Prostaglandin E₂protects murine lungs from bleomycin-induced pulmonary fibrosis and lung dysfunction

Abstract

Prostaglandin E(2) (PGE(2)) is a lipid mediator that is produced via the metabolism of arachidonic acid by cyclooxygenase enzymes. In the lung, PGE(2) acts as an anti-inflammatory factor and plays an important role in tissue repair processes. Although several studies have examined the role of PGE(2) in the pathogenesis of pulmonary fibrosis in rodents, results have generally been conflicting, and few studies have examined the therapeutic effects of PGE(2) on the accompanying lung dysfunction. In this study, an established model of pulmonary fibrosis was used in which 10-12-wk-old male C57BL/6 mice were administered a single dose (1.0 mg/kg) of bleomycin via oropharyngeal aspiration. To test the role of prostaglandins in this model, mice were dosed, via surgically implanted minipumps, with either vehicle, PGE(2) (1.32 μg/h), or the prostacyclin analog iloprost (0.33 μg/h) beginning 7 days before or 14 days after bleomycin administration. Endpoints assessed at 7 days after bleomycin administration included proinflammatory cytokine levels and measurement of cellular infiltration into the lung. Endpoints assessed at 21 days after bleomycin administration included lung function assessment via invasive (FlexiVent) analysis, cellular infiltration, lung collagen content, and semiquantitative histological analysis of the degree of lung fibrosis (Ashcroft method). Seven days after bleomycin administration, lymphocyte numbers and chemokine C-C motif ligand 2 expression were significantly lower in PGE(2)- and iloprost-treated animals compared with vehicle-treated controls (P < 0.05). When administered 7 days before bleomycin challenge, PGE(2) also protected against the decline in lung static compliance, lung fibrosis, and collagen production that is associated with 3 wk of bleomycin exposure. However, PGE(2) had no therapeutic effect on these parameters when administered 14 days after bleomycin challenge. In summary, PGE(2) prevented the decline in lung static compliance and protected against lung fibrosis when it was administered before bleomycin challenge but had no therapeutic effect when administered after bleomycin challenge.

Antifibrotic Effects of Noscapine through Activation of Prostaglandin E2 Receptors and Protein Kinase A

“…Furthermore, the antifibrotic effect of noscapine in our experiments ( Fig. 1) was similar to that shown for PGE 2 , also in the bleomycin model (16). Of note, multiple groups have demonstrated dysregulation of PGE 2 synthesis (as a result of down-regulation of COX-II expression) in the lung of human patients with pulmonary fibrosis as well as in animal models, which was associated with severity of the disease (42)(43)(44)(45)(46)(47), suggesting that activation of PGE 2 receptors could be an attractive approach for treatment of pulmonary fibrosis.…”

“…Previous studies using the bleomycin model of pulmonary fibrosis have shown the protective effects of the prostacyclin analog iloprost or of prostaglandin E 2 (15,16), both of which are known to act through cAMP/PKA signaling. We have shown a similar protective effect of adrenomedullin in a mouse model with genetic sensitization of adrenomedullin signaling in myofibroblasts (17).…”

Extracellular matrix alterations and acute inflammation; developing in parallel during early induction of pulmonary fibrosis

“…23 Fibrosis is thought to be a result of cellular damage initiating an inflammatory response and activation of lung fibroblasts, and thus inhibition or modulation of proliferative signaling (such as TGF-b, HGF, tyrosine kinase, PDGF or PGE 2 , 9,10,24,25 which is in accordance with the increased proliferation and number of myofibroblasts presented in this paper. The specific signaling pathways of this model are still unknown, but most likely mimics the ones previously described.…”

Mechanisms of Lung Fibrosis Resolution

“…63 However, PGE2, when administered to mice 14 days after bleomycin, failed to provide significant therapeutic effects on lung function or fibrosis. 64 Nuclear factor erythroid 2-related factor 2 (NRF2) is regarded as a master regulator of cellular resistance to oxidants and regulates expression of genes, limiting the inflammatory and fibrotic responses. 39 In primary IPF and normal lung fibroblasts, siRNA activation of NRF2 by either Keap1 siRNA or sulforaphane induced myofibroblast dedifferentiation with down-regulation of a-SMA, along with reduced cell proliferation, migration, and contraction, and was associated with restored oxidant/antioxidant balance in the cells.…”