G‐CSFR antagonism reduces mucosal injury and airways fibrosis in a virus‐dependent model of severe asthma

Abstract

Background and Purpose Asthma is a chronic disease that displays heterogeneous clinical and molecular features. A phenotypic subset of late‐onset severe asthmatics has debilitating fixed airflow obstruction, increased neutrophilic inflammation and a history of pneumonia. Influenza A virus (IAV) is an important viral cause of pneumonia and asthmatics are frequently hospitalised during IAV epidemics. This study aims to determine whether antagonising granulocyte colony stimulating factor receptor (G‐CSFR) prevents pneumonia‐associated severe asthma. Experimental Approach Mice were sensitised to house dust mite (HDM) to establish allergic airway inflammation and subsequently infected with IAV (HKx31/H3N2 subtype). A neutralising monoclonal antibody against G‐CSFR was therapeutically administered. Key Results In IAV‐infected mice with prior HDM sensitisation, a significant increase in airway fibrotic remodelling and airways hyper‐reactivity was observed. A mixed granulocytic inflammatory profile consisting of neutrophils, macrophages and eosinophils was prominent and at a molecular level, G‐CSF expression was significantly increased in HDMIAV‐treated mice. Blockage of G‐CSFR reduced neutrophilic inflammation in the bronchoalveolar and lungs by over 80% in HDMIAV‐treated mice without altering viral clearance. Markers of NETosis (dsDNA and myeloperoxidase in bronchoalveolar), tissue injury (LDH activity in bronchoalveolar) and oedema (total bronchoalveolar‐fluid protein) were also significantly reduced with anti‐G‐CSFR treatment. In addition, anti‐G‐CSFR antagonism significantly reduced bronchoalveolar gelatinase activity, active TFGβ lung levels, collagen lung expression, airways fibrosis and airways hyper‐reactivity in HDMIAV‐treated mice. Conclusions and Implications We have shown that antagonising G‐CSFR‐dependent neutrophilic inflammation reduced pathological disruption of the mucosal barrier and airways fibrosis in an IAV‐induced severe asthma model.