Protective and therapeutic effect of felodipine against bleomycin-induced pulmonary fibrosis in mice

Abstract

Idiopathic pulmonary fibrosis (IPF) involves alveolar epithelial injury and abnormal collagen production caused by activated fibroblasts; transforming growth factor (TGF)-β1 is implicated in this activation. In this study, we screened for chemicals capable of inhibiting TGF-β1-induced collagen production in cultured fibroblasts from medicines already in clinical use. We selected felodipine based on its extent of collagen production inhibition, clinical safety profile, and other pharmacological activity. Felodipine is a dihydropyridine Ca2+ channel blocker that has been used clinically to treat patients with high blood pressure. Felodipine suppressed collagen production within LL29 cells in the presence of TGF-β1, but not in its absence. Intratracheal administration of felodipine prevented bleomycin-induced pulmonary fibrosis, alteration of lung mechanics and respiratory dysfunction. Felodipine also improved pulmonary fibrosis, as well as lung and respiratory function when administered after fibrosis development. Furthermore, administration of felodipine suppressed a bleomycin-induced increase in activated fibroblasts in the lung. We also found other dihydropyridine Ca2+ channel blockers (nifedipine and benidipine) inhibited collagen production in vitro and partially prevented bleomycin-induced pulmonary fibrosis, alteration of lung mechanics and respiratory dysfunction in vivo. We propose that these Ca2+ channel blockers may be therapeutically beneficial for IPF patients.

rhCygb reverses bleomycin-induced established pulmonary fibrosis in rats

“…[38] Until now, with increasing technical possibilities, micro-CT provides highresolution anatomical images of small animals, and it allows repeated measurements, which avoid animal euthanasia. [37,39] Interestingly, in our study, we con rmed that a brosis phase in the BLM-induced brosis model has been well established at 7 days by spiral CT, showing alveolar septal thickening, interstitial brosis and honeycombing. This may be due to the animal breed, gender, dose, and administration affecting the results.…”

“…[35,36] However, those papers were based on the hypothesis that lung brosis was induced 3 or 4 weeks after bleomycin instillation without diagnosing the establishment of lung brosis model. Surprisingly, Choi reported that more than half of bleomycin-instilled mice did not show lung brosis at 3 weeks or even 6 weeks by micro-CT. [37] So it is very essential to develop assessment methods or tools for establishment of IPF animal models. CT is used to evaluate the IPF as a non-invasive technique in humans, with the feature of honeycombing or traction bronchiectasis and a reticular abnormality consistent with brosis present in a basal and peripheral predominance.…”

Exploring Animal Models That Resemble Idiopathic Pulmonary Fibrosis

“…Potential therapies are usually administered within 1–7 days following BLM exposure, leading to the conclusion that the therapeutic measures may provide benefit primarily through prevention of the inflammatory cascade rather than reversal of fibrosis, thus limiting their applicability to human IPF ( 40 ). More recent studies have begun to explore administration of drugs after 7 days ( 41 , 42 ). To our knowledge, only two studies to date have evaluated repetitive BLM injury ( 43 , 44 ).…”

Ethyl Pyruvate Improves Pulmonary Function in Mice with Bleomycin-induced Lung Injury as Monitored with Hyperpolarized ¹²⁹Xe MR Imaging

“… 17 , 18 In recent studies, the transforming growth factor-β1 (TGF-β1) involved in the Smad signaling pathway has been widely investigated as a potential therapeutic target. 19 – 20 However, to the best of our knowledge, there exist only one study reporting on the involvement of HMGB1 and the effect of EP in lung fibrosis progression, in which wound healing was not investigated. 11 …”