Abstract
The primary flavonoid, pinocembrin, is thought to have a variety of medical uses which relate to its reported anti-oxidant, anti-inflammatory, anti-microbial and anti-cancer properties. Some studies have reported that this flavonoid has anti-fibrotic activities. In this study, we investigated whether pinocembrin would impede fibrosis, dampen inflammation and improve lung function in a large animal model of pulmonary fibrosis. Fibrosis was induced in two localized lung segments in each of the 10 sheep participating in the study. This was achieved via two infusions of bleomycin delivered bronchoscopically at a two-week interval. Another lung segment in the same sheep was left untreated, and was used as a healthy control. The animals were kept for a little over 5 weeks after the final infusion of bleomycin. Pinocembrin, isolated from Eucalyptus leaves, was administered to one of the two bleomycin damaged lung segments at a dose of 7 mg. This dose was given once-weekly over 4-weeks, starting one week after the final bleomycin infusion. Lung compliance (as a measure of stiffness) was significantly improved after four weekly administrations of pinocembrin to bleomycin-damaged lung segments. There were significantly lower numbers of neutrophils and inflammatory cells in the bronchoalveolar lavage of bleomycin-infused lung segments that were treated with pinocembrin. Compared to bleomycin damaged lung segments without drug treatment, pinocembrin administration was associated with significantly lower numbers of immuno-positive CD8+ and CD4+ T cells in the lung parenchyma. Histopathology scoring data showed that pinocembrin treatment was associated with significant improvement in inflammation and overall pathology scores. Hydroxy proline analysis showed that the administration of pinocembrin did not reduce the increased collagen content that was induced by bleomycin in this model. Analyses of Masson’s Trichrome stained sections showed that pinocembrin treatment significantly reduced the connective tissue content in lung segments exposed to bleomycin when compared to bleomycin-infused lungs that did not receive pinocembrin. The striking anti-inflammatory and modest anti-fibrotic remodelling effects of pinocembrin administration were likely linked to the compound’s ability to improve lung pathology and functional compliance in this animal model of pulmonary fibrosis.
Highlights
The primary flavonoid, pinocembrin, has been identified and isolated from a number of plant species
Pinocembrin administration improves the lung function decline associated with the development of bleomycin-induced pulmonary fibrosis
The lung-segments, which received the damaging agent bleomycin with pinocembrin administration, had higher mean segmental compliance, which was not significantly different from the untreated healthy control lung segments (Fig 3A). Another lung function assessment used was the percentage change in compliance from baseline (Fig 3C). This measured the change in compliance from the start of the study to after the completion of the final pinocembrin treatment
Summary
The primary flavonoid, pinocembrin, has been identified and isolated from a number of plant species. This bioactive molecule is thought to have a variety of medical uses which relate to its reported anti-oxidant, anti-inflammatory, anti-microbial, and anti-cancer properties [1,2,3,4,5,6,7]. A recent study demonstrated Pinocembrin alleviates bleomycin-induced skin fibrosis in mice and suppressed proliferation, migration, and invasion of keloid fibroblasts and mouse primary dermal fibroblasts in vitro [11]. Pinocembrin induced these anti-fibrotic effects via the downregulation of the NF-κβ and TGF-β1/Smad signaling pathways [10, 11]
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