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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Respir+Res
2018 ; 19
(1
): 3
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GM-CSF overexpression after influenza a virus infection prevents mortality and
moderates M1-like airway monocyte/macrophage polarization
#MMPMID29304863
Halstead ES
; Umstead TM
; Davies ML
; Kawasawa YI
; Silveyra P
; Howyrlak J
; Yang L
; Guo W
; Hu S
; Hewage EK
; Chroneos ZC
Respir Res
2018[Jan]; 19
(1
): 3
PMID29304863
show ga
BACKGROUND: Influenza A viruses cause life-threatening pneumonia and lung injury
in the lower respiratory tract. Application of high GM-CSF levels prior to
infection has been shown to reduce morbidity and mortality from pathogenic
influenza infection in mice, but the mechanisms of protection and treatment
efficacy have not been established. METHODS: Mice were infected intranasally with
influenza A virus (PR8 strain). Supra-physiologic levels of GM-CSF were induced
in the airways using the double transgenic GM-CSF (DTGM) or littermate control
mice starting on 3 days post-infection (dpi). Assessment of respiratory
mechanical parameters was performed using the flexiVent rodent ventilator. RNA
sequence analysis was performed on FACS-sorted airway macrophage subsets at 8
dpi. RESULTS: Supra-physiologic levels of GM-CSF conferred a survival benefit,
arrested the deterioration of lung mechanics, and reduced the abundance of
protein exudates in bronchoalveolar (BAL) fluid to near baseline levels.
Transcriptome analysis, and subsequent validation ELISA assays, revealed that
excess GM-CSF re-directs macrophages from an "M1-like" to a more "M2-like"
activation state as revealed by alterations in the ratios of CXCL9 and CCL17 in
BAL fluid, respectively. Ingenuity pathway analysis predicted that GM-CSF surplus
during IAV infection elicits expression of anti-inflammatory mediators and
moderates M1 macrophage pro-inflammatory signaling by Type II interferon (IFN-?).
CONCLUSIONS: Our data indicate that application of high levels of GM-CSF in the
lung after influenza A virus infection alters pathogenic "M1-like" macrophage
inflammation. These results indicate a possible therapeutic strategy for
respiratory virus-associated pneumonia and acute lung injury.