Abstract
Spermidine is an endogenous biological polyamine that plays various longevity-extending roles and exerts antioxidative, antiaging, and cell growth-promoting effects. We previously reported that spermidine levels were significantly reduced in idiopathic pulmonary fibrosis (IPF) of the lung. The present study assessed the potential beneficial effects of spermidine on lung fibrosis and investigated the possible mechanism. Lung fibrosis was established in mice using bleomycin (BLM), and exogenous spermidine was administered daily by intraperitoneal injection (50 mg/kg in phosphate-buffered saline). BLM-induced alveolar epithelial cells showed significant increases in apoptosis and endoplasmic reticulum stress (ERS)-related mediators, and spermidine attenuated BLM-induced apoptosis and activation of the ERS-related pathway. Senescence-associated β-gal staining and decreased expression of p16 and p21 showed that spermidine ameliorated BLM-induced premature cellular senescence. In addition, spermidine enhanced beclin-1-dependent autophagy and autophagy modulators in IPF fibroblasts and BLM-induced mouse lungs, in which inflammation and collagen deposition were significantly decreased. This beneficial effect was related to the antiapoptotic downregulation of the ERS pathway, antisenescence effects, and autophagy activation. Our findings suggest that spermidine could be a therapeutic agent for IPF treatment.
Highlights
1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction Idiopathic pulmonary fibrosis (IPF) is a progressive, devastating lung disease characterized by alveolar epithelial cell (AEC) injury and the subsequent proliferation of activated fibroblasts known as myofibroblasts
Our findings indicate that spermidine protects against BLM-induced lung inflammation and fibrosis
As the incidence of IPF continuously increases with age, age-related mechanisms such as cellular senescence and telomere shortening have been proposed to be pathogenic drivers of lung fibrosis[36,37]
Summary
Idiopathic pulmonary fibrosis (IPF) is a progressive, devastating lung disease characterized by alveolar epithelial cell (AEC) injury and the subsequent proliferation of activated fibroblasts known as myofibroblasts. The exact mechanisms of the development of lung fibrosis remain unclear, repeated. The precise mechanism of AEC damage remains unclear, but increased ERS or the accumulation of unfolded proteins in AECs have recently been implicated in IPF pathogenesis[5,6]. Because the incidence of IPF increases with age, age-related mechanisms such as telomerase attrition and increased AEC senescence are important drivers of the abnormal repair process during the initiation of fibrosis[7,8]. Polyamines are involved in various biological processes, including replication, transcription, translation, posttranslational modification, and membrane stability[11], and they regulate cellular proliferation, differentiation, and Official journal of the Korean Society for Biochemistry and Molecular Biology
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