Alamandine Attenuates Signs and Reduces Fibrotic Markers in a Rat Model of Established Pulmonary Fibrosis

Introduction: Pulmonary fibrosis (PF) is a challenging interstitial lung disease with limited therapeutic options. This study explores the therapeutic effects of alamandine (ALA), a renin-angiotensin system peptide, in reversing established fibrotic progression in an experimental model. Methods: Male Wistar rats were divided into four groups (n=6): control (CO), ALA-treated (ALA), bleomycin-induced fibrosis (BLM), and bleomycin plus ALA treatment (BA). Fibrosis was induced by intratracheal bleomycin (2.5 mg/kg) on day 0. Subcutaneous ALA treatment (50 µg/kg/day) started on day 10 and continued until day 19. Respiratory mechanics, body weight, Ashcroft score, and lung transforming growth factor-beta (TGF-β) content were evaluated. Plasma RAS peptides were quantified by LC-MS/MS. Results: Bleomycin significantly increased respiratory resistance (0.159±0.047 vs 0.104±0.026 cmH₂O/mL/s in CO, p<0.01) and Ashcroft score, and reduced body weight gain. ALA treatment from day 10–20 markedly improved body weight gain (p<0.001), reduced Ashcroft score (1.21±0.40 vs 2.23±0.35 in BLM, p<0.0001), and decreased lung TGF-β1 content (1.10±0.42 vs 3.70±1.7 pg/mg protein in BLM, p<0.005). In addition to significantly reducing thoracic chamber resistance (p < 0.02), ALA treatment reversed TGF-β elevation (p < 0.005) from 3.70 ± 1.7 in the BLM group to 1.10 ± 0.42 in the BA group and was associated with qualitatively improved respiratory effort, suggesting attenuation of bleomycin-induced fibrogenesis. Conclusion: Despite rapid tissue uptake, late ALA treatment attenuates histological fibrosis and TGF-β1 accumulation and improves clinical well-being in rats with established pulmonary fibrosis. These findings suggest potential therapeutic benefit that warrants further dose- and time-ranging studies.