16,16-Dimethyl Prostaglandin E₂ Efficacy on Prevention and Protection from Bleomycin-Induced Lung Injury and Fibrosis

Abstract

In this study, we evaluated the protective effect and therapeutic potential of the prostaglandin E(2) (PGE(2)) synthetic analog 16,16-dimethyl-PGE(2) (dmPGE(2)) in the animal model of pulmonary fibrosis induced by bleomycin. Mice subjected to intratracheal administration of bleomycin (1 mg/kg) received a dmPGE(2) dose of 30 microg/kg/day by continuous subcutaneous infusion. Bronchoalveolar lavage (BAL); immunohistochemical analysis for IL-1, TNF-alpha, and nitrotyrosine; measurement of fluid content in lung; myeloperoxidase activity assay; and lung histology were performed 1 week later. Lung histology and Sircol assay for collagen deposition were performed 3 weeks after treatments. Changes of body weight and survival rate were also evaluated at 1 and 3 weeks. Compared with bleomycin-treated mice, dmPGE(2) co-treated mice exhibited a reduced degree of body weight loss and mortality rate as well as of lung damage and inflammation, as shown by the significant reduction of: (1) lung infiltration by leukocytes; (2) myeloperoxidase activity; (3) IL-1, TNF-alpha, and nitrotyrosine immunostaining; (4) lung edema; and (5) histologic evidence of lung injury and collagen deposition. In a separate set of experiments, dmPGE(2) treatment was started 3 days after bleomycin administration, and the evaluation of lung damage and inflammation was assessed 4 days later. Importantly, delayed administration of dmPGE(2) also was able to protect from inflammation and lung injury induced by bleomycin. These results, indicating that dmPGE(2) is able to prevent and to reduce bleomycin-induced lung injury through its regulatory and anti-inflammatory properties, encourage further research to find new options for the treatment of pulmonary fibrosis.

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

“…It is thus possible that PGE 2 is more likely to be detected in BALF, and prostacyclin would more likely be detected in other compartments, such as urine. Another relevant study that should be noted is the one by Failla and coworkers (17), which showed that treatment with the PGE 2 analog, dmPGE 2 , protects mice from bleomycin-induced pulmonary inflammation and fibrosis (17). Although this study utilized a similar experimental protocol, there are key differences between their report and ours.…”

“…Considering the variability in bleomycin response in different mouse strains, this is an important experimental variable that should be taken into consideration. Finally, the most important difference between our study and the one by Failla et al (17) is that, in addition to examining the role of PGE 2 in the inflammatory, histological, and biochemical response to bleomycin, we also studied the effect of PGE 2 on lung function. Importantly, our data demonstrate significant protective effects of PGE 2 on this endpoint.…”

“…The above mentioned study by Lovgren and coworkers used several in vivo genetic models to elegantly show that prostacyclin, rather than PGE 2 , protects against the development of fibrosis and the decline in lung function in response to bleomycin (39). However, a separate study showed that administration of the PGE 2 analog, 16,16-dimethyl PGE 2 (dmPGE 2 ), protected against bleomycin-induced lung inflammation and fibrosis in mice (17). Unfortunately, this study did not examine the effect of dmPGE 2 on pulmonary function in this model.…”

The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice

“…The relevance of such an impairment is suggested by the facts that pharmacologic (administration of indomethacin) (22) or genetic (gene deletion of Cox2) (23) reduction in PGE 2 synthesis in the lung as well as gene deletion of EP2 (24) augment bleomycin-induced fibrosis in mice. By contrast, protection against experimental fibrosis has been observed when endogenous PGE 2 is overproduced (21,25,26) or when exogenous PGE is administered (27). Interestingly, a reduction in PGE 2 responsiveness mediated by a loss of the EP2 receptor has also been described in fibroblasts derived from bleomycin-treated mice (24) and IPF patients (28).…”

Fibroblast-specific expression of AC6 enhances β-adrenergic and prostacyclin signaling and blunts bleomycin-induced pulmonary fibrosis

“…Agents that increase cAMP levels inhibit various measures of pulmonary fibroblast function, including collagen synthesis, cell proliferation and migration, and collagen gel contraction (12,20,31). Administration of a ␤-adrenergic receptor (␤-AR) antagonist causes an elevation in pulmonary collagen, while treatment with PGE 2 , prostacyclin, or aminophylline [which increases cAMP via inhibition of phosphodiesterases (PDEs)] attenuates bleomycin-stimulated pulmonary fibrosis (10,23,24,29,33). Thus, agents working through the cAMP signaling cascade appear to have antifibrotic potential, but no therapies using these mechanisms have proven effective in humans.…”