F-11 Spermidine attenuated bleomycin induced lung injury/fibrosis by inhibition of endoplasmic reticulum stress (ERS) induced apoptosis and cellular Senescence

BACKGROUND AND AIMS: Spermidine is an endogenous biological polyamine that exhibits broad longevity-extending roles including anti-oxidative, anti-aging, and cell growth-promoting activities. We previously reported that spermidine level is significantly reduced in the IPF lung. The aim of the present study was to assess the potential beneficial effects of spermidine on lung injury/ fibrosis and determine its possible mechanism. METHODS AND RESULTS: Lung injury/fibrosis was established by bleomycin- inhaled mice, and exogenous spermidine was administered by intraperitoneal injection (50mg/kg in PBS, D0-10 for preventive, D10-21 for therapeutic effect). Spermidine treated mice had significantly less lung inflammation, collagen deposition as well as decreased levels of lung IL-1b,TNF-a and TGF-b1. Bronchial epithelial cells were exposed to H2O2 showed significantly increased apoptosis and ERS related mediators. The addition of spermidine attenuated H2O2 induced apoptosis and ERS related pathway; IRE1a, ATF6. Senescence-associated beta-gal staining showed that spermidine interferes with bleomycin induced premature cellular senescence. The expression of p16 and pRB was lower in spermidine-treated cells. CONCLUSIONS: Spermidine have protective and therapeutic effects against bleomycin induced lung injury/fibrosis in mice. This beneficial effect were related to anti-apoptotic , down regulation of excessive ERS pathway and anti-senescence effect.