Increased expression of senescence markers in cystic fibrosis airways

Abstract

Cystic Fibrosis (CF) is a chronic lung disease characterized by chronic neutrophilic airway inflammation and increased levels of neutrophil elastase (NE) in the airways. We have previously reported that NE treatment triggers cell cycle arrest. Cell cycle arrest can lead to senescence, a complete loss of replicative capacity. Importantly, senescent cells can be proinflammatory and would perpetuate CF chronic inflammation. By immunohistochemistry, we evaluated whether airway sections from CF and control subjects expressed markers of senescence, including p16INK4a(p16), a cyclin-dependent kinase inhibitor, phospho-Histone H2A.X (γH2A.X), and phospho-checkpoint 2 kinase (phospho-Chk2), which are also DNA damage response markers. Compared with airway epithelium from control subjects, CF airway epithelium had increased levels of expression of all three senescence markers. We hypothesized that the high load of NE in the CF airway triggers epithelial senescence by upregulating expression of p16, which inhibits cyclin-dependent kinase 4 (CDK4). Normal human bronchial epithelial (NHBE) cells, cultured in air-liquid interface were treated with NE (0, 200, and 500 nM) to induce visible injury. Total cell lysates were collected and evaluated by Western analysis for p16 protein expression and CDK4 kinase activity. NE significantly increased p16 expression and decreased CDK4 kinase activity in NHBE cells. These results support the concept that NE triggers expression of senescence markers in CF airway epithelial cells.

Platelets in myeloproliferative neoplasms have a distinct transcript signature in the presence of marrow fibrosis

“…H2AX (H2A Histone Family Member X, previously termed H2AFX ) encodes a protein that is important for arresting cell cycle progression for repair of DNA double strand breaks (Martinez et al , ). Phosphorylated H2AX is commonly used as a marker of double strand DNA damage, and has been reported in association with JAK2 V617F mutation as well as with fibrosis in the liver and lungs (Shao et al , ; Li et al , ; Fischer et al , ; Marty et al , ; Chen et al , ). CCND1 encodes cyclin D1, which regulates endomitosis and polyploidisation (Huang et al , ; Muntean et al , ).…”

Biomarkers to identify and isolate senescent cells

“…These accumulating senescent cells can (iii) damage surrounding cells (Biran and Krizhanovsky, 2015) and cause (iv) cancer (Leikam et al, 2015) and (v) other agerelated diseases, such as atherosclerosis (Erusalimsky and Kurz, 2005;Fischer et al, 2013;Nishimatsu et al, 2015). Although senescent cells play an important role in (vi) tumor suppression (Tominaga, 2015), (vii) wound healing (Demaria et al, 2014) and development, (viii) periodically removing them does not produce significant side-effects .…”

Absolute Leukocyte Telomere Length in HIV-Infected and Uninfected Individuals: Evidence of Accelerated Cell Senescence in HIV-Associated Chronic Obstructive Pulmonary Disease

“…Unlike relative telomere length measurements in which quantification is dependent on the type of single copy gene standard chosen by each laboratory, absolute measurements allow for comparison across studies, providing a standardized method while still maintaining high volume capacity. aTL measurements are now becoming the preferred method for studying telomere length [ 18 , 19 ] and in future may be a more useful biomarker of aging given its standardization. The ability of aTL to predict which HIV-infected patients are at greatest risk for developing age-associated conditions such as COPD has yet to be determined, but our study suggests promise for future exploration.…”