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INVESTIGATING THE PATHOPHYSIOLOGY OF LUNG DISEASE IN STAT3-HYPER IGE SYNDROME
Abstract
Background and Aims
STAT3-hyper IgE syndrome (STAT3-HIES) patients suffer from recurrent lung infections, leading to tissue destructive changes with pneumatocele formation and severe lung defects. To improve the pulmonary therapy of STAT3-HIES patients, we aim to better understand the pathophysiology underlying the destructive lung disease.
Methods
Using a transgenic mouse model (mutStat3) with a STAT3-HIES like immunologic phenotype carrying the dominant negative mutation Stat3-ΔV463 (Steward-Tharp et al. Blood 2014), we model lung infections by inducing acute lung injury with intratracheal instillation of lipopolysaccharide (LPS). Inflammatory responses and tissue injury were analyzed by quantification of bronchoalveolar lavage (BAL) cells, ELISA, and protein quantification of BAL fluid. Lung tissue was collected for histology and expression analysis.
Results
Instillation of LPS induced lung injury in a dosage-dependent manner in wildtype (wt) and mutStat3 mice as shown by an overall increase in BAL protein concentrations with higher levels in mutStat3 compared to wt samples. We found increased immune cell infiltration predominantly neutrophils and increased TNFalpha release into the air space significant higher in mutStat3 compared to control animals. Quantification of immunohistologically stained lung tissue with pro surfactant protein C (pro-SpC) as a marker for alveolar type II (AT2) cells, showed reduced positive pro-SpC cells in lung tissue in mutStat3 compared to wt mice after LPS challenge.
Conclusions
Our in vivo mutStat3 mouse model of lung injury indicates a higher susceptibility to pulmonary tissue damage with elevated lung inflammation and deficient epithelial recovery in STAT3-HIES after pulmonary injury.