Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
Pulmonary Immunology and Physiology Laboratory, Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
Am J Physiol Lung Cell Mol Physiol. 2020 Apr 1;318(4):L571-L579. doi: 10.1152/ajplung.00296.2019. Epub 2020 Jan 29.
Inhaled granulocyte/macrophage colony-stimulating factor (GM-CSF) shows promise as a therapeutic to treat viral and bacterial pneumonia, but no mouse model of inhaled GM-CSF has been described. We sought to ) develop a mouse model of aerosolized recombinant mouse GM-CSF administration and ) investigate the protection conferred by inhaled GM-CSF during influenza A virus (IAV) infection against secondary bacterial infection with pneumococcus. To assess lower respiratory tract delivery of aerosolized therapeutics, mice were exposed to aerosolized fluorescein (FITC)-labeled dextran noninvasively via an aerosolization tower or invasively using a rodent ventilator. The efficiency of delivery to the lower respiratory tracts of mice was 0.01% noninvasively compared with 0.3% invasively. The airway pharmacokinetics of inhaled GM-CSF fit a two-compartment model with a terminal phase half-life of 1.3 h. To test if lower respiratory tract levels were sufficient for biological effect, mice were infected intranasally with IAV, treated with aerosolized recombinant mouse GM-CSF, and then secondarily infected with . Inhaled GM-CSF conferred a significant survival benefit to mice against secondary challenge with ( < 0.05). Inhaled GM-CSF did not reduce airway or lung parenchymal bacterial growth but significantly reduced the incidence of bacteremia ( < 0.01). However, GM-CSF overexpression during influenza virus infection did not affect lung epithelial permeability to FITC-dextran ingress into the bloodstream. Therefore, the mechanism of protection conferred by inhaled GM-CSF appears to be locally mediated improved lung antibacterial resistance to systemic bacteremia during IAV infection.
吸入粒细胞/巨噬细胞集落刺激因子（GM-CSF）作为治疗病毒和细菌性肺炎的方法具有一定的潜力，但目前尚未有吸入 GM-CSF 的小鼠模型被描述。我们试图：）开发一种吸入重组小鼠 GM-CSF 给药的小鼠模型，）研究在流感病毒（IAV）感染期间吸入 GM-CSF 对抗肺炎链球菌继发细菌感染的保护作用。为了评估吸入治疗药物在肺部的传递情况，通过雾化塔或使用啮齿动物通气机对小鼠进行无创或有创的气溶胶化荧光素（FITC）标记葡聚糖。与有创方法相比，无创方法下将气溶胶化药物递送至肺部的效率为 0.01%，而有创方法为 0.3%。吸入 GM-CSF 的气道药代动力学符合双室模型，终末半衰期为 1.3 小时。为了测试下呼吸道的药物浓度是否足以产生生物学效应，将 IAV 经鼻腔感染小鼠，用气溶胶化重组小鼠 GM-CSF 进行治疗，然后用 进行继发感染。吸入 GM-CSF 显著提高了小鼠的存活率，减少了继发感染 （<0.05）。吸入 GM-CSF 并未减少气道或肺实质中的细菌生长，但显著降低了 菌血症的发生率（<0.01）。然而，GM-CSF 在流感病毒感染期间的过表达并未影响肺上皮细胞对 FITC-葡聚糖进入血液的通透性。因此，吸入 GM-CSF 所赋予的保护机制似乎是通过局部介导来提高肺部对 IAV 感染期间全身菌血症的抗菌抵抗力。
