The Study On The Lung Pathological Aging Of Smad7 Conditional Knockout Mice

With the aging of the population is faster and faster,China has officially entered the early stage of an aging society.In the past few years,the aging in the population has become the highest risk factor to chronic non-communicable diseases and has led directly to increases in the incidence and mortality of age-related diseases.Lung is one of the tissues or organs aging early.Some respiratory-related diseases such as chronic obstructive pulmonary disease(COPD),lung cancer,asthma and idiopathic pulmonary fibrosis(IPF)are closely related to aging of lung tissue.In this study,we used lung tissue-specific Smad7 conditional knockout mice as a model to analyze the impact of deleting Smad7 in lungs on lung aging and cell senescence of alveolar epithelial type Ⅱ cells(AECⅡ)that features adult stem cells.We found that the number of senescence-associated β-galactosidase(SA-β-gal)positive cells were significantly increased,and cell cycle arrest associated p21,p16 were significantly elevated in the lungs of Smad7 conditional knockout mice compared with that of wild-type(WT)mice.The lung fibrosis markers α-SMA and type 1 collagen were also significantly elevated in the lungs of Smad7 conditional knockout mice compared with that of wild-type(WT)mice.Further analysis showed that the stained rates labeled by p21,p16 or senescence-associated heterochromatin foci(SAHF)marker HP1γ in AECⅡ cells were all significantly increased in the lungs of Smad7 conditional knockout mice compared with that of WT mice.These results suggest that significant lung aging and AECⅡ cell senescence occurs in the lung tissue of the Smad7 mice.In addition,we found that the expressions of cytokine IL1 a,IL4,and natural killer cell marker NK1.1 were significantly increased in the Smad7 mouse lungs compared with WT mouse lungs,suggesting that deleting Smad7 in lungs causes lung inflammation,and this may due to senescence-associated secretory phenotype(SASP).Moreover,because Smad7 acts as an inhibitor of TGF-β/Smads signaling pathway and negatively regulates the activity of this pathway,we expected and have found that the expressions of TGF-β1,R-Smads and Co-Smads,phosphorylated Smad3 were elevated in the lung tissues of Smad7 conditionalknockout mice compared with that of WT mice.This suggests the phenotype of lung pathological aging we observed in the Smad7 mice is caused by markedly activating TGF-β/Smads signaling pathway.