Abstract
The tumor suppressor p53 limits tumorigenesis by inducing apoptosis, cell cycle arrest, and senescence. Although p53 is known to limit inflammation during tumor development, its role in regulating chronic lung inflammation is less well understood. To elucidate the function of airway epithelial p53 in such inflammation, we subjected genetically modified mice, whose bronchial epithelial club cells lack p53, to repetitive inhalations of lipopolysaccharide (LPS), an exposure that leads to severe chronic bronchitis and airway senescence in wild-type mice. Surprisingly, the club cell p53 knockout mice exhibited reduced airway senescence and bronchitis in response to chronic LPS exposure and were significantly protected from global lung destruction. Furthermore, pharmacological elimination of senescent cells also protected wild-type mice from chronic LPS-induced bronchitis. Our results implicate p53 ininduction of club-cell senescence and correlate epithelial cell senescence of chronic airway inflammation and lung destruction.
Highlights
Mice expressing Cre recombinase from the club cell secretory protein (CCSP) promoter (CCSP-Cre mice) were crossed with mice in which exons 2 to 10 of p53 genes are surrounded by LoxP sites (p53-loxP) (Jonkers et al, 2001)
To verify cell-type-specific expression of the Cre recombinase, we combined these mice with Lox-STOP-Lox (LSL) monomeric red fluorescent protein mice, whose mRFP is expressed in cells from which Cre recombinase excises the LSL cassette (Luche et al, 2007)
Analysis of lungs of CCSPCre;LSL-mRFP mice revealed, as expected, that mRFP expression was restricted to club cells of the bronchial epithelia (Figure 1B)
Summary
Sagiv et al find that senescence and p53 in bronchial epithelial cells promote chronic lung inflammation and COPD-like disease. Genetic or pharmacological reduction in senescent cell number blunts chronic inflammation and limits disease progression. 2018, Cell Reports 22, 3468–3479 March 27, 2018 a 2018 The Author(s).
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