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 S. pneumoniae 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, while intratracheal application of PGE₂ worsened lung fibrosis in mice. Both interventions had no effect on S. pneumoniae 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-b/AT II cell-mediated fibrosis. These data support the efficacy of COX/PGE₂ interventions in the setting of non-exacerbating lung fibrosis.

中文翻译：

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COX2-PGE ₂轴在肺炎链球菌诱导的实验性纤维化恶化中的作用

特发性肺纤维化（IPF）是一种间质性肺疾病（ILD），与高发病率和高死亡率相关。患有ILD的患者经常会出现疾病的急性加重，这可能是由病毒和/或细菌感染引起的。前列腺素E ₂（PGE ₂）是以环加氧酶2（COX2）依赖性方式释放的类花生酸，被认为有助于调节肺纤维化。但是，它在感染引起的肺纤维化加重中的作用尚不清楚。我们发现ILD患者肺组织中PGE _2的水平显着增加。PGE ₂水平升高在患有AdTGF-β1诱导的肺纤维化的小鼠的肺组织中也发现了这些蛋白，在肺炎链球菌中更是如此，这加剧了肺纤维化。II型肺泡上皮细胞（AT II细胞）和肺泡巨噬细胞（AM）在加剧纤维化过程中促进了PGE _2的释放。应用帕瑞昔布抑制PGE ₂合成可改善肺纤维化，而气管内应用PGE _2可加重小鼠肺纤维化。两种干预对肺炎链球菌加重的肺纤维化均无影响。在一起，我们发现COX2 / PGE ₂轴在可能相互抵消的纤维化中具有双重作用：PGE ₂帮助解决感染/减轻纤维化加剧中的炎症，但会加剧TGF-b / AT II细胞介导的纤维化。这些数据支持了COX / PGE ₂干预措施在非加重性肺纤维化中的功效。