Role of the COX2-PGE₂ axis in <i>S. pneumoniae</i>-induced exacerbation of experimental fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease (ILD) associated with high morbidity and mortality. Patients with ILD frequently develop an acute exacerbation of their disease, which may be triggered by viral and/or bacterial infections. Prostaglandin E₂ (PGE₂) is an eicosanoid released in a cyclooxygenase-2 (COX2)-dependent manner and is considered to contribute to regulation of lung fibrosis. However, its role in infection-induced exacerbation of lung fibrosis is poorly defined. We found significantly increased levels of PGE₂ in lung tissue of patients with ILD. Increased levels of PGE₂ were also found in lung tissue of mice with AdTGF-β1-induced lung fibrosis and even more so in <i>Streptococcus pneumoniae</i> exacerbated lung fibrosis. Type II alveolar epithelial cells (AT II cells) and alveolar macrophages (AM) contributed to PGE₂ release during exacerbating fibrosis. Application of parecoxib to inhibit PGE₂ synthesis ameliorated lung fibrosis, whereas intratracheal application of PGE₂ worsened lung fibrosis in mice. Both interventions had no effect on <i>S. pneumoniae</i>-exacerbated lung fibrosis. Together, we found that the COX2-PGE₂ axis has dual roles in fibrosis that may offset each other: PGE₂ helps resolve infection/attenuate inflammation in fibrosis exacerbation but accentuates TGF-β/AT II cell-mediated fibrosis. These data support the efficacy of COX/PGE₂ interventions in the setting of non-exacerbating lung fibrosis.