Abstract
The severity of sepsis is significantly affected by advanced age; however, age-dependent molecular mechanisms of this susceptibility are unknown. Nuclear liver X receptor-α (LXRα) is a regulator of lipid metabolism with associated anti-inflammatory properties. Here, we investigated the role of LXRα in age-dependent lung injury and outcome of sepsis. Male C57BL/6, LXRα-deficient (LXRα−/−) and wild type (WT) (LXRα+/+) mice of different ages were subjected to sepsis by cecal ligation and puncture (CLP). In pharmacological studies, treatment with the LXRα ligand T0901317 reduced lung neutrophil infiltration in C57BL/6 mice aged from 1 to 8 mo when compared with vehicle-treated animals subjected to CLP. The LXRα ligand improved survival in young mice (2–3 mo old) but did not affect survival or neutrophil infiltration in mature adult mice (11–13 mo old). Immunoblotting revealed an age-dependent decrease of lung LXRα levels. Young LXRα−/− mice (2–3 mo old) exhibited earlier mortality than age-matched WT mice after CLP. Lung damage and neutrophil infiltration, lung activation of the pro-inflammatory NF-κB and plasma IL-6 levels were higher in LXRα−/− mice 18 h after CLP compared with LXRα+/+ mice. This study suggests that the anti-inflammatory properties of LXRα in sepsis are age-dependent and severely compromised in mature adult animals.
Highlights
Sepsis is a systemic response to infection characterized by hemodynamic and metabolic derangements that may result in septic shock, multiple organ system failure and death
In order to achieve a similar magnitude of organ inflammatory response and mortality between different groups of age and to evaluate the potential therapeutic efficacy of liver X receptor-a (LXRa) activation, we used a severe model of cecal ligation and puncture (CLP) (22-G needle) without antibiotics to produce high mortality during the early phase
As a serious consequence of sepsis is the occurrence of multiple organ failure, which is preceded by accumulation of neutrophils in major vital organs, we evaluated the effect of the LXRa ligand T0901317 on sepsisinduced lung neutrophil infiltration by measurement of the activity of MPO, an enzyme specific to neutrophil lysosomes
Summary
Sepsis is a systemic response to infection characterized by hemodynamic and metabolic derangements that may result in septic shock, multiple organ system failure and death It occurs in people of all ages, the incidence and mortality of sepsis is disproportionately increased in elderly adults.[1] Currently, the treatment of sepsis is centered on general organ supportive measures, ventilator strategies and antibiotic therapy to control the infectious focus. These approaches are not always efficacious in reducing the high mortality.[2] age-dependent pathophysiological mechanisms of the systemic inflammatory process, innate immune dysfunction and organ damage are yet to be identified. LXRa is expressed in lung, macrophages, liver, spleen, kidney, adipose tissue and small intestine, whereas LXRb is ubiquitously expressed.[6,7] In addition
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
