tetano
Editor, Senior Moderator
Am J Physiol Lung Cell Mol Physiol. 2020 Jan 29. doi: 10.1152/ajplung.00296.2019. [Epub ahead of print] [h=1]Lower Respiratory Tract Delivery, Airway Clearance, and Preclinical Efficacy of Inhaled GM-CSF in a Post-influenza Pneumococcal Pneumonia Model.[/h]
Umstead TM[SUP]1[/SUP], Hewage EK[SUP]1[/SUP], Mathewson M[SUP]1[/SUP], Beaudoin S[SUP]1[/SUP], Chroneos ZC[SUP]1[/SUP], Wang M[SUP]2[/SUP], Halstead ES[SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Inhaled GM-CSF shows promise as a therapeutic to treat viral and bacterial pneumonia, but to date, no mouse model of inhaled GM-CSF has been described. We sought to: 1) develop a mouse model of the administration of aerosolized recombinant mouse GM-CSF; and 2) 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-labeled dextran non-invasively via an aerosolization tower, or invasively using a rodent ventilator. The efficiency of delivery to the lower respiratory tracts of mice was 0.01% non-invasively as compared to 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, then secondarily infected infected with Streptococcus pneumoniae. Inhaled GM-CSF conferred a significant survival benefit to mice against secondary challenge with S. pneumoniae (p<0.05). Inhaled GM-CSF did not reduce airway or lung parenchymal bacterial growth, but significantly reduced the incidence of S. pneumoniae bacteremia (p<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.
[h=4]KEYWORDS:[/h] aerosol; gm-csf; inhaled; pharmacokinetics; pneumonia
PMID: 31994895 DOI: 10.1152/ajplung.00296.2019
Umstead TM[SUP]1[/SUP], Hewage EK[SUP]1[/SUP], Mathewson M[SUP]1[/SUP], Beaudoin S[SUP]1[/SUP], Chroneos ZC[SUP]1[/SUP], Wang M[SUP]2[/SUP], Halstead ES[SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Inhaled GM-CSF shows promise as a therapeutic to treat viral and bacterial pneumonia, but to date, no mouse model of inhaled GM-CSF has been described. We sought to: 1) develop a mouse model of the administration of aerosolized recombinant mouse GM-CSF; and 2) 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-labeled dextran non-invasively via an aerosolization tower, or invasively using a rodent ventilator. The efficiency of delivery to the lower respiratory tracts of mice was 0.01% non-invasively as compared to 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, then secondarily infected infected with Streptococcus pneumoniae. Inhaled GM-CSF conferred a significant survival benefit to mice against secondary challenge with S. pneumoniae (p<0.05). Inhaled GM-CSF did not reduce airway or lung parenchymal bacterial growth, but significantly reduced the incidence of S. pneumoniae bacteremia (p<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.
[h=4]KEYWORDS:[/h] aerosol; gm-csf; inhaled; pharmacokinetics; pneumonia
PMID: 31994895 DOI: 10.1152/ajplung.00296.2019