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Patients with ILD frequently develop an acute exacerbation of their disease, which may be triggered by viral and\/or bacterial infections. Prostaglandin E<jats:sub>2<\/jats:sub> (PGE<jats:sub>2<\/jats:sub>) is an eicosanoid released in a cyclooxygenase-2 (COX2)\u2013dependent 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 PGE<jats:sub>2<\/jats:sub> in lung tissue of patients with ILD. Increased levels of PGE<jats:sub>2<\/jats:sub> were also found in lung tissue of mice with AdTGF-\u03b21\u2013induced lung fibrosis and even more so in Streptococcus pneumoniae exacerbated lung fibrosis. Type II alveolar epithelial cells (AT II cells) and alveolar macrophages (AM) contributed to PGE<jats:sub>2<\/jats:sub> release during exacerbating fibrosis. Application of parecoxib to inhibit PGE<jats:sub>2<\/jats:sub> synthesis ameliorated lung fibrosis, whereas intratracheal application of PGE<jats:sub>2<\/jats:sub> worsened lung fibrosis in mice. Both interventions had no effect on S. pneumoniae-exacerbated lung fibrosis. Together, we found that the COX2-PGE<jats:sub>2<\/jats:sub> axis has dual roles in fibrosis that may offset each other: PGE<jats:sub>2<\/jats:sub> helps resolve infection\/attenuate inflammation in fibrosis exacerbation but accentuates TGF-\u03b2\/AT II cell\u2013mediated fibrosis. 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