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Can Emphysema Be Reversed? Preclinical Evidence Via Local STAT3/VEGF Stimulation

Dhapare S, Li H, Sakagami M.

RDD Europe 2019. Volume 1, 2019: 7-16.

Abstract:

To date, emphysema is irreversible and incurable, as no drug has been proven to reverse its progressive alveolar structural destruction. Since impaired vascular endothelial growth factor (VEGF) signaling becomes a potential underlying pathobiologic mechanism, we hypothesized that salvianolic acid B (Sal-B) activated an upstream VEGF regulator, signal transducer and activator of transcription 3 (STAT3), and enabled alveolar structural recovery via VEGF stimulation in emphysema. In vitro lung endothelial and epithelial cell-based experiments showed that Sal-B was effective at 25 µM in protecting against emphysema-like induced cell death, and promoting cell proliferation and migration, in a STAT3/VEGF-dependent fashion. In rats, local lung treatments of Sal-B at 0.2 mg/kg caused significantly increased STAT3 phosphorylation and VEGF stimulation/elevation in the lungs. Accordingly, Sal-B at 0.2 mg/kg to the lung was shown to reverse established emphysema induced with porcine pancreatic elastase (PPE) in rats, as follows. Relative to the saline-treated rats, the Sal-B-treated rats displayed 1) 80% improved exercise endurance from impairment; 2) 56 and 63% reduced airspace enlargement and alveolar destruction, respectively; 3) 59-94% restoration from induction in the lung tissue matrix metalloproteinase (MMP) activities and apoptotic cleaved caspase-3 expression; 4) 1.6-fold stimulation of the proliferative cell nuclear antigen (PCNA; a lung cell proliferation marker); and 5) the near healthy levels of the lung’s STAT3 phosphorylation and VEGF expression. Sal-B also exerted analogous reversal activities in the cigarette smoke extract (CSE)-induced rat model of established emphysema. Hence, Sal-B, a polyphenol present in the Chinese herbal medicine, danshen or Salvia miltiorrhiza, may be a lead molecule in a potentially paradigm-shifting class of novel drug candidates by virtue of its capability to reverse alveolar structural destruction via local STAT3/VEGF stimulation and therefore potentially cure emphysema.