Enhancing natriuretic peptide bioactivity prevents bleomycin-induced pulmonary fibrosis
© Baliga et al; licensee BioMed Central Ltd. 2011
Published: 1 August 2011
Idiopathic pulmonary fibrosis (IPF) is a progressive fibro-proliferative disorder of unknown etiology, with no effective treatment regimen, and a median survival of just 3–5 years following diagnosis . Pulmonary Hypertension (PH) often complicates IPF and is associated with higher mortality. Augmentation of endogenous natriuretic peptide (NP) stimulated cGMP, using a neutral endopeptidase inhibitor (NEPi) in combination with a phosphodiesterase 5 inhibitor (PDE5i), synergistically prevents pathogenesis in a hypoxic model of PH . Herein, we assessed the efficacy of this novel NEPi/PDE5i combination therapy in a model of pulmonary fibrosis.
Littermate wild-type (WT) and NP receptor-A knockout (NPR-A KO) mice (male; 20-25g; C57BLK6 background) were instilled with saline (control) or Bleomycin (Bleo; 1mg/kg) in the absence or presence of the PDE5i sildenafil (30mg/kg/day; p.o.) or the NEPi ecadotril (60mg/kg/day; p.o.). Haemodynamic and morphological parameters were measured 14 days post Bleo administration.
Bleo instillation enhanced total lung collagen accumulation (index of fibrosis) which was ameliorated by concomitant administration of sildenafil, ecadotril or the combination (Control: 1.692±0.2, Bleo: 4.4±0.35, Bleo+combination: 2.124±0.12*; *P<0.05 versus Bleo).
NPR-A KO mice, lacking the bioactivity of ANP and BNP, exhibited an exaggerated haemodynamic response to Bleo (WT Bleo RSVP: 31.77±1.96mmHg, KO Bleo RSVP: 41.68±2.78mmHg; P<0.05), and the beneficial effects of the combination therapy were lost (KO Bleo+combination RSVP: 39.84±2.41mmHg; P>0.05 versus KO Bleo). A similar loss in efficacy of the combination treatment was observed against RVH (KO Bleo RV/LV+S: 0.252±0.008, KO Bleo+combination RV/LV+S: 0.234±0.017; P>0.05). Figure 1.
The NEPi/PDE5i combination is effective in ameliorating both the haemodynamic aberrations and fibrotic lung disease in this model. This beneficial pharmacodynamic activity depends on the bioactivity of NPs, which represent an endogenous protective mechanism limiting disease progression. This work substantiates the therapeutic potential of manipulating NP and cyclic GMP signalling for PH and IPF.
- Eickelberg O, Selman M: Update in diffuse parenchymal lung disease 2009. Am J Respir Crit Care Med. 2010, 181: 883-888. 10.1164/rccm.201001-0124UP.View ArticlePubMedGoogle Scholar
- Baliga RS, Zhao L, Madhani M, Lopez-Torondel B, Visintin C, Selwood D: Synergy between natriuretic peptides and phosphodiesterase 5 inhibitors ameliorates pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008, 178: 861-869. 10.1164/rccm.200801-121OC.PubMed CentralView ArticlePubMedGoogle Scholar
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