Cell senescence predisposes lungs to pneumonia
MedWire News: The accumulation of senescent cells associated with aging predisposes the lung to infection with pneumonia-causing bacteria, research suggests.
Cellular senescence is a protective mechanism against tumor growth, whereby damaged cells lose the ability to replicate and are instead programmed for death through apoptosis. Interestingly, cells that become senescent also produce an increased number of pro-inflammatory cytokines.
It has previously been demonstrated that, as animals age, an increasing number of senescent cells accumulate in various sites including the skin, liver, atherosclerotic lesions, and muscle. The development of a novel senescence marker also led to the recent discovery that senescent cells accumulate in the lungs of otherwise healthy aged animals.
As inflammation is a risk factor for community-acquired pneumonia, the finding that senescent, and therefore pro-inflammatory, cells are present in aged lung tissues led Carlos Orihuela (University of Texas Health Science Center, San Antonio, USA) and colleagues to hypothesize that senescent cells might prime a tissue for infection with pneumococcal bacteria.
To test this idea, Orihuela and team measured levels of senescence markers and pneumococcal ligands expression in cells in lung samples from human volunteers of various ages, and in young and old mice.
As expected, senescent cells were significantly more common in older compared with younger human and mouse lung tissues. In addition, lung tissues from aged mice had higher levels of pro-inflammatory cytokines and, consequently, interstitial and peribronchial tissues were more inflamed than in young mice.
Further analysis revealed that levels of various factors that enhance pneumococcal bacterial adhesion, such as keratin 10, laminin receptor, and platelet activating factor receptor, were increased in aged animal lung tissues. This resulted in a five-fold increase in susceptibility to pneumococcal infection in aged compared with young mice.
To confirm the link between cellular damage, the resulting senescence, and enhanced bacterial adhesion, the investigators caused genotoxic stress by administering bleomycin or hydrogen peroxide to the trachea of mice for 3 weeks. This resulted in "dramatic" changes in lung histology compared with control mice, the authors report.
They also found increased levels of inflammatory cytokines, and, 2 days after the first administration, up to 100-fold increases in bacteria levels in the lung and bloodstream.
In the journal Aging Cell, the authors conclude that their findings "clearly suggest that cellular senescence impacts inflammation and infectious disease in the lungs and provide an additional molecular explanation for the increased incidence of community-acquired pneumonia in the elderly and those with chronic obstructive pulmonary disease."
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By Philip Ford