Abstract
Chronic obstructive pulmonary disease (COPD) has been recently characterized as a disease of accelerated lung aging, but the mechanism remains unclear. Tetraspanins have emerged as key players in malignancy and inflammatory diseases. Here, we found that CD9/CD81 double knockout (DKO) mice with a COPD-like phenotype progressively developed a syndrome resembling human aging, including cataracts, hair loss, and atrophy of various organs, including thymus, muscle, and testis, resulting in shorter survival than wild-type (WT) mice. Consistent with this, DNA microarray analysis of DKO mouse lungs revealed differential expression of genes involved in cell death, inflammation, and the sirtuin-1 (SIRT1) pathway. Accordingly, expression of SIRT1 was reduced in DKO mouse lungs. Importantly, siRNA knockdown of CD9 and CD81 in lung epithelial cells additively decreased SIRT1 and Foxo3a expression, but reciprocally upregulated the expression of p21 and p53, leading to reduced cell proliferation and elevated apoptosis. Furthermore, deletion of these tetraspanins increased the expression of pro-inflammatory genes and IL-8. Hence, CD9 and CD81 might coordinately prevent senescence and inflammation, partly by maintaining SIRT1 expression. Altogether, CD9/CD81 DKO mice represent a novel model for both COPD and accelerated senescence.
Highlights
Chronic obstructive pulmonary disorder (COPD) is a progressive disease state characterized by poorly reversible airflow limitation and an abnormal inflammatory response of the lungs to noxious particles, cigarette smoke (CS)[1]
These findings indicate that aged CD9/CD81 double KO (DKO) mice exhibited a variety of accelerated aging phenotypes
Given that SIRT1 in epithelial cells is regarded as a key molecule in COPD23, and that genes associated with the SIRT1 pathway were differentially regulated in DKO lungs (Fig. 4c), we focused our analysis on the SIRT1 pathway
Summary
Chronic obstructive pulmonary disorder (COPD) is a progressive disease state characterized by poorly reversible airflow limitation and an abnormal inflammatory response of the lungs to noxious particles, cigarette smoke (CS)[1]. By immunostaining for p21, a senescence associated molecule, the number of p21-positive cells increased in lung sections in DKO mice (Supplemental Fig. 2).
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