Uso da frutose-1,6-bisfosfato no tratamento da fibrose pulmonar experimental

Abstract

Pulmonary fibrosis is a specific form of interstitial pneumonia characterized by progressive worsening of dyspnea and lung function and associated with a poor prognosis. In addition to the idiopathic cause, pulmonary fibrosis may be caused by drugs such as bleomycin (BLM) - used in lymphomas and germinative tumors treatments. Fructose-1,6-bisphosphate (FBP) is a high energy endogenous glycolytic compound that has antifibrotic, anti-inflammatory and immunomodulatory effects. The aim of this study was to assess the effect of FBP on BLM-induced pulmonary fibrosis model in mice and investigate its effect using a human embryonic lung fibroblast (MRC-5) culture system. C57BL/6 were divided into Control, FBP, BLM and BLM plus FBP. A single dose of bleomycin (7.5 U/kg) was administered intratracheally in mice and survival, body weight, Ashcroft Score and histological analysis (hematoxylin-eosin, Masson’s trichrome and picrosirius) were performed. Pulmonary function and bronchoalveolar lavage fluid (BALF) were also evaluated after a single dose of bleomycin (1.2 U/kg – intratracheally). Treatment with FBP (500 mg/kg) was given on day 0 intraperitoneally. Fibroblasts (MRC-5 cells) were used to access the effect of FBP in vitro. In vivo, FBP increased survival rate and reduced the body weight loss when BLM and BLM plus FBP were compared (p< 0.05). FBP also prevented the loss of pulmonary function caused by BLM and decreased BALF inflammatory cells. The level of fibrosis and the superficial collagen density were lower in the lungs of animals that received BLM plus FBP as compared to BLM only (p<0.05). In vitro, FBP (0.62 and 1.25 mM) had inhibitory activity on MRC-5 cells and was able to induce senescence in fibroblasts. These results showed that FBP has the potential of reducing the toxic effects of BLM and may provide supportive therapy for conventional methods used for the treatment of cancer.