Cellular senescence increase expression of bacterial ligands in the lungs and is positively correlated with increased susceptibility to pneumococcal pneumonia

Department of Microbiology and Immunology Department of Medicine, Division of Cardiology Department of Pathology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
Aging cell (Impact Factor: 6.34). 05/2011; 10(5):798-806. DOI: 10.1111/j.1474-9726.2011.00720.x
Source: PubMed


Cellular senescence is an age-associated phenomenon that promotes tumor invasiveness owing to the secretion of proinflammatory cytokines, proteases, and growth factors. Herein we demonstrate that cellular senescence also potentially increases susceptibility to bacterial pneumonia caused by Streptococcus pneumoniae (the pneumococcus), the leading cause of infectious death in the elderly. Aged mice had increased lung inflammation as determined by cytokine analysis and histopathology of lung sections. Immunoblotting for p16, pRb, and mH2A showed that elderly humans and aged mice had increased levels of these senescence markers in their lungs vs. young controls. Keratin 10 (K10), laminin receptor (LR), and platelet-activating factor receptor (PAFr), host proteins known to be co-opted for bacterial adhesion, were also increased. Aged mice were found to be highly susceptible to pneumococcal challenge in a PsrP, the pneumococcal adhesin that binds K10, dependent manner. In vitro senescent A549 lung epithelial cells had elevated K10 and LR protein levels and were up to 5-fold more permissive for bacterial adhesion. Additionally, exposure of normal cells to conditioned media from senescent cells doubled PAFr levels and pneumococcal adherence. Genotoxic stress induced by bleomycin and oxidative stress enhanced susceptibility of young mice to pneumonia and was positively correlated with enhanced p16, inflammation, and LR levels. These findings suggest that cellular senescence facilitates bacterial adhesion to cells in the lungs and provides an additional molecular mechanism for the increased incidence of community-acquired pneumonia in the elderly. This study is the first to suggest a second negative consequence for the senescence-associated secretory phenotype.

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    • "However, PAFr showed a gradual increase in the protein levels from mature (54–65 years) to aged group human tissue biopsies (65–84 years) versus the young biopsy samples. Aged mice (19–22 months) also displayed significant increase in the levels of PBPs versus their younger counterparts (4-5 months) [19]. "
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    ABSTRACT: Streptococcus pneumonia, (Spn, the pneumococcus), is the leading cause of community-acquired pneumonia (CAP) and is responsible for 15-40% deaths in the elderly worldwide. A primed inflammatory status is a significant risk factor for the increased severity of infectious diseases among the elderly (≥65 years of age). Studies have shown that expression of host receptors that the pneumococci bind to invade the tissues are increased thereby increasing the susceptibility to pneumococcal challenge in aged mice. Cellular senescence, an age-related phenomenon that leads to cell cycle arrest may also contribute to increased inflammation in aged mice. Evidence of cellular senescence in aged lungs of humans and mice adds credits to the concept of inflammaging and enhanced bacterial ligands expression during aging. Furthermore, cell senescence has been shown to occur in age-associated lung pathologies such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) that may predispose the elderly to pathogenic assaults, including S. pneumoniae. This review highlights the aspects of: chronic inflammation in the aged population; contribution of cellular senescence to age-associated inflammation and their impact on host receptor expression; and, increased susceptibility of fibrosis and emphysematous lesions-bearing lungs to microbial infections.
    05/2012; 2012:267101. DOI:10.5402/2012/267101
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    • "Thus, the cellular senescence is an important cellular status that allows the damaged cells to adapt to stress or undergo programmed cell death in the pathogenesis of COPD/emphysema. The cellular senescence also facilitates bacterial adhesion to the lung cells under the persistent SIPS leading to exacerbations of the disease (Shivshankar et al., 2011; Zhou et al., 2011). "
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    ABSTRACT: Chronic inflammation and cellular senescence are intertwined in the pathogenesis of premature aging, which is considered as an important contributing factor in driving chronic obstructive pulmonary disease (COPD). Sirtuin1 (SIRT1), a nicotinamide adenine dinucleotide (NAD(+))-dependent protein/histone deacetylase, regulates inflammation, senescence/aging, stress resistance, and deoxyribonucleic acid (DNA) damage repair via deacetylating intracellular signaling molecules and chromatin histones. The present review describes the mechanism and regulation of SIRT1 by environmental agents/oxidants/reactive aldehydes and pro-inflammatory stimuli in lung inflammation and aging. The role of dietary polyphenols in regulation of SIRT1 in inflammaging is also discussed. Analysis of current research findings on the mechanism of inflammation and senescence/aging (i.e., inflammaging) and their regulation by SIRT1 in premature aging of the lung. COPD is a disease of the lung inflammaging, which is associated with the DNA damage response, transcription activation and chromatin modifications. SIRT1 regulates inflammaging via regulating forkhead box class O 3, p53, nuclear factor kappa B, histones and various proteins involved in DNA damage and repair. Polyphenols and its analogs have been shown to activate SIRT1 although they have anti-inflammatory and antioxidant properties. Targeting lung inflammation and cellular senescence as well as premature lung aging using pharmacological SIRT1 activators or polyphenols would be a promising therapeutic intervention for COPD/emphysema.
    Preventive Medicine 12/2011; 54 Suppl:S20-8. DOI:10.1016/j.ypmed.2011.11.014 · 3.09 Impact Factor
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    • "Importantly, exposure of A549 cells to conditioned media from senescent lung cells was able to increase the expression of PAFr and increase their permissiveness to pneumococcal adhesion [47]. Thus, we propose a model by which the accumulation of senescent lung cells due to aging or exposure to genotoxic agents such as cigarette smoke could enhance LR, PAFr and K10 in the lungs thereby promoting bacterial attachment and susceptibility to pneumococcal pneumonia (Figure 1). "
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    ABSTRACT: Advances in modern medicine have led to an increase in the median life span and an expansion of the world's population over the age of 65. With increasing numbers of the population surviving to the extreme of age, those at risk for the development of pneumonia will approach 2 billion by the year 2050. Numerous age-related changes in the lung likely contribute to the enhanced occurrence of pneumonia in the elderly. Inflammation in the elderly has been shown to increase risk prior to infection; age-associated inflammation enhances bacterial ligand expression in the lungs which increases the ability of bacteria to attach and invade host cells. Conversely, the elaboration of the acute inflammatory response during early infection has been found to decrease with age resulting in a delayed immune response and diminished bacterial killing. Finally, the resolution of the inflammatory response during the convalescent stage back to "baseline" is often prolonged in the elderly and associated with negative outcomes, such as adverse cardiac events. The focus of this review will be to discuss our current understanding of the potential mechanisms by which dysregulated inflammation (both prior to and following an infectious insult) enhances susceptibility to and severity of community acquired pneumonia (CAP) in the elderly with an emphasis on pneumococcal pneumonia, the leading cause of CAP.
    Aging and Disease 12/2011; 2(6):487-500. · 3.07 Impact Factor
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