Inhibiting S100A8/A9 Attenuates Airway Obstruction in a Mouse Heterotopic Tracheal Transplantation Model

Abstract

<h3>Purpose</h3> Chronic lung allograft dysfunction (CLAD) is a major cause of mortality after lung transplantation (LTx). The main pathogenesis of CLAD is fibrosis of the small airways or lung parenchyma. Neutralizing antibodies against S100A8/A9, an inflammatory protein, have been shown to inhibit lung fibrosis in mouse models. In the present study, we tested the hypothesis that S100A8/A9 antibodies suppress airway fibrosis in a mouse model. <h3>Methods</h3> A mouse heterotopic tracheal transplantation model was used. The anti-S100A8/A9 monoclonal antibody or control IgG were intraperitoneally administered twice a week. The rate of graft lumen occlusion, the positivity of the fibroblast marker α-smooth muscle actin (SMA), and mRNA expression of cytokines and chemokines were evaluated. <h3>Results</h3> The luminal obstruction ratio at day 21 was significantly higher in the treatment group than in the control group (p = 0.0023) (Fig.1A, 1B and 2A). The αSMA-positive area in submucosal layer was significantly smaller in the treatment group than in the control group (p = 0.0376) (Fig 1C, 1D and 2B). The expression levels of TGFβ (p = 0.0026) and Collagen 3a1 (p = 0.0238) at day 21 by qPCR were significantly lower in the treatment group than in the control group. Conversely, expression levels of inflammatory cytokines in the treatment group was equivalent to those in the control group. <h3>Conclusion</h3> S100A8/A9 antibody ameliorated airway obstruction by reducing collagen production of αSMA positive myofibroblast without suppression of inflammatory responses in a mouse model. The heterodimer S100A8/A9 can be a novel therapeutic target for CLAD after LTx.