是细胞外基质的主要成分 对维持肺泡气-血屏障的正常结构至关重要。在多种肺部疾病中 包括急性肺损伤（ALI）、哮喘、COPD或肺性高血压，HA通过 透明质酸酶、活性氧和氮物质以及炎症介质。降解产物， 低分子量（LMW）HA具有炎症特性，可降低内皮细胞屏障 功能并诱导炎症介质的表达。在ARDS患者中， LMW HA与肺损伤评分增加相关。令人惊讶的是，HMW HA具有生物活性， 与基于LMW HA的性质相反，主要是由于其分子大小。因此，调查人员 先前研究了外源性施用HMW HA在肺部疾病中的治疗用途。尽管 有希望的临床前数据，使用HMW HA治疗ARDS的一个主要限制仍然是 对严重感染的患者进行免疫抑制治疗。在目前的提案中，我们假设 HMW HA给药将进一步恢复严重细菌性肺炎和/或 脓毒症部分通过增加（1）抗微生物活性和（2）通过中和炎症 细胞外囊泡（EV）在ALI渗出期释放。在目标1中，我们将确定 在建立的严重细菌性肺炎小鼠模型中HMW HA给药的治疗效果。 我们推测，HMW HA治疗作用的潜在机制是由于增加了 先天免疫细胞的抗微生物活性，结合渗出期早期释放的炎性EV 的ALI，并通过恢复内皮糖萼层。为了使临床前的小动物 在目的2中，我们将确定HMW HA给药的治疗效果 在用严重的大肠杆菌或绿脓杆菌细菌损伤的离体灌注的人肺中， 肺炎为了克服灌注的人类肺的一些局限性，例如缺乏肝脏， 和脾脏是HA降解的主要部位，在目的3中，我们将确定 在烟雾吸入诱导的感染性休克的成熟绵羊模型中给予HMW HA， 绿脓杆菌肺炎。如果成功，HMW HA，一种廉价的，非免疫原性的生物制剂， 已经在临床试验中用于其他无菌炎症性肺病，如COPD，可能证明， 是一种可行的治疗ARDS和/或败血症的方法。