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Roflumilast Prevents the Metabolic Effects of Bleomycin-Induced Fibrosis in a Murine Model.

Milara J, Morcillo E, Monleon D, Tenor H, Cortijo J - PLoS ONE (2015)

Bottom Line: These differences include increases in proline, glycine, lactate, taurine, phosphocholine and total glutathione and decreases in global fatty acids.This profile suggests that bleomycin produces alterations in the oxidative equilibrium, a strong inflammatory response and activation of the collagen synthesis among others.Roflumilast prevented most of these metabolic effects associated to pulmonary fibrosis suggesting a favorable anti-fibrotic profile.

View Article: PubMed Central - PubMed

Affiliation: Clinical Research Unit, University General Hospital Consortium, Valencia, Spain; CIBERES, Health Institute Carlos III, Valencia, Spain; Research Foundation of General Hospital of Valencia, Av. tres cruces s/n., E-46014, Valencia, Spain.

ABSTRACT
Fibrotic remodeling is a process common to chronic lung diseases such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, acute respiratory distress syndrome and asthma. Based on preclinical studies phosphodiesterase 4 (PDE4) inhibitors may exhibit beneficial anti-inflammatory and anti-remodeling properties for the treatment of these respiratory disorders. Effects of PDE4 inhibitors on changes in the lung metabolome in models of pulmonary fibrotic remodeling have not yet been explored. This work studies the effects of the PDE4 inhibitor roflumilast on changes in the lung metabolome in the common murine model of bleomycin-induced lung fibrosis by nuclear magnetic resonance (NMR) metabolic profiling of intact lung tissue. Metabolic profiling reveals strong differences between fibrotic and non-fibrotic tissue. These differences include increases in proline, glycine, lactate, taurine, phosphocholine and total glutathione and decreases in global fatty acids. In parallel, there was a loss in plasma BH4. This profile suggests that bleomycin produces alterations in the oxidative equilibrium, a strong inflammatory response and activation of the collagen synthesis among others. Roflumilast prevented most of these metabolic effects associated to pulmonary fibrosis suggesting a favorable anti-fibrotic profile.

No MeSH data available.


Related in: MedlinePlus

Effects of roflumilast on bleomycin-induced metabolites related to branched chain amino acids leucine and isoleucine, glucose and lactate in mouse lungs.Mice received a single dose of bleomycin (3.75 U/kg) intratracheally at day 1 and roflumilast (1 or 5 mg·kg-1·d-1 p.o., once daily) or vehicle was administered from day 1 to 14 (preventive protocol) until analysis at day 14. Leucine (A), isoleucine (B), glucose (C), and lactate (D) were assessed as described in Methods in murine lung control tissue (n = 17), lung tissue from animals treated with bleomycin + vehicle (n = 14), lung tissue from animals treated with bleomycin + roflumilast 1 mg/kg/day (n = 8) and lung tissue from animals treated with bleomycin + roflumilast 5 mg/kg/day (n = 4). Results are given as mean ± SD *P<0.05 versus control, **P<0.02 versus control, #P<0.05 versus bleomycin + vehicle.
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pone.0133453.g005: Effects of roflumilast on bleomycin-induced metabolites related to branched chain amino acids leucine and isoleucine, glucose and lactate in mouse lungs.Mice received a single dose of bleomycin (3.75 U/kg) intratracheally at day 1 and roflumilast (1 or 5 mg·kg-1·d-1 p.o., once daily) or vehicle was administered from day 1 to 14 (preventive protocol) until analysis at day 14. Leucine (A), isoleucine (B), glucose (C), and lactate (D) were assessed as described in Methods in murine lung control tissue (n = 17), lung tissue from animals treated with bleomycin + vehicle (n = 14), lung tissue from animals treated with bleomycin + roflumilast 1 mg/kg/day (n = 8) and lung tissue from animals treated with bleomycin + roflumilast 5 mg/kg/day (n = 4). Results are given as mean ± SD *P<0.05 versus control, **P<0.02 versus control, #P<0.05 versus bleomycin + vehicle.

Mentions: Other amino acids, such as glutamate, alanine, arginine experience a moderate but statistically significant increase following bleomycin (S1 Table). Along the same line, branched chain amino acids leucine, isoleucine and valine show a strong increase under bleomycin suggesting inhibited protein synthesis or increased protein degradation (Fig 5A and 5B, S1 Table). These changes in branched chain amino acids levels were not prevented by roflumilast at either doses suggesting that the PDE4 inhibitor does not affect bleomycin-induced changes in protein synthesis.


