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

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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.Mice were sensitized 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.In IAV-infected mice with prior HDM sensitisation, a significant increase in airway fibrotic remodelling and airways hyper-reactivity (AHR) 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 (BAL) and lungs by over 80% in HDMIAV-treated mice without altering viral clearance. Markers of netosis (dsDNA and MPO in BAL), tissue injury (LDH activity in BAL) and oedema (total BAL-fluid protein) were also significantly reduced with anti-G-CSFR treatment. In addition, anti-G-CSFR antagonism significantly reduced BAL gelatinase activity, active TFGβ lung levels, collagen lung expression, airways fibrosis and AHR in HDMIAV-treated mice.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.

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Authors: Hao Wang, Christian Aloe, Jonathan Mcqualter, Angelica Papanicolaou, Ross Vlahos, Nick Wilson, Steven Bozinovski