Roflumilast Prevents the Metabolic Effects of Bleomycin-Induced Fibrosis in a Murine Model.

Milara J, Morcillo E, Monleon D, Tenor H, Cortijo J - PLoS ONE (2015)

Effects of roflumilast on bleomycin-induced metabolites related to branched chain amino acids leucine and isoleucine, glucose and lactate in mouse lungs.Mice received a single dose of bleomycin (3.75 U/kg) intratracheally at day 1 and roflumilast (1 or 5 mg·kg-1·d-1 p.o., once daily) or vehicle was administered from day 1 to 14 (preventive protocol) until analysis at day 14. Leucine (A), isoleucine (B), glucose (C), and lactate (D) were assessed as described in Methods in murine lung control tissue (n = 17), lung tissue from animals treated with bleomycin + vehicle (n = 14), lung tissue from animals treated with bleomycin + roflumilast 1 mg/kg/day (n = 8) and lung tissue from animals treated with bleomycin + roflumilast 5 mg/kg/day (n = 4). Results are given as mean ± SD *P<0.05 versus control, **P<0.02 versus control, #P<0.05 versus bleomycin + vehicle.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4507994&req=5

pone.0133453.g005: Effects of roflumilast on bleomycin-induced metabolites related to branched chain amino acids leucine and isoleucine, glucose and lactate in mouse lungs.Mice received a single dose of bleomycin (3.75 U/kg) intratracheally at day 1 and roflumilast (1 or 5 mg·kg-1·d-1 p.o., once daily) or vehicle was administered from day 1 to 14 (preventive protocol) until analysis at day 14. Leucine (A), isoleucine (B), glucose (C), and lactate (D) were assessed as described in Methods in murine lung control tissue (n = 17), lung tissue from animals treated with bleomycin + vehicle (n = 14), lung tissue from animals treated with bleomycin + roflumilast 1 mg/kg/day (n = 8) and lung tissue from animals treated with bleomycin + roflumilast 5 mg/kg/day (n = 4). Results are given as mean ± SD *P<0.05 versus control, **P<0.02 versus control, #P<0.05 versus bleomycin + vehicle.
Mentions: Other amino acids, such as glutamate, alanine, arginine experience a moderate but statistically significant increase following bleomycin (S1 Table). Along the same line, branched chain amino acids leucine, isoleucine and valine show a strong increase under bleomycin suggesting inhibited protein synthesis or increased protein degradation (Fig 5A and 5B, S1 Table). These changes in branched chain amino acids levels were not prevented by roflumilast at either doses suggesting that the PDE4 inhibitor does not affect bleomycin-induced changes in protein synthesis.

Bottom Line: These differences include increases in proline, glycine, lactate, taurine, phosphocholine and total glutathione and decreases in global fatty acids.This profile suggests that bleomycin produces alterations in the oxidative equilibrium, a strong inflammatory response and activation of the collagen synthesis among others.Roflumilast prevented most of these metabolic effects associated to pulmonary fibrosis suggesting a favorable anti-fibrotic profile.

View Article: PubMed Central - PubMed

Affiliation: Clinical Research Unit, University General Hospital Consortium, Valencia, Spain; CIBERES, Health Institute Carlos III, Valencia, Spain; Research Foundation of General Hospital of Valencia, Av. tres cruces s/n., E-46014, Valencia, Spain.

ABSTRACT
Fibrotic remodeling is a process common to chronic lung diseases such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, acute respiratory distress syndrome and asthma. Based on preclinical studies phosphodiesterase 4 (PDE4) inhibitors may exhibit beneficial anti-inflammatory and anti-remodeling properties for the treatment of these respiratory disorders. Effects of PDE4 inhibitors on changes in the lung metabolome in models of pulmonary fibrotic remodeling have not yet been explored. This work studies the effects of the PDE4 inhibitor roflumilast on changes in the lung metabolome in the common murine model of bleomycin-induced lung fibrosis by nuclear magnetic resonance (NMR) metabolic profiling of intact lung tissue. Metabolic profiling reveals strong differences between fibrotic and non-fibrotic tissue. These differences include increases in proline, glycine, lactate, taurine, phosphocholine and total glutathione and decreases in global fatty acids. In parallel, there was a loss in plasma BH4. This profile suggests that bleomycin produces alterations in the oxidative equilibrium, a strong inflammatory response and activation of the collagen synthesis among others. Roflumilast prevented most of these metabolic effects associated to pulmonary fibrosis suggesting a favorable anti-fibrotic profile.

No MeSH data available.


Related in: MedlinePlus